Alpha Lipoic Acid: 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 Alpha lipoic acid; Compounding; Food, Drug and Cosmetic Act, Section 503B; Food and Drug Administration; Outsourcing facility; Drug compounding; Legislation, Drug; United States Food and Drug Administration; Thioctic Acid

Rights Attribution-NonCommercial-NoDerivatives 4.0 International

Download date 23/09/2021 19:16:20

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

Link to Item http://hdl.handle.net/10713/12046 Summary Report

Alpha Lipoic Acid

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.

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Table of Contents

REVIEW OF NOMINATION ...... 4 METHODOLOGY ...... 4 Background information ...... 4 Systematic literature review ...... 4 Outreach to medical specialists and specialty organizations...... 7 Survey ...... 7 CURRENT AND HISTORIC USE ...... 9 Summary of background information ...... 9 Summary of literature review ...... 10 Summary of focus groups/interviews of medical experts and specialty organizations...... 29 Summary of survey results ...... 31 CONCLUSION ...... 35 APPENDICES ...... 36 Appendix 1. References ...... 36 Appendix 2. Survey instrument ...... 64

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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 ...... 10 Table 6. Number of studies by country ...... 11 Table 7. Number of studies by combinations...... 13 Table 8. Dosage by indication – US ...... 14 Table 9. Dosage by indication – non-US countries ...... 18 Table 10. Compounded products – US ...... 27 Table 11. Compounded products – non-US countries ...... 28 Table 12. Overview of interviewees ...... 29 Table 13. Characteristics of survey respondents ...... 31 Table 14. Types of products used, prescribed, or recommended ...... 32 Table 15. Compounded use of ALA in practice ...... 33 Table 16. Indications for which ALA is considered a standard therapy ...... 34 Table 17. Reasons for using a compounded product instead of any FDA-approved products ...... 34 Table 18. Change in frequency of compounded ALA usage over the past 5 years ...... 35 Table 19. Do you stock non-patient specific compounded ALA in your practice?...... 35 Table 20. Questions related to stocking non-patient specific compounded ALA ...... 35

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REVIEW OF NOMINATION Alpha lipoic acid (ALA; UNII code: 73Y7P0K73Y) was nominated for inclusion on the 503B Bulks List by Fagron for treatment of neuropathy via a 25mg/mL and 40mg/mL intravenous injection. Reasons provided for nomination to the 503B Bulks List include that there is no FDA-approved product and there is always a need for an effective treatment with low side effect profiles.

METHODOLOGY Background information The national medicine registers of 13 countries and regions were searched to establish the availability of ALA 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 ALA; name variations of ALA 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 ALA. 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 September 8, 2018. The search included a combination of ("thioctic acid"[TIAB] OR "lipoic acid"[TIAB]) AND ("treatment"[TIAB] OR "neuropathy"[TIAB] OR "liver toxicity"[TIAB] OR "amanita"[TIAB] OR poison*[TIAB] OR "hepatitis"[TIAB] OR "cirrhosis"[TIAB] OR "cancer"[TIAB] OR onco*[TIAB] OR "fibromyalgia"[TIAB] OR "pain"[TIAB] OR "muscle"[TIAB] OR nephro*[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.

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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 ALA or the implementation of ALA 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 ALA 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 ALA compared to alternative therapies. Results Please refer to Figure 1.

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

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Outreach to medical specialists and specialty organizations Using the indication from the nomination and the results of the literature review, eighteen (18) medical specialties that would potentially use ALA were identified: cardiology, dermatology, endocrinology, gastroenterology, hepatology, naturopathy, nephrology, neurology, obstetrics and gynecology, oncology, ophthalmology, oral medicine, pain management, primary care, psychiatry, pulmonology, rheumatology, and toxicology. 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. Nine (9) experts were contacted for interviews, of which four (4) accepted. Two (2) experts, one (1) specializing in hepatology and one (1) specializing in psychiatry, replied with a statement that they do not utilize the substance. Two (2) experts, one (1) specializing in neurology and one (1) in oncology 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 cardiology, dermatology, endocrinology, gastroenterology, hepatology, naturopathy, nephrology, neurology, ophthalmology, obstetrics and gynecology, oncology, oral medicine, pain management, primary care, psychiatry, pulmonology, rheumatology, and toxicology, identified from the nomination, literature review, and interviews, 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. An online survey was created using Qualtrics® software (Provo, UT). The survey link was distributed to twenty-five (25) 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.

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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)

Nephrology Renal Physicians Association (RPA)

American Academy of Ophthalmology (AAO)

Ophthalmology American Society of Cataract and Refractive Surgery (ASCRS)

American Society of Retina Specialist (ASRS)

Oral Medicine American Academy of Oral Medicine (AAOM)

Pain Medicine American Academy of Pain Medicine (AAPM)

Primary Care American Academy of Environmental Medicine (AAEM)

Rheumatology American College of Rheumatology (ACR)

Toxicology American College of Medical Toxicology (ACMT)

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

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

Nephrology American Society of Nephrology (ASN) Failed to respond

Neurology American Academy of Neurology (AAN) Failed to respond

Obstetrics and American College of Obstetricians and Declined, survey not approved for Gynecology Gynecologists (ACOG) distribution

Declined, “they are unable to share Oncology American Society of Clinical Oncology (ASCO) survey with members”

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

Declined, “we have put this ask to our members and unfortunately, we have Psychiatry American Psychiatric Association (APA) not received any information on psychiatrists using compounded products”

Pulmonology American Thoracic Society (ATS) Declined

CURRENT AND HISTORIC USE Summary of background information • ALA is not available as an FDA-approved product. • ALA is available as an OTC product in the US. • There is a current United States Pharmacopeia (USP) monograph for ALA. • ALA is available in Latvia. In Australia, ALA is available as a combination product with various other active pharmaceutical ingredients (API). In Abu Dhabi and Hong Kong, it is available in a dosage form that differs from the nomination.

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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

600mg/24mL, Solution for Acidum thiocticum - Latvia Prescription 9/26/1996 12mg/mL injection 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: 440 studies (145 descriptive, 249 experimental, and 46 observational). • Most of the studies were from the US (98). • The most common indication for the use of ALA in the US and non-US studies was diabetes. • Compounded products were identified from both the US and non-US studies. Four (4) non-US studies utilized ALA in the nominated form and for the nominated indication.

Table 5. Types of studies

Types of Articles Number of Studies

Descriptive1–145 145

Experimental146–394 249

Observational395–440 46

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Table 6. Number of studies by countrya

Number Country of Studies

Argentina80,134,141,146,167,290,370,384 8

Australia10,11,84,106,127,186 6

Austria193,382 2

Belgium171,272 2

Bosnia and Herzegovina208,322,391 3

Brazil67,105,180,185,216,221,222,245,250,256,326,336,405,407 14

Bulgaria152,192,217,268,269 5

Canada28,39,65,66,271,283,295 7

Chile389 1

China42,46,71,79,81,82,162–165,234,239,263,270,288,293,294,296,298,303,305,306,378,385,387 25

Croatia61 1

Egypt258,340,343–346,363,381 8

France12,13,15,33,56,59,341 7

Georgia96,97 2

Germany26,48,49,51,52,74,112,120,132,148,154,158,198,205,224,238,244,308–310,312,355,359,360,372,374–376,380,390,394,395,433 33

Greece34,329 2

Ghana314 1

Hungary37,38,83,107,280 5

India23,104,122,168,211,214,275,281 8

Iran8,69,108,109,194,200,201,206,255 9

Iraq50,351 2

Israel183 1

Italy19,55,64,93,102,110,119,137,161,170,172,174–177,188,191,196,199,202,203,207,227,230,231,235,237,240,243,252– 254,260,266,267,285,287,311,313,316,317,319,323–325,330,335,338,339,349,361,362,364–369,373,396,399–401,406,410,415–418,420– 80 427,431,432,437

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Japan94,264,265,434 4

Kazakhstan195 1

Kuwait115 1

Mexico189,197,282,358,430 5

The Netherlands27,35,53,62,100 5

New Zealand173 1

Norway274 1

Poland54,68,143,228,342,397 6

Romania91,179,204,321 4

Russia5,153,157,184,219,262,302,392,393 9

Serbia85,236,284,398 4

Singapore220 1

Slovakia210 1

South Africa347 1

South Korea63,88,89,150,151,155,156,160,212,213,377,439,440 13

Spain101,142,169,209,388,414,428 7

Sweden6,315 2

Switzerland24,31,273 3

Thailand9,226,419 3

Turkey126,276,277,299,301,328,331,379,413 9

Ukraine16,75,86,279,402,403,412 7

United Arab Emirates190 1

UK234,29,45,78,124,129,178,182,229,327,333,350,352,353 14

US 2,3,25,30,32,36,40,41,43,44,47,57,4,58,60,70,72,73,76,77,87,90,92,7,95,98,99,103,111,113,114,116– 118,14,121,123,125,128,130,131,133,135,136,138,17,139,140,144,145,147,149,159,166,181,187,18,215,225,232,233,241,242,246,247,249,251,20,257,2 98 59,261,286,289,291,292,297,300,304,21,318,320,332,334,348,356,357,371,383,386,22,404,408,409,411,429,435,436,438

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Multiple Countries • Germany, Indonesia354 • Germany, Russia, Israel307 4 • Italy, The Netherlands337 • UK, Canada, Finland, Australia218

Total US: 98 Total Non-US Countries: 341 aStudies 1 and 248 do not mention country.

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

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Table 8. Dosage by indication – US

Indication Dose Concentration Dosage Form ROA Duration of Treatment

Antioxidant for type 1 diabetes mellitus (T1DM)386 600-1200mg/day – Tablet Oral 3 months

T1DM complications404 1200mg/day – Tablet Oral 28 days

300-1800mg/day Tablet Oral 7 days – 24 months T2DM20,144,232,408 – 600mg/day – Intravenous 3 weeks

Improves metabolic disruptions in T2DM57 300-600mg/day – – Oral –

500mg/day Solution Intravenous 10 days Insulin sensitivity in T2DM147,348 – 600-1800mg/day Tablet Oral 4 weeks

Non-insulin dependent DM7 – – – – –

600mg/day Intravenous 3 weeks Reduction of oxidative stress in diabetes3 – – 600-1800mg/day Oral 3-6 months

50-1800mg/day Solution Intravenous 2 weeks – 2 years Diabetic neuropathy2,4,18,40,70,73,76,77,103,113,117,139,145,257,411 – 600-1800mg/day Tablet Oral 2 weeks – 2 years

Chemo-induced peripheral neuropathy138,139,371 600-1800mg/day – Capsule Oral 24 weeks

Cardiac autonomic neuropathy2,225 600-1200mg/day – Tablet Oral 6 weeks – 24 months

Tablet Oral 6 months Oxaliplatin neurotoxicity409,436 600mg/day – – Intravenous 3-5 weeks

Burning mouth syndrome17,22,44,92,125,133,136,435 200-800mg/day – – – 10 days - 26.6 weeks

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Neurodegenerative disorders118 200-1200mg/day – – Intravenous 3 weeks

Alzheimer’s disease18,116,259,357 500-600mg/day – Tablet Oral 16 weeks – 12 months

Dementia58 – – – – –

Depression7,58 – – – – –

Bipolar depression320 600-1800mg/day – Capsule Oral 12 weeks

Nonalcoholic fatty liver disease215,278,289,300 300mg/day – – Oral 6 months

Alcohol intoxication60 90mg/day – – – 1 week

Hepatitis C47,140 600mg/day – – Oral 1 year

A.phalloides-type mushroom poisoning30,121,130,311 150-300mg/day – Solution Intravenous 3-26 days

Mushroom poisoning60 400mg/day – – – 1 week

Amanita virosa acute hepatic necrosis131 100-300mg/day – – Intravenous 9 days

Mycotoxicosis140 – – – – –

1200mg/day Tablet Oral 96 weeks - 2 years Multiple sclerosis18,43,261,332 – 600-1200mg/day – Intravenous, oral 2 weeks

Chronic inflammation187,249,304 600-1200mg/day – Capsule Oral 4-24 weeks

Cancer32 – – – – –

Improving QOL after dx of metastatic pancreatic cancer25,36 300-600mg/day – – Intravenous 3 months

Treatment-resistant stage IV cancer111 8-12 teaspoons – – Oral –

Renal cell carcinoma14 300-600mg/day – – Intravenous 1 week

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Human immunodeficiency virus (HIV)123 400-1200mg/day – – – 14 days – 10 weeks

HIV-associated cognitive impairment318 1200mg/day – – Oral 10 weeks

Improve lymphocyte function in HIV patients149 900mg/day – Tablet Oral 6 months

Chronic obstructive pulmonary disease242,334 600mg/day – Capsule Oral –

Polycystic ovary syndrome429 1200mg/day – – Oral 16 weeks

Metabolic syndrome21,128 300-600mg/day – Tablet Oral 4 weeks

Presbyopia159 – 1.5% Solution Topical 91 days

Chronic progressive external ophthalmoplegia95 600mg/day – – – –

Acute optic neuritis297 1200mg/day – – Oral 6 weeks

Post viral olfactory dysfunction72 600mg/day – – Oral 3-11 months

Trigeminal trophic syndrome356 300mg/day – Tablet Oral 3 weeks

Atypical facial pain438 600mg/day – Tablet Oral 2 months

Migraine99 – – – – –

Coronary artery disease181 200mg/day – Tablet Oral 8 weeks

Peripheral arterial disease286 600mg/day – Capsule – 2-3 months

Reduce oxidative damage to the microvasculature57 100-200mg/day – – Oral –

Atrial fibrillation251 600mg/day – – Oral 12 months

Stage 1 hypertension232 – – – Oral once

Regulation of central/peripheral hemodynamics during exercise in 300mg/day – Capsule – – heart failure patients291

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Weight loss87 300-1800mg/day – – Oral 2-12 months

Tourette syndrome90 250mg/day – – – –

Manganese-induced encephalopathy166 600mg/day – – Intravenous, oral 2 months

Lipoamide dehydrogenase deficiency with primary lactic acidosis98 25-50mg/kg – – Oral 2 years

Chronic diseases114 200-600mg/day – – – 4 years

Chronic kidney disease233 600mg/day – Capsule Oral 8 weeks

Antioxidant for hemodialysis383 600mg/day – Capsule Oral 6 months

Bone loss241 600-1200mg/day – – Oral 1 year

Collagen enhancing246 – – – Topical 2-3 weeks

Photoaging247 – – Cream Topical 2 weeks

Metabolic myopathy with polyarteritis nodosa41 – – – – –

Mild/moderate distal ulcerative colitis292 – – – Oral – Abbreviations: “–“, not mentioned; ROA, route of administration.

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Table 9. Dosage by indication – non-US countries

Indication Dose Concentration Dosage Form ROA Duration of Treatment

Acute exhaustive eccentric exercise413 1200mg/day – Capsule Oral 2 weeks

Acute liver necrosis273 893mg/day – Solution Intravenous –

Hearing loss265 60mg/day – – – 8 weeks

Alcohol-related liver disease178 300mg/day – – – 24 weeks

600-1800mg/day Capsule Oral 4-48 months Alzheimer’s disease104,106,224,349,375,376 – – – – –

200-700mg/day Intravenous 2-12 days Amanita mushroom poisoning6,51,107,141 – – – – –

Anemia in chronic renal failure346 600mg/day – Tablet Oral 3 months

– - Intravenous Once

Capsule 1 month 200-600mg/day Solution Oral 10 days - 3 month Anti-inflammatory, antioxidant54,142,175,264,285,368,402,403,422,423 – 200-300mg/day – 10 days - 11 months

400mg/day Tablet Vaginal 30 days

300mg/day – – 4 weeks

Asthma282 600mg/day – – Oral 8 weeks

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300-1800mg/day Capsule 10-12 weeks

Weight loss155,156,163,389 – Tablet Oral 8 weeks 1200mg/day – –

Back pain235,311 600mg/day – – Oral 42-60 days

600mg/day Capsule 2 months

600-800mg/day Tablet Oral 1-4 months Burning mouth syndrome45,84,105,167,169,177,209,245,324,326,331,336,341,350,428 – 400-800mg/day 2 months – 200-800mg/day – 1-12 months

Cancer115,267 300-1200mg/day – – Oral 2-30 months

Tablet 16-24 weeks Oral Cancer-related cachexia/anorexia170,174,266,416,421,424,427 300mg/day – 15-16 weeks – – 4 months

Pain management for cancer401 1600mg/day – Tablet Oral 28 days

400mg/day – Intravenous 3-4 weeks

800mg/day Tablet 4-6 months Cardiac autonomic neuropathy16,83,88,154,160,219,312 – Oral 600-1200mg/day 3-6 months – 1200mg/day – 24 weeks

Cardiac surgery127 300mg/day – – – 36 days - 6 weeks

Cardiovascular disease risk in obesity182 1g/day – – – –

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300-600mg/day Capsule 120 days Oral Carpal tunnel syndrome93,197,207,339,431 300-600mg/day – Tablet 3-6 months

600mg/day – – 4 months

Charles bonnet syndrome379 600mg/day – – – 2-3 weeks

240mg/day Tablet 12 weeks Chemo-induced peripheral neuropathy10,11,59,338 – Oral 1800mg/day – 24 weeks

600mg/day Solution Intravenous Chemo-resistant cancer12,13,15 – – 600-1600mg/day Tablet Oral

Capsule 17 months Chemotherapy425,426 300mg/day – Oral – 10 months

Chemo-induced alopecia434 16mL/day – – Topical –

Polyarthritis430 – – – – –

150mg/day Capsule Oral 16 weeks Chronic fatigue syndrome186,419 – – – – –

Chronic hepatitis C183 150mg/day – Capsule Oral 20 weeks

Leg wound202 600mg/day – Capsule Oral 8 weeks

300-600mg/day Tablet 12 weeks - 9 months Pelvic pain172,364,406,414 – Oral 600mg/day – 180 days

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Tablet 4 years Sciatic pain313,437 600mg/day – Oral – 60 days

Contrast-induced nephropathy69,151 1800mg/day – Tablet Oral 2 days

Contrast-induced neuropathy328 1800mg/day – Tablet Oral –

Degenerative polydiscopathy85 – – – – –

600-1000mg/day Solution 2-3 weeks Intravenous 500-1200mg/day – 10-21 days

Diabetes52,56,66,68,89,119,124,137,143,148,152,158,165,193,196,198,201,203,208,210,211,213,226,234,252, 266-1200mg/day Capsule 3-6 months – 275,281,288,296,298,299,303,306,333,342,344,358,359,366,382,387,394,395,397 200-1800mg/day Tablet Oral 1 month – 4 years

600-1800mg/day 10 days - 4 months – 100-1800mg/day – 2 weeks - 18 months

800mg/day Capsule Oral Diabetic renal disease55,63,206 – 12 weeks 600-800mg/day – –

Diabetic foot279 – – – – –

Diabetic gastroparesis86 600mg/day – – – 3 weeks

Diabetic macular edema380 600mg/day – – Oral 24 months

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100-600mg/day 12mg/mL Solution Once – 3 months Intravenous 100-1200mg/day – 5 days – 4 years

300-1600mg/day Capsule 6 weeks – 4 years Diabetic neuropathy1,5,27,29,33-35,37,38,42,46,48,49,53,62,64,65,71,74,75,78,79,81,82,91,96,97,100,112, 120,122,132,134,146,150,153,157,168,179,189,204,214,216,217,220,228,238,239,243,244,248,262,263,268,269,280, 300-1200mg/day Tablet Oral 21 days – 24 months 301,302,307-310,316,321,322,327,329,335,345,354,361,372,374,377,378,385,391,393,398,415,418,433,439 – 20-1800mg/day – 3 days – 5 years

600mg/day Tablet 4 years – 600-1800mg/day – Once – 1 year

Diabetic retinopathy110 400-600mg/day – – – 2 years

Tablet Oral Diabetic ulcer191 – – 12 months Ointment Topical

Down syndrome200,369 100-200mg/day – Capsule Oral 4 months

Age-related macular degeneration270 200mg/day – Capsule Oral 3 months

Dyspareunia317 600mg/day – – – 2 months

Tablet Oral 90 days Dyspermia230,253 – – – Oral Once

Tablet Oral 12 months Menopause/postmenopause101,256,420 600mg/day – – – 3 months

Intravenous 7 days Erectile dysfunction192 600mg/day – – Oral 12 weeks

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Heavy metal detoxification26 – – Solution Intravenous Once

Hepatic coma31 930-9300mg/day – Solution Intravenous 41 days

600mg/day Capsule 12 weeks Hypertension39,185 – Oral – – 2 weeks

300-1200mg/day Capsule 3 months Oral Multiple sclerosis8,39,240,255 – – 2 weeks – 1200mg/day – –

100mg/day Oral Leigh’s encephalomyelopathy61,94 – – – 30mg/kg/day –

Hypertriglyceridemia213 600mg/day – – Intravenous 4 days

300mg/day Solution 3 weeks Intravenous Hypothyroidism195,294 600mcg/day – 10 days – – Oral 3 months

Hypoxia205 600mg/day – Capsule Oral 2 weeks

Disgeusia352 600mg/day – Tablet Oral 60 days

600mg/day Solution Intravenous 3 weeks Impaired fasting glucose293,330 – 220mg/day Tablet Oral 8 weeks

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600mg/day 600mg/250mL Solution Intravenous 2-3 weeks

300mg/day Capsule 10 weeks Overweight/obesity108,276,295,305,325,388 800mg/day – Tablet Oral 4 months

300-1800mg/day – 2-48 weeks

600mg/day Capsule Oral 2 months Mitochondrial diseases19,28,102,129,218,271 – 300-600mg/day – – 1-2 month

Acute coronary syndrome164 600mg/day – – Intravenous 5 days

300-600mg/day Solution At least 2 months

800mg/day Tablet Oral 6 months Polycystic ovary syndrome50,231,392,399,400,410 – 600mg/day 3 months – 800mg/day – –

Solution Intravenous Once Ischemic reperfusion injury80,290,370,384, 600mg/day – – – Once

– Intravenous 5 days

Ischemic stroke184,194,440 600mg/day – Capsule 12 weeks Oral Tablet 1 year

Kwashiorkor314 100mg/day – – Oral 20 days

Lepiota poisoning126 75mg/day – – – 3 days

HIV-related lipoatrophy188 200mg/day – – – 48 weeks

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Intravenous Lyme neuroborreliosis229 600mg/day – – – Oral

Melasma272 – – – Topical 3 months

Meniere’s syndrome237 – – Tablet Oral 2 months

300mg/day Tablet Oral 2 years

Schizophrenia236,250,284,347 500-1200mg/day – Capsule 10 weeks – 3 months – 100-1200mg/day – 4 months

Capsule 1 year 600mg/day Oral Metabolic syndrome173,323,396 – Tablet 180 days

– – – 6 months

800mg/day Capsule 6 months

300mg/day Tablet Oral 1 month Migraine9,109,171,340,417 – – 3 months 600mg/day – – 3 months

Miscarriage/pre-term delivery432 600mg/day – – Oral At least 7 weeks

Exercise-induced oxidative stress353 1000mg/day – Tablet Oral 14 days

Parkinson’s disease405 – – – – –

Nonalcoholic fatty liver disease365 400mg/day – Capsule Oral 12 months

Nonketolytic hyperglycinemia24 – – – Oral –

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600mg/day Oral 3-11 months Olfactory disorder390,407 – – – – –

1800mg/day Tablet Oral 6 months Chemo-induced polyneuropathy287,360,363 – 3200mg/day – – 6 months

Painful bladder syndrome199 600mg/day – Capsule Oral 12 weeks

Periodontitis412 600mg/day – – Oral 2.5 months

Presbycusis221 60mg/day – – Oral 6 months

Prevent DNA injury in diagnostic radiation exposure283 600mg/day – – – Once

Diabetic left ventricular dysfunction381 600mg/day – – – 4 months

Acute mountain sickness223 600mg/day – Capsule Oral 27 days

Psoriasis260 150mg/day – Capsule Oral 3 months

Pillar pain319 800mg.day – Tablet Oral 40 days

Rheumatoid arthritis212 900mg/day – Capsule Oral 4 weeks

Sensory peripheral neuropathy in breast cancer367 300mg/day – Solution Oral –

Neck pain161 600mg/day – – – 2 months

Sickle cell disease180 200mg/day – – Oral 3 months

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200mg/day – Tablet Oral 6 months

5% Cream 12 weeks Skin aging190,258,274,315,343 – 5-30% Gel Topical 3-6 months

– – Twice

Subchorionic hematoma227 600mg/day – – Oral –

Takotsubo syndrome176 600mg/day – – Oral 12 months

Tinnitus222 60mg/day – Capsule Oral 6 months

400mg/day Tablet Oral 8 months Vitiligo162,337 – 300mg/day – – 6 months

Wound healing in hyperbaric oxygen therapy362,373 300mg/day – Capsule Oral 14-30 days Abbreviations: “–“, not mentioned; ROA, route of administration.

Table 10. Compounded products – US

Indication Publication Year Compounding Method Dosage Form Final Strength

A. phalloides-type mushroom • For IV infusion, needs to be compounded in a solution of glucose and 1976 – – poisoning135 water Abbreviation: “–“, not mentioned.

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Table 11. Compounded products – non-US countries

Indication Compounding Method Dosage Form Final Strength

Prevention of acute mountain sickness223 • Combined with ascorbic acid, a tocopherol acetate Capsule –

Inhibition of tumor development267 • Combined with hydroxycitrate – –

Chronic lower back pain311 • Combined with superoxide dismutase – –

• Superoxide dimutase316 Diabetic neuropathy204,308,316,391 • Ampules containing 20ml ALA in 100ml 0.9% sodium chloride204 Solution – • In 250ml 0.9% sodium chloride308

Diabetic macular edema380 – – –

Nonalcoholic fatty liver disease365 – Capsule –

Stroke194 • Capsulated powder Capsule –

Tinnitus222 – Capsule –

Anti-wrinkle258 • P407 gels loaded with ALA cubosomes Gel 30%

• With Q10 coenzyme, krill oil, resveratrol, vitis vinifera seedoil, vitamine E, Psoriasis260 Capsule – selenium

• Mixture of unithiol, sodium calcium edetate, procaine, sodium bicarbonate and Heavy metal detoxification26 Solution – ALA

T2DM with ED303 • In normal saline 250ml Solution –

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Summary of focus groups/interviews of medical experts and specialty organizations Four (4) interview were conducted. Two (2) interviews were conducted with the same person on different dates.

Table 12. Overview of interviewees

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

• One of the most frequently used substances. NAT_01A, Allergy and • Uses for a variety of indications Private, NAT_01B, ND autoimmunity/ Yes • Would stock in office, at least 10 vials. outpatient NAT_02 immunology • Usually use OTC product or combination. • No side effect noticed with the compounded products.

• Both AASLD and European guideline do not mention use of ALA. Gastroenterology, • There does not appear to be a compelling reason to use it in terms of GAS_01 MD Hospital No internal medicine benefit. • Vitamin E is more favorable antioxidant due to stronger data.

Pediatrics, Academic • Has not used much but remember there being a couple of people who PED_01 MD No internal medicine medical institute wanted ALA instead of carpal tunnel surgery.

• Used for neuropathy due to patient preferences, either as an adjuvant or monotherapy. • Usually has patients use OTC products, has never used a Inpatient, END_02 MD Endocrinology Yes compounded product. Sometimes will write a prescription for outpatient Metanx. • No need to be made by outsourcing facility since it is available OTC. • Not sure about intravenous uses. Abbreviations: MD, Doctor of Medicine; ND, Naturopathic Doctor.

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Indications • First-line for cancer, diabetes, Lyme disease, and wrinkles. Also used for hair loss, headache, heart conditions, hypothyroidism, PCOS, and weight loss. o Cream: daily. Write Rx for it to be compounded. o Intravenous: 100-400, 1-2 times/week for Lyme, cancer, diabetes. o Oral: 600-1000mg, 1-2 times/day for diabetes. • Standard therapy for detox. Also used for neurodegenerative illnesses, vitamin and mineral repletion. o Can do oral, IV, cream. • Neuropathy – infrequent use, not the first line therapy. o Oral: 600mg/day, used as long as patients are having symptoms. • Combination compounded for diabetes or thyroid: ALA / chromium / inositol / selenium. Use over an FDA-approved product • One (1) interviewee stated, “If there is no FDA-approved product, then we have to use the compounded version. A lot of times, patients are sensitive, and so you can get the compounding pharmacy to take out certain ingredients that they may react to. So, it allows for, I would say, the purest form of it because it doesn't have to be shelf-stable. It can be made right then.” • One (1) interviewee stated, “If I can't find a formula that has the specific things I want, that a compounding pharmacy will do it. Also, the additives are an issue.” • One (1) interviewee stated, “A lot of people don't want to take the neuropath meds, so that's the tricky part. A lot of people don't want to just take meds, and they'd rather take this stuff. The neuropathy meds are tricky because it's either anti-depressants or anti-epileptics are the two main categories and they come with their whole hosts of side effects, potential side effects. So people do want these natural alternatives especially for things like that. Sometimes the pain or discomfort is not that severe, so they don't have to take another drug with potential side effects also. In those cases, ALA or sometimes some B vitamins and stuff, we'll recommend that.” Office use • One (1) interviewee stocks it in office, but the others do not, either because there is an OTC product available or because it is not used in their practice.

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Summary of survey results Table 13. Characteristics of survey respondents [134 people responded to the surveya]

Board Certification DMD/DDS DO MD ND PharmD PhD No Response

Addiction Medicine 0 0 3 0 0 0 0

Anesthesiology 0 0 1 0 0 0 0

Clinical Pharmacology 0 0 1 0 0 0 0

Emergency Medicine 0 5 25 0 0 0 0

Family Medicine 0 0 1 0 0 0 0

Fellow of the American Board of Naturopathic Oncology 0 0 0 1 0 0 0

Internal Medicine 0 0 6 0 0 0 0

Medical Toxicology 0 3 31 0 0 1 0

National Registry of Certified Chemists 0 0 0 0 0 1 0

Naturopathic Doctor 0 0 0 6 0 0 0

Naturopathic Physician 0 0 0 5 0 0 0

Neurology 0 0 1 0 0 0 0

Nephrology 0 0 1 0 0 0 0

Occupational Medicine 0 0 2 0 0 1 0

Oral medicine 2 0 0 0 0 0 0

Ophthalmology 0 0 23 0 0 0 0

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Pain Medicine 1 0 3 0 0 0 0

Pediatrics 0 0 2 0 0 0 0

Preventive Medicine 0 0 1 0 0 0 0

Rheumatology 0 1 0 0 0 0 0

Sleep Medicine 1 0 0 0 0 0 0

Toxicology 0 0 0 0 1 0 0

No Board Certification 0 0 1 3 0 0 0

No Response 0 0 0 0 0 0 56 Abbreviations: DMD/DDS, Doctor of Medicine in Dentistry; DO, Doctor of Osteopathic Medicine; MD, Doctor of Medicine; ND, Naturopathic Doctor; PharmD, Doctor of Pharmacy; PhD, Doctor of Philosophy. 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=27a)

Compounded 9b

FDA-approved 2

Over-the-counter 6

Dietary 16

Unsure 5

No Response 0 aOut of 134 respondents, 27 reported using, prescribing, or recommending multiple types of ALA products. bOne (1) respondent used in combination: vitamin D, multiple vitamin Bs, protopic, capric triglycerides in Versabase cream.

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Table 15. Compounded use of ALA in practicea

Dosing Dosage Duration of Patient Populationb Indication Strength ROA frequency Form Treatment

Atopic dermatitis 2-5% BID Topical Topical 2-4 months Both sexes children and adults

“Prediabetes, type IIi diabetes, PCOS, insulin 600mg BID-TID caps Oral 3-12 months resistance” Blood sugar regulation 1-3 every 100-300mg – Intravenous 30-60 minutes – week

1-3 every 100-300mg – Intravenous 30-60 minutes – week Diabetic neuropathy 300mg BID-TID caps Oral 3-6 months Lyme disease patients, MS, diabetes

Autism, Lyme disease, cardiac disease, Mitochondria dysfunction 300mg BID-TID caps Oral Ongoing myasthenia graves, most autoimmune diseases

Psoriasis 2-5% BID Topical Topical Indefinite Children adults both sexes

1-3 every Weak chelation, antioxidant 100-300mg – Intravenous 30-60 minutes – week Abbreviations: “–“, not mentioned; ROA, route of administration; BID, twice daily; TID, three times a day. aThree (3) respondents. bQuotations are direct words from respondents.

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Table 16. Indications for which ALA is considered a standard therapy

Standard Therapy Indication Compounded, n Non-compounded, n Unsure, n (N=5) (N=9) (N=13)

Blood sugar regulation 0 1 0

Burning mouth syndrome 0 1 0

Cancer 1 1 0

CHF 0 1 0

Diabetes 1 3 0

Diabetic neuropathy 2 7 1

Fatigue 0 1 0

Mitochondrial dysfunction 1 0 0

Neurological 0 1 0

Psoriasis atropic dermatitis 1 0 0

None 0 1 0

Othera 0 1 0

No response 5 1 4 a“Varies depending on individual patient circumstances” bSome respondents reported more than one indication.

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

Theme Reasons

Availability “I do not believe it is commercially available for IV use”

“Because it makes compliance better with different j gradients and the bases used allow for better Compliance penetration and one can customize for an individual”

Quality “Quality”

Sensitivity “Patients have reported sensitivity to the non-compounded products previously.”

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

Respondents, n (N=9)

No–use has remained consistent 1

Yes–I use it LESS often nowa 2

Yes–I use it MORE often now 2

No Response 4 aOne (1) respondent wrote “Better biological drugs for psoriasis so lead need for steroid soaring [sic] topicals”.

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

Respondents, n (N=9)

No 4

Yes 1

No Response 4

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

CONCLUSION ALA (UNII code: 73Y7P0K73Y) was nominated for inclusion on the 503B Bulks List by Fagron for treatment of neuropathy as an intravenous injection. ALA is not approved in the US but is approved in Latvia. From the literature review conducted, the most common indication for use of ALA in the US and non-US studies was diabetes. Compounded products were identified from both the US and non-US studies. Four (4) non-US studies utilized ALA in the nominated dosage form and for the nominated indication. From the interviews, two (2) interviewees used ALA in their practice and one (1) would stock it in their office. Reasons provided for using compounded ALA over an FDA-approved product was that there are no FDA-approved products available, patient sensitivity, a specific formula is required, and patient preference. From the survey responses, 27 out of 134 respondents used ALA. The most common indication respondents reported using compounded ALA for was diabetic neuropathy and blood sugar regulation. The availability of an IV product, compliance, quality, and patient sensitivity were some of the reasons provided for using compounded ALA product over an FDA-approved product. One (1) out of nine (9) respondents who reported using compounded ALA reported stocking non-patient specific compounded ALA in their practice, but no details were provided regarding how the product was obtained or the reasons for stocking in-office.

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358. García-Martínez BI, Rosado-Pérez J, Ruiz-Ramos M, Mendoza-Núñez VM. Effect of alpha lipoic acid on oxidative stress and chronic inflammation markers in diabetic older adults. Free Radic Biol Med. 2017;112:130. doi:10.1016/j.freeradbiomed.2017.10.196 359. Garcia-Alcala H, Santos Vichido CI, Islas Macedo S, et al. Treatment with α-lipoic acid over 16 weeks in type 2 diabetic patients with symptomatic polyneuropathy who responded to initial 4- week high-dose loading. J Diabetes Res. 2015;2015:189857. doi:10.1155/2015/189857 360. Gedlicka C, Scheithauer W, Schüll B, Kornek G. Effective treatment of oxaliplatin-induced cumulative polyneuropathy with alpha-lipoic acid. J Clin Oncol. 2002;20:3359-3361. 361. Gemignani F. Symptomatic and pathogenetic treatment of diabetic neuropathy: Role of alpha- lipoic acid. Neural Regen Res. 2010;5(10):781-788. 362. Alleva R, Nasole E, Di Donato F, Borghi B, Neuzil J, Tomasetti M. α-Lipoic acid supplementation inhibits oxidative damage, accelerating chronic wound healing in patients undergoing hyperbaric oxygen therapy. Biochem Biophys Res Commun. 2005;333(2):404-410. doi:10.1016/j.bbrc.2005.05.119 363. Ghali R, Basiuony M, Elleithy M. Role of alpha-lipoic acid in improvement of paclitaxel/carboplatin induced neuropathy in metastatic breast cancer: An egyptian experience. Neuro oncol. 2012;14(3):iii80-iii81. 364. Giammusso B, Di Mauro R, Bernardini R. The efficacy of an association of palmitoylethanolamide and alpha-lipoic acid in patients with chronic prostatitis/chronic pelvic pain syndrome: A randomized clinical trial. Arch Ital di Urol e Androl. 2017;89(1):17-21. doi:10.4081/aiua.2017.1.17 365. Gianturco V, Bellomo A, D’Ottavio E, et al. Impact of therapy with α-lipoic acid (ALA) on the oxidative stress in the controlled NIDDM: A possible preventive way against the organ dysfunction? Arch Gerontol Geriatr. 2009;49(1):129-133. 366. Gianturco V, Troisi G, Bellomo A, et al. Impact of combined therapy with alpha-lipoic and ursodeoxycolic acid on nonalcoholic fatty liver disease: Double-blind, randomized clinical trial of efficacy and safety. Hepatol Int. 2013;7(2):570-576. doi:10.1007/s12072-012-9387-y 367. Ginocchi L, Allegrini G, Lucchesi S, et al. (R)-a-lipoic acid reduces sensorial peripheral neurotoxicity in breast cancer patients receiving weekly paclitaxel. Ann Oncol. 2015;26(suppl 6):vi22. doi:10.1093/annonc/mdv336.66 368. Grandi G, Pignatti L, Ferrari F, Dante G, Neri I, Facchinetti F. Vaginal alpha-lipoic acid shows an anti-inflammatory effect on the cervix, preventing its shortening after primary tocolysis. A pilot, randomized, placebo-controlled study. J Matern Neonatal Med. 2017;30(18):2243-2249. doi:10.1080/14767058.2016.1245282 369. Gualandri W, Gualandri L, Demartini G, et al. Redox balance in patients with Down’s syndrome before and after dietary supplementation with α-lipoic acid and L-cysteine. Int J Clin Pharmacol Res. 2003;23(1):23-30. 370. Guerrieri D, Petroni J, Nicolás A, et al. α-lipoic acid protects the ischemia reperfusion injury in simultaneous kidney-pancreas transplant patients. Am J Transplant. 2013;13(suppl 5):440-441. 371. Guo Y, Jones D, Palmer JL, et al. Oral alpha-lipoic acid to prevent chemotherapy-induced peripheral neuropathy: A randomized, double-blind, placebo-controlled trial. Support Care Cancer. 2014;22(5):1223-1231. doi:10.1007/s00520-013-2075-1 372. Haak E, Usadel K., Kusterer K, et al. Effects of alpha-lipoic acid on microcirculation in patients with peripheral diabetic neuropathy. Exp Clin Endocrinol Diabetes. 2000;108(3):168-174.

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373. Alleva R, Tomasetti M, Sartini D, et al. α-Lipoic acid modulates extracellular matrix and angiogenesis gene expression in non-healing wounds treated with hyperbaric oxygen therapy. Mol Med. 2008;14(3-4):175-183. doi:10.2119/2007-00095.Alleva 374. Haak ES, Usadel KH, Kohleisen M, Yilmaz A, Kusterer K, Haak T. The effect of α-lipoic acid on the neurovascular reflex arc in patients with diabetic neuropathy assessed by capillary microscopy. Microvasc Res. 1999;58(1):28-34. doi:10.1006/mvre.1999.2151 375. Hager K, Kenklies M, McAfoose J, Engel J, Münch G. α-lipoic acid as a new treatment option for Alzheimer’s disease - a 48 months follow-up analysis. J Neural Transm. 2007;72:189-193. 376. Hager K, Marahrens A, Kenklies M, Riederer P, Münch G. Alpha-lipoic acid as a new treatment option for Azheimer type dementia. Arch Gerontol Geriatr. 2001;32(3):275-282. 377. Hahm JR, Kim B-J, Kim K-W. Clinical experience with thioctacid (thioctic acid) in the treatment of distal symmetric polyneuropathy in Korean diabetic patients. J Diabetes Complications. 2004;18(2):79-85. doi:10.1016/S1056-8727(03)00033-3 378. Han Y, Wang M, Shen J, et al. Differential efficacy of methylcobalamin and alpha-lipoic acid treatment on symptoms of diabetic peripheral neuropathy. Minerva Endocrinol. 2018;43(1):11-18. doi:10.23736/S0391-1977.16.02505-0 379. Hanoglu L, Yildiz S, Polat B, et al. Therapeutic effects of rivastigmine and alfa-lipoic acid combination in the Charles Bonnet syndrome: Electroencephalography correlates. Curr Clin Pharmacol. 2016;11(4):270-273. doi:10.2174/1574884711666161003153616 380. Haritoglou C, Gerss J, Hammes HP, Kampik A, Ulbig MW. Alpha-lipoic acid for the prevention of diabetic macular edema. Ophthalmologica. 2011;226(3):127-137. doi:10.1159/000329470 381. Hegazy SK, Tolba OA, Mostafa TM, Eid MA, El-Afify DR. Alpha-lipoic acid improves subclinical left ventricular dysfunction in asymptomatic patients with type 1 diabetes. Rev Diabet Stud. 2013;10(1):58-67. doi:10.1900/RDS.2013.10.58 382. Heinisch BB, Francesconi M, Mittermayer F, et al. Alpha-lipoic acid improves vascular endothelial function in patients with type 2 diabetes: A placebo-controlled randomized trial. Eur J Clin Invest. 2010;40(2):148-154. doi:10.1111/j.1365-2362.2009.02236.x 383. Himmelfarb J, Ikizler TA, Ellis C, et al. Provision of antioxidant therapy in hemodialysis (PATH): A randomized clinical trial. J Am Soc Nephrol. 2014;25(3):623-633. doi:10.1681/asn.2013050545 384. Ambrosi N, Arrosagaray V, Guerrieri D, et al. α-lipoic acid protects against ischemia-reperfusion Injury in simultaneous kidney-pancreas transplantation. Transplantation. 2016;100(4):908-915. doi:10.1097/TP.0000000000000981 385. Hong Y, Peng J, Cai X, Zhang X, Liao Y, Lan L. Clinical efficacy of alprostadil combined with α- lipoic acid in the treatment of elderly patients with diabetic nephropathy. Open Med. 2017;12(1):323-327. doi:10.1515/med-2017-0046 386. Huang EA, Gitelman SE. The effect of oral alpha-lipoic acid on oxidative stress in adolescents with type 1 diabetes mellitus. Pediatr Diabetes. 2008;9(II):69-73. doi:10.1111/j.1399- 5448.2007.00342.x 387. Huang Z, Wan X, Liu J, et al. Short-term continuous subcutaneous insulin infusion combined with insulin sensitizers rosiglitazone, metformin, or antioxidant α-lipoic acid in patients with newly diagnosed type 2 diabetes mellitus. Diabetes Technol Ther. 2013;15(10):859-869. doi:10.1089/dia.2013.0013 388. Huerta A, Martínez J, Moreno-Aliaga M. Effects of a-lipoic acid and eicosapentaenoic acid on inflammation and cardiovascular risk markers in overweight/obese women following an energy-

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restricted diet. Obes Facts. 2015;8:247. 389. Huerta AE, Navas-Carretero S, Prieto-Hontoria PL, Martínez JA, Moreno-Aliaga MJ. Effects of α- lipoic acid and eicosapentaenoic acid in overweight and obese women during weight loss. Obesity. 2015;23(2):313-321. doi:10.1002/oby.20966 390. Hummel T, Heilmann S, Hüttenbriuk K-B. Lipoic acid in the treatment of smell dysfunction following viral infection of the upper respiratory tract. Laryngoscope. 2002;112(11):2076-2080. 391. Ibrahimpasic K. Alpha lipoic acid and glycaemic control in diabetic neuropathies at type 2 diabetes treatment. Med Arch. 2013;67(1):7-9. doi:10.5455/medarh.2013.67.7-9 392. Ivanova L, Rostovtseva O, Pachomova A. Influence of thioctic acid on polycystic ovary syndrome. Endocr Rev. 2014;35(3). 393. Ivanova L, Rostovtseva O. Treatment for chronic pain syndrome of diabetic peripheral neuropathy in type 2 diabetics with thioctic acid and standardised protein-free dialysate of calf blood. Diabetologia. 2013;56(1):S498. 394. Jacob S, Henriksen E., Schiemann A., et al. Enhancement of glucose disposal in patients with type 2 diabetes by alpha-lipoic acid. Arzneimittel-Forschung/Drug Res. 1995;45(8):872-874. 395. Borcea V, Nourooz-Zadeh J, Wolff S., et al. α-lipoic acid decreases oxidative stress even in diabetic patients with poor glycemic control and albuminuria. Free Radic Biol Med. 1999;26(11- 12):1495-1500. 396. Cianci A, Panella M, Fichera M, Falduzzi C, Bartolo M, Caruso S. D-chiro-Inositol and alpha lipoic acid treatment of metabolic and menses disorders in women with PCOS. Gynecol Endocrinol. 2015;31(6):483-486. doi:10.3109/09513590.2015.1014784 397. Ciszewska K, Swiech-Zubilewicz A, Mackiewicz J, Oseka M, Borsukiewicz A. Effect of the oral administration of alpha-lipoic acid, B1 and B2 vitamins and rutoside on retinal sensitivity in patients with diabetes. Invest Ophthalmol Vis Sci. 2017;58(8):5790. 398. Cvijanović M, Simić S, Kopitović A, Raičević R. Neurophysiological evaluation of short-term outcome of pharmacological treatment of diabetic neuropathy. Vojnosanit Pregl. 2017;74(8):722- 727. doi:10.2298/VSP151209261C 399. De Cicco S, Immediata V, Romualdi D, et al. Myoinositol combined with alpha-lipoic acid may improve the clinical and endocrine features of polycystic ovary syndrome through an insulin- independent action. Gynecol Endocrinol. 2017;33(9):698-701. doi:10.1080/09513590.2017.1313972 400. De Cicco S, Tropea A, Valentina I, et al. Effects of a combined supplementation of alpha-lipoic acid and myoinositol on endocrine and metabolic features in overweight PCOS patients. Reprod Sci. 2016;23(1):342A. 401. De Santis S, Borghesi C, Giovannoni D, Migliorino M. Novel combination of oxycodone/naloxone and pregabalin proves effective control of CNP(cancer-related neuropathic pain) and BTCP. Pain Pr. 2014;14:25-26. 402. Demidov V, Demidov S. Laparoscopic method of adhesions prevention. Surg Endosc. 2013;27:S65. 403. Demidov V, Demidov S. Surgical way of adhesions formation prevention. Surg Endosc. 2012;26:S405. 404. Du X, Edelstein D, Brownlee M. Oral benfotiamine plus α-lipoic acid normalises complication- causing pathways in type 1 diabetes. Diabetologia. 2008;51(10):1930-1932. doi:10.1007/s00125-

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008-1100-2 405. Dünschede F, Erbes K, Kircher A, et al. Reduction of ischemia reperfusion injury after liver resection and hepatic inflow occlusion by α-lipoic acid in humans. World J Gastroenterol. 2006;12(42):6812-6817. 406. Caruso S, Iraci Sareri M, Casella E, Ventura B, Fava V, Cianci A. Chronic pelvic pain, quality of life and sexual health of women treated with palmitoylethanolamide and α-lipoic acid. Minerva Ginecol. 2015;67(5):413-419. 407. Gregorio LL, Caparroz F, Nunes LMA, Neves LR, Macoto EK. Olfaction disorders: Retrospective study. Braz J Otorhinolaryngol. 2014;80(1):11-17. doi:10.5935/1808-8694.20140005 408. Grise DE, Mcallister HM, Langland J. Improved clinical outcomes of patients with type 2 diabetes mellitus utilizing integrative medicine: A case report. Glob Adv Heal Med. 2015;4(3):57-61. doi:10.7453/gahmj.2014.071 409. Grothey A. Clinical management of oxaliplatin-associated neurotoxicity. Clin Colorectal Cancer. 2005;5(suppl 1):S38-S46. doi:10.3816/CCC.2005.s.006 410. Torge N, Iezzi MM., Varriale G, et al. Polycystic ovary syndrome in adolescence: New therapeutic approach with inositol and alpha-lipoic acid. Horm Res Paediatr. 2016;86(supplement 1):255-256. 411. Kapoor S. Pain management in patients with diabetic nephropathy: The emerging role of α-lipoic acid. Foot Ankle Spec. 2012;5(4):228-229. doi:10.1177/1938640012451317 412. Lakhtin Y. Comparative evaluation of short- and long-term treatment of periodontitis with alpha- lipoic acid. Georgian Med News. 2013;218(5):19-22. 413. Lappalainen Z. Effect of alpha-lipoic acid and time-of-day on interleukin-6 response to exhaustive exercise in humans. African J Pharm Pharmacol. 2011;5(1):42-47. doi:10.5897/ajpp10.390 414. Lete I, Mendoza N, de la Viuda E, Carmona F. Effectiveness of an antioxidant preparation with N- acetyl cysteine, alpha lipoic acid and bromelain in the treatment of endometriosis-associated pelvic pain: LEAP study. Eur J Obstet Gynecol Reprod Biol. 2018;228:221-224. doi:10.1016/j.ejogrb.2018.07.002 415. Maddaloni E, Maurizi A., Minutolo A, et al. Palmitoylethanolamide in add-on to alpha lipoic acid for control of symptoms of diabetic peripheral neuropathy. Diabetes. 2018;67(suppl 1):A149. 416. Madeddu C, Dessi M, Orgiano L, et al. Efficacy and safety of a two drug-combination regimen for cancer-related cachexia in the clinical practice. J Clin Oncol. 2013;31(15):1. 417. Cavestro C, Bedogni G, Molinari F, Mandrino S, Rota E, Frigeri MC. Alpha-lipoic acid shows promise to improve migraine in patients with insulin resistance: A 6-month exploratory study. J Med Food. 2018;21(3):269-273. doi:10.1089/jmf.2017.0068 418. Maderna L, Gregorini F, Riccardi B, et al. Effects of r(+)-thioctic acid supplementation in type ii diabetic neuropathy: Neurophysiological evaluation and oxidative stress detection in blood. J Peripher Nerv Syst. 2014;19(suppl 1):S19. 419. Maes M, Leunis JC. Attenuation of autoimmune responses to oxidative specific epitopes, but not nitroso-adducts, is associated with a better clinical outcome in Myalgic Encephalomyelitis/chronic fatigue syndrome. Neuroendocrinol Lett. 2014;35(7):577-585. 420. Mainini G, Rotondi M, Di Nola K, et al. Oral supplementation with antioxidant agents containing alpha lipoic acid: Effects on postmenopausal bone mass. Clin Exp Obstet Gynecol. 2012;30(4):489-493. 421. Mantovani G, Macciò A, Madeddu C, et al. A phase II study with antioxidants, both in the diet and

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supplemented, pharmaconutritional support, progestagen, and anti-cyclooxygenase-2 showing efficacy and safety in patients with cancer-related anorexia/cachexia and oxidative stress. Cancer Epidemiol Biomarkers Prev. 2006;15(5):1030-1034. doi:10.1158/1055-9965.EPI-05-0538 422. Mantovani G, Macciò A, Madeddu C, et al. Phase II study of subcutaneously administered interleukin-2 in combination with medroxyprogesterone acetate and antioxidant agents as maintenance treatment in advanced cancer responders to previous chemotherapy. Oncol Rep. 2002;9(4):887-896. 423. Mantovani G, Macciò A, Madeddu C, et al. The impact of different antioxidant agents alone or in combination on reactive oxygen species, antioxidant enyzmes and cytokines in a series of advanced cancer patients at different sites: Correlation with disease progression. Free Radic Res. 2003;37(2):213-223. doi:10.1080/10715760303849 424. Mantovani G, Maccio A, Mulas C, et al. Dose-intense phase II study of weekly cisplatin and epidoxorubicin plus medroxyprogesterone acetate and recombinant interleukin 2 in stage IIIB-IV non-small cell lung cancer. Oncol Rep. 2002;9(3):661-670. 425. Mantovani G, Maccio A, Madeddu C, et al. Immunotherapy (recombinant interleukin 2), hormone therapy (medroxyprogesterone acetate) and antioxidant agents as combined maintenance treatment of responders to previous chemotherapy. Int J Oncol. 2001;18(2):383-391. 426. Mantovani G, Madeddu C, Gramignano G, et al. Subcutaneous interleukin-2 in combination with medroxyprogesterone acetate and antioxidants in advanced cancer responders to previous chemotherapy: Phase II study evaluating clinical, quality of life, and laboratory parameters. J Exp Ther Oncol. 2003;3(4):205-219. 427. Mantovani G, Madeddu C, Macciò A, et al. Cancer related anorexia/cachexia and oxidative stress: An innovative approach beyond current treatment. Cancer Epidemiol Biomarkers Prev. 2004;13(10):1651-1659. 428. Cembrero-Saralegui H, Imbernón-Moya A. RF-burning mouth syndrome: New treatments. Actas Dermosifiliogr. 2017;108(1):63-64. 429. Masharani U, Gjerde C, Evans J., Youngren J., Goldfine I. Effects of controlled-release alpha lipoic acid in lean, nondiabetic patients with polycystic ovary syndrome. J Diabetes Sci Technol. 2010;4(2):359-364. 430. Núñez E, Garrido J, Alba H, Olán F. Clinical and biochemical profile in a series of patients with chikungunya related polyarthritis. J Clin Rheumatol. 2016;22(3):153-154. 431. Pajardi G, Bortot P, Ponti V, Novelli C. Clinical usefulness of oral supplementation with alpha- lipoic acid, curcumin phytosome, and B-group vitamins in patients with carpal tunnel syndrome undergoing surgical treatment. Evidence-based Complement Altern Med. 2014;2014. doi:10.1155/2014/891310 432. Parente E, Colannino G, Picconi O, Monastra G. Safety of oral alpha-lipoic acid treatment in pregnant women: A retrospective observational study. Eur Rev Med Pharmacol Sci. 2017;21(18):4219-4227. 433. Ruessmann H-J. Switching from pathogenetic treatment with α-lipoic acid to gabapentin and other analgesics in painful diabetic neuropathy: A real-world study in outpatients. J Diabetes Complications. 2009;23(3):174-177. doi:10.1016/j.jdiacomp.2008.02.002 434. Sagawa N, Kono Y, Ohno S, et al. The preventive effect of DHL-hisznna, an α-lipoic acid derivative, for chemotherapy-induced alopecia: A single-arm phase 3 study. Support Care Cancer. 2018;26(suppl 2):S246.

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435. Steele JC, Bruce AJ, Drage LA, Rogers RS. α-Lipoic acid treatment of 31 patients with sore, burning mouth. Oral Dis. 2008;14(6):529-532. doi:10.1111/j.1601-0825.2007.01414.x 436. Cersosimo RJ. Oxaliplatin-associated neuropathy: A review. Ann Pharmacother. 2005;39(1):128- 135. doi:10.1345/aph.1E319 437. Checchia G, Mauro G, Morico G, et al. Observational multicentric study on chronic sciatic pain: Clinical data from 44 Italian centers. Eur Rev Med Pharmacol Sci. 2017;21:1653-1664. 438. Chen Y, Doshi T. Alpha-lipoic acid for the treatment of atypical facial pain: Case report. Pain Med (United States). 2018;19(4):880. 439. Choi K, Kim J, Park M. Lipoic acid use and functional outcome after tissue plasminogen activator treatment in patients with acute ischemic stroke and diabetic polyneuropathy. Cerebrovasc Dis. 2016;42(1):40. 440. Choi K-H, Park M-S, Kim J-T, et al. Lipoic acid use and functional outcomes after thrombolysis in patients with acute ischemic stroke and diabetes. PLoS One. 2016;11(9):e0163484. doi:10.1371/journal.pone.0163484

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

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

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Q2. Please list any conditions or diseases for which you use compounded alpha lipoic acid 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 include frequency(ies) form(s) administration therapy population 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 alpha lipoic acid 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 alpha lipoic acid as a single agent active ingredient, or as one active ingredient... != Combination Display This Question: If Loop current: Do you use compounded alpha lipoic acid as a single agent active ingredient, or as one active ingredient... = Combination Q4. Please list all combination products in which you use compounded alpha lipoic acid.

______Q5. For which, if any, diseases or conditions do you consider compounded alpha lipoic acid standard therapy? ______Q6. Does your specialty describe the use of compounded alpha lipoic acid in medical practice guidelines or other resources? ______Q7. Over the past 5 years, has the frequency in which you have used compounded alpha lipoic acid changed? o Yes - I use it MORE often now (briefly describe why) ______o Yes - I use it LESS often now (briefly describe why) ______

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

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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

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