Betahistine HCl: Summary Report

Item Type Report

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

Publication Date 2019-12

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

Rights Attribution-NoDerivatives 4.0 International

Download date 02/10/2021 00:26:22

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

Link to Item http://hdl.handle.net/10713/12065 Summary Report

Betahistine hydrochloride

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

December 2019

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

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Table of Contents

REVIEW OF 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 ...... 8 Summary of background information ...... 8 Summary of literature review ...... 10 Summary of focus groups/interviews of medical experts and specialty organizations...... 13 Summary of survey results ...... 14 CONCLUSION ...... 15 APPENDICES ...... 15 Appendix 1. References ...... 15 Appendix 2. Survey instrument ...... 19

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Table of Tables

Table 1. Participating associations ...... 7 Table 2. Associations that declined participation ...... 8 Table 3. Currently approved products – US ...... 8 Table 4. Currently approved products – select non-US countries and regions ...... 9 Table 5. Types of studies ...... 10 Table 6. Number of studies by country ...... 10 Table 7. Number of studies by combinations...... 11 Table 8. Dosage by indication – US ...... 12 Table 9. Dosage by indication – non-US countries ...... 12 Table 10. Compounded products – US ...... 13 Table 11. Compounded products – non-US countries ...... 13 Table 12. Overview of interviewee ...... 13 Table 13. Characteristics of survey respondents ...... 14 Table 14. Types of products used, prescribed, or recommended ...... 14 Table 15. Compounded use of betahistine HCl in practice ...... 14 Table 16. Indications for which betahistine HCl is considered a standard therapy ...... 14 Table 17. Reasons for using compounded product instead of the FDA-approved products ...... 14 Table 18. Change in frequency of compounded betahistine HCl usage over the past 5 years ...... 14 Table 19. Do you stock non-patient specific compounded betahistine HCl in your practice?...... 14 Table 20. Questions related to stocking non-patient specific compounded betahistine ...... 14

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REVIEW OF NOMINATION Betahistine hydrochloride (HCl) (betahistine HCl; UNII code: 49K58SMZ7U) was nominated for inclusion on the 503B Bulks List by Triangle Compounding Pharmacy, Inc. for balance disorders or to alleviate vertigo symptoms associated with Ménière's disease and tinnitus via oral 4 mg, 8 mg, and 16 mg capsules and liquid formulations. The reasons provided for nomination to the 503B Bulks List include patient allergies to excipients and that some patients who may not respond to an FDA-approved product, may respond to betahistine HCl. METHODOLOGY Background information The national medicine registers of 13 countries and regions were searched to establish the availability of betahistine HCl 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 (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 betahistine HCl; name variations of betahistine HCl were entered if the initial search retrieved no results. The following information from the search results of each register was recorded in a spreadsheet: product trade name; active ingredient(s); strength; form; ROA; status and/or schedule; approval date. Information was recorded only for products with strengths, forms, and/or ROAs 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 betahistine HCl. 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 December 20, 2018. The search included a combination of (betahistine[TIAB] OR betaserc[TIAB] OR dihydrochloride[TIAB]) AND (therapy[TIAB] OR treatment[TIAB] OR therapeutic*[TIAB] OR clinical[TIAB] OR “balance disorder*”[TIAB] OR balance[TIAB] OR vertigo[TIAB] OR dizz*[TIAB] OR ménière*[TIAB] OR tinnitus[TIAB] OR ear[TIAB] OR otolog*[TIAB] OR hear*[TIAB] OR pressure*[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 betahistine HCl or the implementation of betahistine HCl 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 betahistine HCl 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 betahistine HCl 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 indications from the nomination and the results of the literature review, four (4) medical specialties that would potentially use betahistine HCl were identified: endocrinology, naturopathy, neurology, and otolaryngology. 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. Three (3) experts were contacted for interviews, of which one (1) accepted and two (2) declined interviews. The interview was 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 (FDA) 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 endocrinology, naturopathy, neurology, and otolaryngology, identified from the nominations, 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 survey was created using Qualtrics® software (Provo, UT). The survey link was distributed to eight (8) 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. Betahistine HCl was included on one (1) survey distributed to the association in Table 1. Due to the identification of additional substances relevant to this association, betahistine HCl was included on a survey with boric acid, deoxy-d-glucose, DMPS, edetate disodium (EDTA), pitcher plant, and tranilast. Participation was anonymous and voluntary. The estimated time for completion was 30 minutes with a target of 50 responses per survey. The Office of Management and Budget (OMB) approved this project.

Table 1. Participating associations

Specialty Association

Naturopathy American Association of Naturopathic Physicians (AANP)

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Table 2. Associations that declined participation

Specialty Association Reasons for Declining

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

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

American Academy of Neurology Neurology Failed to respond (AAN)

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

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

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

CURRENT AND HISTORIC USE Summary of background information • Betahistine HCl is not an FDA-approved product. • Betahistine HCl is not available as an OTC product in the US. • There is a current United States Pharmacopeia (USP) monograph for betahistine HCl. • Betahistine HCl is available in all 12 foreign regulatory databases searched. In Hong Kong, all betahistine HCl products are available OTC. Table 3. Currently approved products – US

No approved products in the US

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

Approved For Use Active Concentration Dosage Form ROA Ingredientb Country Status Approval Datec

Australia 11/05/1997

Belgium 07/15/1970

Canada 08/17/2001

EU 06/02/2009

Ireland Prescription 04/01/1979 8mg, 16mg, Betahistine HCl Tablet Oral Latvia 02/16/2000 24mg New Zealand 05/04/2000

Saudi Arabia –

UK 10/07/1998

Abu Dhabi – – Namibia 08/18/2004 Abbreviations: “–“, not mentioned; ROA, route of administration. aMedicine registers of national regulatory agencies were searched if they met the following criteria: freely accessible; able to search and retrieve results in English language; and desired information (product trade name, active ingredient, strength, form, ROA, and approval status) provided in a useable format. Information was recorded only for products with strengths, forms, and/or ROAs similar to those requested in the nominations. See Methodology for full explanation. bBetahistine HCl used as standard for name variations, including betahistine dihydrochloride and betahistini dihydrochloridum. cIf multiple approval dates and/or multiple strengths, earliest approval date provided.

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Summary of literature review • Total number of studies included: 63 studies (6 descriptive, 52 experimental, and 5 observational studies). • Most of the studies were from the Netherlands (7 studies), UK (7 studies), Italy (6 studies), US (6 studies), and multiple countries (6 studies). • There was not a most common indication in the US. One US study discussed the use in Meniere’s disease. • From the non-US studies, the most common indications were vertigo, Meniere’s disease, and tinnitus. • No compounded products were identified from any studies.

Table 5. Types of studies

Types of Studies Number of Studies

Descriptive1-6 6

Experimental7-58 52

Observational59-63 5

Table 6. Number of studies by country

Country Number of Studies

Austria45 1

Belgium6 1

Bosnia40 1

Brazil60 1

Bulgaria38,50 2

Canada16,59 2

Croatia30 1

Czech Republic26 1

Finland7 1

France22,23 2

Germany9,54,61 3

India29 1

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Iran27,48 2

Ireland55 1

Italy10,18,19,31,43,62 6

Malaysia25 1

Poland28,32 2

Russia53 1

Spain14 1

Switzerland39 1

The Netherlands2,5,24,33,34,37,44 7

Turkey13,15,35,47 4

UK3,4,17,20,21,52,58 7

US1,11,12,42,46,57 6

Multiple Countries • Czech Republic and Germany51,63 • Finland and Denmark8 • France and Switzerland41 7 • Ireland and the Netherlands56 • Russia and Ukraine36 • The Netherlands and UK49

Total US: 6 Total non-US Countries: 57

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

Arteriosclerotic dementia46 36mg/day – – Oral 6 months

Meniere’s disease1 24mg/day 8mg – Oral 9 months

Motion sickness57 4mg/day – Capsule – –

Obesity11 48-144mg/day 16-48mg Capsule Oral 3 days

Peripheral vascular disease12 4-16mg/day – – Oral 4 days

Vertebrobasilar arterial insufficiency with 32mg/day 4mg Tablet – 6 weeks dementia42 Abbreviations: “–“, not mentioned; ROA, route of administration

Table 9. Dosage by indication – non-US countries

Indication Dose Concentration Dosage Form ROA Duration of Treatment

Vertigo2,4,10,14,17,18,21- 2-72mg/day 8-24mg Capsule, tablet Oral 10 days-at most 1 year 23,25,27,30,31,33,36,39,45,50,52-54,58

Meniere’s disease3,5- 24-480mg/day 8-24mg Capsule, tablet Oral 1 week-at least 10 years 9,16,19,24,39,40,44,48,51,55,56,58,59,61-63

Tinnitus15,26,35,43,47,60 32-144mg/day 24mg Capsule, tablet Oral 6 weeks-6 months

Hearing loss13,32,43,49 24-48mg/day 8mg Tablet – 2 weeks-at most 4 years

Induced vestibular nystagmus20,34 8-32mg/day 8mg Capsule Oral 3 days

Vestibular disorders39,60 24-144mg/day 8-16mg – – 42-120 days

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Auditory and vestibular disturbances38 24-48mg/day – Tablet Oral 45 days

Cerebrovascular disease37 24mg/day 8mg – – 8 weeks

Vertebrobasilar insufficiency28 24-48mg/day – – Oral 120-180 days

Unilateral vestibular loss41 48mg/day 24mg – Oral 90 days

Unilateral vestibular paralysis39 24mg/day 8-16mg – – 6 weeks 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. Two (2) otolaryngologists were contacted for interviews. One (1) otolaryngologist referred us to a colleague. The referred otolaryngologist indicated interest but did not respond to interview requests.

Table 12. Overview of interviewee

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

Endocrinology, Diabetes and END_02 MD Academic medical institution No • Does not use betahistine Metabolism Abbreviation: MD, Doctor of Medicine

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Summary of survey results Table 13. Characteristics of survey respondents [6 people responded to the surveya]

Board Certification ND No Response

Fellow of the American Board 1 0 of Naturopathic Oncology

Naturopathic Doctor 3 0

Naturopathic Physician 3 0

No Response 0 2 Abbreviation: ND, Naturopathic Doctor. aSome respondents reported more than one terminal clinical degree or one board certification.

Table 14. Types of products used, prescribed, or recommended No survey respondents provided information for this section

Table 15. Compounded use of betahistine HCl in practice No survey respondents provided information for this section

Table 16. Indications for which betahistine HCl is considered a standard therapy No survey respondents provided information for this section

Table 17. Reasons for using compounded product instead of the FDA-approved products No survey respondents provided information for this section

Table 18. Change in frequency of compounded betahistine HCl usage over the past 5 years No survey respondents provided information for this section

Table 19. Do you stock non-patient specific compounded betahistine HCl in your practice? No survey respondents provided information for this section

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

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CONCLUSION Betahistine HCl (UNII code: 49K58SMZ7U) was nominated for inclusion on the 503B Bulks List for the treatment of balance disorders or to alleviate vertigo symptoms associated with Ménière's disease and tinnitus via oral 4 mg, 8 mg, and 16 mg capsules and liquid formulations. Betahistine HCl is available in all 12 foreign regulatory databases searched. From the literature review, there was not a most common indication in the US. One US study discussed use in Meniere’s disease. From the non-US studies, the most common indications were vertigo, Meniere’s disease, and tinnitus. No compounded products were identified from the studies. The one (1) medical expert interviewed was not familiar with using betahistine HCl. Out of the six (6) survey respondents, zero (0) used betahistine HCl. APPENDICES Appendix 1. References 1. Crowson MG, Patki A, Tucci DL. A Systematic Review of Diuretics in the Medical Management of Ménière's Disease. Otolaryngol Head Neck Surg. 2016;154(5):824-834. 2. Fischer AJ. Histamine in the treatment of vertigo. Acta Otolaryngol Suppl. 1991;479:24-28. 3. James AL, Burton MJ. Betahistine for Menière's disease or syndrome. Cochrane Database Syst Rev. 2001(1):CD001873. 4. Murdin L, Hussain K, Schilder AG. Betahistine for symptoms of vertigo. Cochrane Database Syst Rev. 2016(6):CD010696. 5. Nauta JJ. Meta-analysis of clinical studies with betahistine in Ménière's disease and vestibular vertigo. Eur Arch Otorhinolaryngol 2014;271(5):887-897. 6. Segers JM, Boedts D. Clinical trials of betahistine hydrochloride in the treatment of Ménière's disease. Acta Otorhinolaryngol Belg. 1975;29(5):814-821. 7. Aantaa E. Treatment of acute vestibular vertigo. Acta Otolaryngol Suppl. 1991;479:44-47. 8. Aantaa E, Skinhoj A. Controlled clinical trial comparing the effect of betahistine hydrochloride and prochlorperazine maleate on patients with Meniére's disease. Ann Clin Res. 1976;8(4):284- 287. 9. Adrion C, Fischer CS, Wagner J, Gürkov R, Mansmann U, Strupp M. Efficacy and safety of betahistine treatment in patients with Meniere's disease: primary results of a long term, multicentre, double blind, randomised, placebo controlled, dose defining trial (BEMED trial). BMJ (Clinical research ed). 2016;352:h6816. 10. Albera R, Ciuffolotti R, Di Cicco M, et al. Double-blind, randomized, multicenter study comparing the effect of betahistine and flunarizine on the dizziness handicap in patients with recurrent vestibular vertigo. Acta Otolaryngol. 2003;123(5):588-593. 11. Ali AH, Yanoff LB, Stern EA, et al. Acute effects of betahistine hydrochloride on food intake and appetite in obese women: a randomized, placebo-controlled trial. Am J Clin Nutr. 2010;92(6):1290-1297. 12. Allison RD, Barnes RN. The role of betahistine hydrochloride in the treatment of peripheral vascular arterial disease. Tex Med. 1971;67(11):85-92.

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13. Aslan I, Oysu C, Veyseller B, Baserer N. Does the addition of hyperbaric oxygen therapy to the conventional treatment modalities influence the outcome of sudden deafness? Otolaryngol Head Neck Surg. 2002;126(2):121-126. 14. Ballve Moreno JL, Carrillo Muñoz R, Villar Balboa I, et al. Effectiveness of the Epley's maneuver performed in primary care to treat posterior canal benign paroxysmal positional vertigo: study protocol for a randomized controlled trial. Trials. 2014;15:179. 15. Beriat GK, Ezerarslan H, Akmansu SH, et al. Comparison of efficacy of different treatment methods in the treatment of idiopathic tinnitus. Kulak Burun Bogaz Ihtis Derg.21(3):145-153. 16. Bertrand RA. Meniere's disease: Subjective end objective evaluation of medical treatment with betahistine HCl. Acta Otolaryngol. 1972(SUPPL. 305):48-69. 17. Canty P, Valentine J. Betahistine in peripheral vertigo: a double-blind, placebo-controlled, cross- over study of Serc versus placebo. The Journal of laryngology and otology. 1981;95(7):687-692. 18. Cesarani A. Ginkgo biloba (EGb 761) in the treatment of equilibrium disorders. Adv Ther. 1998;15(5):291-304. 19. Colletti V. Medical treatment in Ménière's disease: avoiding vestibular neurectomy and facilitating postoperative compensation. Acta Otolaryngol Suppl. 2000;544:27-33. 20. Cullen JR, Hall SJ, Allen RH. Effect of betahistine dihydrochloride compared with cinnarizine on induced vestibular nystagmus. Clin Otolaryngol Allied Sci. 1989;14(6):485-487. 21. Deering RB, Prescott P, Simmons RL, Downey LJ. A double-blind crossover study comparing betahistine and cinnarizine in the treatment of recurrent vertigo in patients in general practice. Curr Med Res Opin. 1986;10(4):209-214. 22. Elbaz P. Flunarizine and betahistine. Two different therapeutic approaches in vertigo compared in a double-blind study. Acta Oto-Laryngologica, Supplement. 1989;107(460):143-148. 23. Fraysse B, Bebear JP, Dubreuil C, Berges C, Dauman R. Betahistine dihydrochloride versus flunarizine. A double-blind study on recurrent vertigo with or without cochlear syndrome typical of Menière's disease. Acta Otolaryngol Suppl. 1991;490:1-10. 24. Frew IJ, Menon GN. Betahistine hydrochloride in Méniére's disease. Postgrad Med J. 1976;52(610):501-503. 25. Hashim ND, Abdullah A, Ami M, Rahman RA. Effectiveness of vestibular exercise in acute vertigo. Rawal Medical Journal. 2015;40(1):65-70. 26. Holy R, Prazenica P, Stolarikova E, et al. Hyperbaric oxygen therapy in tinnitus with normal hearing in association with combined treatment. Undersea Hyperb Med.43(3):201-205. 27. Jafarzadeh S, Pourbakht A, Bahrami E, Jalaie S, Bayat A. Effect of early vestibular rehabilitation on vertigo and unsteadiness in patients with acute and sub-acute head trauma. Iranian Journal of Otorhinolaryngology. 2018;30(2):85-90. 28. Kaźmierczak H, Pawlak-Osińska K, Kaźmierczak W. Betahistine in vertebrobasilar insufficiency. The international tinnitus journal. 2004;10(2):191-193. 29. Kirtane MV, Biswas A. Efficacy of Betahistine by Patient-Reported Outcomes and its Tolerability Profile in Indian Patients with Vestibular Vertigo. J Assoc Physicians India. 2017;65(4):18-24. 30. Maslovara S, Soldo SB, Puksec M, Balaban B, Penavic IP. Benign paroxysmal positional vertigo (BPPV): influence of pharmacotherapy and rehabilitation therapy on patients' recovery rate and life quality. NeuroRehabilitation. 2012;31(4):435-441.

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31. Mira E, Guidetti G, Ghilardi L, et al. Betahistine dihydrochloride in the treatment of peripheral vestibular vertigo. Eur Arch Otorhinolaryngol. 2003;260(2):73-77. 32. Narozny W, Sicko Z, Przewozny T, Stankiewicz C, Kot J, Kuczkowski J. Usefulness of high doses of glucocorticoids and hyperbaric oxygen therapy in sudden sensorineural hearing loss treatment. Otol Neurotol. 2004;25(6):916-923. 33. Oosterveld WJ. Betahistine dihydrochloride in the treatment of vertigo of peripheral vestibular origin. A double-blind placebo-controlled study. The Journal of laryngology and otology. 1984;98(1):37-41. 34. Oosterveld WJ. Effect of betahistine dihydrochloride on induced vestibular nystagmus: a double blind study. Clin Otolaryngol Allied Sci. 1987;12(2):131-135. 35. Oz I, Arslan F, Hizal E, et al. Effectiveness of the combined hearing and masking devices on the severity and perception of tinnitus: a randomized, controlled, double-blind study. ORL J Otorhinolaryngol Relat Spec. 2013;75(4):211-220. 36. Parfenov VA, Golyk VA, Matsnev EI, et al. Effectiveness of betahistine (48 mg/day) in patients with vestibular vertigo during routine practice: The VIRTUOSO study. PLoS One. 2017;12(3):e0174114. 37. Pathy J, Menon G, Reynolds A, Van Strik R. Betahistine hydrochloride (Serc) in cerebrovascular disease: a placebo-controlled study. Age Ageing. 1977;6(3):179-184. 38. Petrova D, Sachansca T, Datcov E. Investigation of Betaserc in auditory and vestibular disturbances. Int Tinnitus J. 2004;10(2):177-182. 39. Pfaltz CR, Aoyagi M. Calcium-entry blockers in the treatment of vestibular disorders. Acta Oto- Laryngologica, Supplement. 1989;107(460):135-142. 40. Ramos Alcocer R, Ledezma Rodríguez JG, Navas Romero A, et al. Use of betahistine in the treatment of peripheral vertigo. Acta Otolaryngol. 2015;135(12):1205-1211. 41. Redon C, Lopez C, Bernard-Demanze L, et al. Betahistine treatment improves the recovery of static symptoms in patients with unilateral vestibular loss. J Clin Pharmacol. 2011;51(4):538- 548. 42. Rivera VM, Meyer JS, Baer PE, Faibish GM, Mathew NT, Hartmann A. Vertebrobasilar arterial insufficiency with dementia. Controlled trials of treatment with betahistine hydrochloride. J Am Geriatr Soc. 1974;22(9):397-406. 43. Salvinelli F, Frari V, Rocco ML, Rosso P, Aloe L. Enhanced presence of NGF and mast cells number in nasal cavity after autologous stimulation: relation with sensorineural hearing deficit. Eur Rev Med Pharmacol Sci. 2015;19(3):381-391. 44. Schmidt JT, Huizing EH. The clinical drug trial in Menière's disease with emphasis on the effect of betahistine SR. Acta Otolaryngol Suppl. 1992;497:1-189. 45. Scholtz AW, Hahn A, Pritschow BW, Weisshaar G, Medzhidieva D. Cinnarizine + dimenhydrinate versus betahistine for vertigo. Otolaryngol - Head Neck Surg. 2017;157(1):P237. 46. Seipel JH, Fisher R, Blatchley RJ, Floam J, Bohm M. Rheoencephalographic and other studies of betahistine in humans. IV. Prolonged administration with improvement in arteriosclerotic dementia. J Clin Pharmacol.17(2-3):140-161. 47. Sönmez O, Külahlı I, Vural A, Sahin MI, Aydın M. The evaluation of ozone and betahistine in the treatment of tinnitus. Eur Arch Otorhinolaryngol. 2013;270(7):1999-2006.

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48. Seyed Tootoonchi SJ, Ghiasi S, Shadara P, Samani SM, Fouladi DF. Hearing function after betahistine therapy in patients with Ménière's disease. Braz J Otorhinolaryngol.82(5):500-506. 49. Soucek SO, Stephens SDG, Limburg CM, Kastein TE. Betahistine dihydrochloride in patients with idiopathic progressive sensorineural hearing loss. IRCS Med Sci. 1985;13(1):70-71. 50. Stambolieva K, Angov G. Effect of treatment with betahistine dihydrochloride on the postural stability in patients with different duration of benign paroxysmal positional vertigo. Int Tinnitus J. 2010;16(1):32-36. 51. Strupp M, Hupert D, Frenzel C, et al. Long-term prophylactic treatment of attacks of vertigo in Menière's disease--comparison of a high with a low dosage of betahistine in an open trial. Acta Otolaryngol. 2008;128(5):520-524. 52. Todd PA, Benfield P. Flunarizine. A reappraisal of its pharmacological properties and therapeutic use in neurological disorders. Drugs. 1989;38(4):481-499. 53. Vorobyev PA, Lesnicheva MV, Morozova SV, Suleymanov SS, Sarvilina IV, Kupayev VI. Economical evaluation of different forms of betahistine in patients with vertigo. Value Health. 2010;13(3):A140. 54. Weiser M, Strösser W, Klein P. Homeopathic vs conventional treatment of vertigo: a randomized double-blind controlled clinical study. Arch Otolaryngol Head Neck Surg. 1998;124(8):879-885. 55. Wilmot TJ. An objective study of the effect of betahistine hydrochloride on hearing and vestibular function tests in patients with Ménière's disease. J Laryngol Otol. 1971;85(4):369-373. 56. Wilmot TJ, Menon GN. Betahistine in Ménière's disease. J Laryngol Otol. 1976;90(9):833-840. 57. Wood CD, Graybiel A. Evaluation of antimotion sickness drugs: A new effective remedy revealed. Aerosp Med. 1970;41(8):932-933. 58. Drug treatment of vertigo and Ménière's disease. Cinnarizine and betahistine. Drug Ther Bull. 1981;19(5):17-18. 59. Bertrand RA. Long-term evaluation of the treatment of Menière's disease with betahistine HCl. Adv Otorhinolaryngol. 1982;28:104-110. 60. Ganança MM, Caovilla HH, Gazzola JM, Ganança CF, Ganança FF. Betahistine in the treatment of tinnitus in patients with vestibular disorders. Braz J Otorhinolaryngol.77(4):499-503. 61. Lezius F, Adrion C, Mansmann U, Jahn K, Strupp M. High-dosage betahistine dihydrochloride between 288 and 480 mg/day in patients with severe Menière's disease: a case series. Eur Arch Otorhinolaryngol. 2011;268(8):1237-1240. 62. Monzani D, Barillari MR, Alicandri Ciufelli M, et al. Effect of a fixed combination of nimodipine and betahistine versus betahistine as monotherapy in the long-term treatment of Ménière's disease: a 10-year experience. Acta Otorhinolaryngol Ital. 2012;32(6):393-403. 63. Strupp M, Kraus L, Schautzer F, Rujescu D. Menière's disease: combined pharmacotherapy with betahistine and the MAO-B inhibitor selegiline-an observational study. J Neurol. 2018;265(Suppl 1):80-85.

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Appendix 2. Survey instrument Betahistine HCl

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 betahistine. 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: Betahistine HCl

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

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

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Q2 Please list any conditions or diseases for which you use compounded betahistine 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)

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Q3 Do you use compounded betahistine 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 betahistine as a single agent active ingredient, or as one active ingredien... != Combination

Display This Question: If Loop current: Do you use compounded betahistine as a single agent active ingredient, or as one active ingredien... = Combination

Q4 Please list all combination products in which you use compounded betahistine.

______

Q5 For which, if any, diseases or conditions do you consider compounded betahistine standard therapy?

______

Q6 Does your specialty describe the use of compounded betahistine in medical practice guidelines or other resources?

______

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Q7 Over the past 5 years, has the frequency in which you have used compounded betahistine 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 betahistine instead of any FDA-approved drug product?

______

Q9 Do you stock non-patient-specific compounded betahistine in your practice location?

o Yes

o No

Skip To: End of Block If Do you stock non-patient-specific compounded betahistine in your practice location? = No

Display This Question: If Do you stock non-patient-specific compounded betahistine in your practice location? = Yes

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Q10 In what practice location(s) do you stock non-patient-specific compounded betahistine? 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 betahistine? Please check all that apply.

▢ Purchase from a compounding pharmacy

▢ Purchase from an outsourcing facility

▢ Compound the product yourself

▢ Other (please describe) ______

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Q12 Why do you keep a stock of non-patient-specific compounded betahistine? 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 betahistine? Please check all that app... = Convenience Skip To: End of Block If Why do you keep a stock of non-patient-specific compounded betahistine? Please check all that app... = Emergencies Skip To: End of Block If Why do you keep a stock of non-patient-specific compounded betahistine? Please check all that app... = Other (please describe)

Q13 For which, if any, diseases or conditions do you consider betahistine standard therapy?

______

Q14 Does your specialty describe the use of betahistine in medical practice guidelines or other resources?

______

End of Block: Betahistine HCl

Start of Block: Background Information

25

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)______

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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

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▢ 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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