Center for Drug Evaluation and Research DATE

TO: File

FROM: Center for Drug Evaluation and Research

DATE: March 24, 2021

SUBJECT: Nomination and Review of Clinical Need for Quinacrine Hydrochloride to be Included on the 503B Bulk Drug Substances List

This memorandum reflects the discussions of the 503B Working Group, comprised of representatives from the following: CDER Office of New Drugs, Office of Pharmaceutical Quality, Office of Regulatory Policy, Office of Compliance, and Office of Regulatory Affairs.

The Food and Drug Administration (FDA or Agency) is developing a list of bulk drug substances that can be used in compounding by outsourcing facilities under section 503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 353b). Section 503B of the FD&C Act describes the conditions that must be satisfied for drug products compounded by an outsourcing facility to be exempt from requirements concerning FDA approval prior to marketing (section 505 (21 U.S.C. 355)); labeling of drugs with adequate directions for use (section 502(f)(1) (21 U.S.C. 352(f)(1))); and drug supply chain security requirements (section 1 582 (21 U.S.C. 360eee-1)).

To qualify for the exemptions available in section 503B of the FD&C Act, a drug product must be compounded in an outsourcing facility that does not compound using bulk drug substances unless: (1) the bulk drug substance appears on a list established by the Secretary of Health and Human Services identifying bulk drug substances for which there is a clinical need (the 503B Bulks List), or (2) the drug compounded from such bulk drug substances appears on the drug shortage list in effect under section 506E of the FD&C Act (21 U.S.C. 356e) at the time of compounding, distribution, and dispensing.

Quinacrine hydrochloride (referred to as “quinacrine” in this document) is nominated by FDA for inclusion on the list of bulk drug substances for use in compounding under section 503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act) based on the Agency’s identification of

1 In general, drug products compounded under the conditions in section 503B must meet current good manufacturing practice (CGMP) requirements in section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)(B)). Outsourcing facilities are also subject to FDA inspections according to a risk-based schedule, specific adverse event reporting requirements, and other conditions that help to mitigate the risks of the drug products they compound. Outsourcing facilities may or may not obtain prescriptions for identified individual patients and can, therefore, distribute compounded drugs to healthcare practitioners for “office stock,” to hold in their offices in advance of patient need.

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a potential clinical need for its use in treating cutaneous lupus erythematosus (CLE). We evaluated quinacrine for potential inclusion on the 503B Bulks List under the clinical need standard in section 503B, consistent with the interpretation and policies described in FDA’s March 2019 guidance, “Evaluation of Bulk Drug Substances Nominated for Use in Compounding Under Section 503B of the Federal Food, Drug, and Cosmetic Act” (the Clinical Need Guidance). Because quinacrine is not a component of an FDA-approved drug, we did not ask the questions in the Part 1 analysis described in the Clinical Need Guidance. Consistent with the Part 2 analysis in the Clinical Need Guidance, we have considered data and information regarding the physical and chemical characterization of quinacrine, safety issues raised by use of this substance in compounding, available evidence of effectiveness or lack of effectiveness, and historical and current use in compounding.2

For the reasons stated below, we conclude that the Agency should propose adding the bulk drug substance quinacrine to the 503B Bulks List with a limitation for oral use only.

I. Background

A. Nominated Product

Quinacrine was previously reviewed in 2016 as part of FDA’s consideration of this bulk drug substance for inclusion on the list of bulk drug substances for use in compounding under section 503A of the FD&C Act (503A Bulks List).3 As part of this review:

 The Division of Anti-Infective Products (DAIP), now the Division of Anti-Infectives (DAI), recommended that quinacrine not be added to the 503A Bulks List for nominated uses as an antimalarial, antiprotozoal and anti-tapeworm drug (see Appendix A). Due to the effectiveness of other drugs and non-drug treatments for those indications, as well as safety concerns associated with quinacrine, the review identified treatment of refractory giardiasis as the primary anti-infective use of quinacrine, and this use occurred almost exclusively outside the U.S. The review noted that the risk-benefit considerations of this substance might be weighted differently for other treatment areas.

 The Division of Pulmonary, Allergy and Rheumatology Products (DPARP), now the Division of Rheumatology and Transplant Medicine (DRTM), recommended that quinacrine be added to the 503A Bulks List because of the data supporting the effectiveness of quinacrine in treating CLE and systemic lupus erythematosus (SLE) and

2 See Federal Food, Drug, and Cosmetic Act §503B(a)(2)(a) and FDA’s guidance titled “Evaluation of bulk Drug Substances Nominated for Use in Compounding Under Section 503B of the Federal Food, Drug, and Cosmetic Act” available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/evaluation-bulk-drug- substances-nominated-use-compounding-under-section-503b-federal-food-drug-and). 3 See: https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompounding AdvisoryCommittee/UCM486146.pdf for the Background Package that FDA prepared for the March 8-9, 2016 PCAC meeting. More information about the PCAC meeting can be found at: https://www.fda.gov/advisorycommittees/pharmacy-compounding-advisory-committee/2016-meeting-materials-pharmacy-compounding- advisory-committee.

the expectation that serious safety issues, including aplastic anemia, could be addressed with appropriate dosing and monitoring by clinical specialty prescribers (see Appendix B).4

 The Division of Bone, Reproductive and Urologic Products (DBRUP), now the Division of Urology, Obstetrics and Gynecology (DUOG), evaluated the nomination of quinacrine for intrauterine administration for non-surgical female sterilization and recommended that quinacrine should not be included on the 503A Bulks List this use (see Appendix C). This recommendation was based on the lack of information on efficacy comparable to other available methods of female sterilization and serious safety concerns of mutagenicity, cytotoxicity and possible carcinogenicity in use of quinacrine for this indication and route of administration.

 An OND summary memo recommended that quinacrine not be added to the 503A Bulks List (see Appendix D). In “balancing” four criteria as required by regulation (physical and chemical characterization, safety, efficacy, and history of use),5 the memo cites serious adverse effects that can be associated with quinacrine. The summary noted that, while OND believed many rheumatologists are familiar with quinacrine’s serious adverse effects, placing quinacrine on the 503A Bulks List would allow prescribers without the same specialized knowledge to use it as well. OND also expressed concern with the fact that safety labeling would not be required for compounded quinacrine under 503A. The memo therefore recommended that quinacrine be available to patients under an expanded access investigational new drug (IND) application.

Quinacrine was presented to the Pharmacy Compounding Advisory Committee (PCAC) on March 8, 2016. The PCAC vote in response to the question “Should quinacrine hydrochloride be placed on the (503A) list?” was YES: 5, NO: 6, ABSTAIN: 0. The public record from the PCAC meeting contains support by individual clinical specialists, patients and associations, including the American Academy of Dermatology Association, for the availability of compounded quinacrine for the treatment of CLE.6 As of the date of this memo, FDA has not issued a proposed rule addressing whether quinacrine should be included on the 503A Bulks List.

FDA is nominating quinacrine HCl in oral dosage forms at strengths of 25 – 100 mg for the treatment of cutaneous lupus erythematosus.7 FDA believes that there is a well-defined population who appear to benefit from quinacrine (patients with CLE). As described in the review below, there is a significant body of evidence in the scientific literature regarding the safety profile of quinacrine, including compounded quinacrine and data supporting the potential

4 The DPARP memo is a general statement about the available evidence supporting the effectiveness of different drug products for the treatment of CLE and SLE based on studies reported in the literature that were performed under a variety of conditions and with differing evidentiary value. While these data support the conclusion that there may be a clinical need for drug products compounded from quinacrine, it does not reflect a judgment that any particular drug product is safe and effective and would thus meet the approval standard under section 505 of the FDCA. 5 21 CFR 216.23(c). See also 84 FR 4696 for additional information. 6 Appendix F: Comments submitted for the March 8 and 9, 2016 PCAC Meeting 7 Appendix G: FDA’s nomination of quinacrine for the 503B Bulks List 3

effectiveness of compounded drug products containing quinacrine, especially in patients with CLE, and patients who are not fully clinically responsive to, or are intolerant of, treatment with FDA approved products alone. These patients may respond to use of quinacrine with other drugs, or to the use of quinacrine alone. The historic use of quinacrine in such cases, as documented in the scientific literature, provides support for a finding that there is a clinical need for quinacrine. Quinacrine has a long history of being used in compounded products, appears to be effective in this distinct population of patients, and it has a well characterized safety profile. Subsequent to the 2016 PCAC meeting, and after discussions with other government agencies, investigators treating CLE patients using quinacrine, and pharmaceutical company representatives, FDA was not able to identify an entity willing to submit an IND for quinacrine for treatment of CLE. To date, no IND has been submitted for quinacrine, and it has become evident that the IND process will not be a realistic option to make quinacrine available for patients with CLE. In support of its nomination and evaluation of quinacrine HCl for the 503B Bulks List, FDA reviewed the materials prepared for the 2016 PCAC meeting as well as relevant literature and safety information published or submitted to FDA since the 503A evaluation.

FDA is not nominating quinacrine for use in non-surgical female sterilization and treatment of infectious disease.

A. Non-surgical female sterilization

The 503A review by (then) DBRUP recommended that quinacrine not be included on the 503A Bulks List, given that quinacrine is known to be genotoxic and cytotoxic. The review cited an October 14, 1998, warning letter issued by FDA requesting that unapproved quinacrine pellets for non-surgical female sterilization be immediately removed from the market.8 In addition, the review concluded there was “lack of compelling evidence of efficacy” that (use of quinacrine) is at least comparable to currently available methods of female sterilization, such as surgical procedures. The World Health Organization’s 2009 interim statement, recommending that “quinacrine should not be used for non-surgical sterilization of women either in clinical or research settings” has not been updated or removed as of the date of this review.9 Quinacrine use for female chemical sterilization was placed by FDA in Category 2 for purposes of FDA’s Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A in 2016, as having significant safety risks.10

FDA conducted a literature review of PubMed to identify articles published between January 1, 2016 and October 8, 2020 that provided updates from 503A review and 2016 PCAC about quinacrine’s use in this indication. FDA reached the decision not to nominate quinacrine for this use based on both the 2016 503A reviews and the 2020 literature update, as summarized here.

8 Division of Reproductive and Urologic Drug Products (DRUDP), 1998, Health Hazard Evaluation Summary of a Kit for Intrauterine Insertion of Quinacrine Hydrochloride Pellets for Female Sterilization, log number DRUDP 137, available at https://www.fda.gov/media/96263/download. 9 https://apps.who.int/iris/handle/10665/70085 10 https://www.fda.gov/drugs/human-drug-compounding/safety-risks-associated-certain-bulk-drug-substances- nominated-use-compounding 4

There were three articles identified in the previously described literature review related to quinacrine’s use as a chemical sterilization agent. Lawrie (2016) updated the 2011 Cochrane Library review first published in 2002. Of the 19 randomized, controlled trials investigating techniques for the interruption of tubal patency for female sterilization, none involved the use of chemical inserts, including quinacrine. Jones et al. (2017, 2018) completed a retrospective cohort study of a population of Vietnamese women who underwent sterilization or contraception procedures between 1989 and 1996. These patients were interviewed regarding health outcomes approximately 16 years post exposure to compare the quinacrine pellet system (10503 interviews) versus intrauterine devices (9204 interviews) or tubal ligation (1333 interviews) for contraception. A 95% response rate based on the treated population resulted in a total of 21,040 interviews and found no significant excess of long-term risk of reproductive tract cancer, hysterectomy or ectopic pregnancy associated with quinacrine. These data updates do not provide adequate evidence regarding the safety profile for intrauterine quinacrine and the potential effectiveness of drugs compounded from quinacrine for female chemical sterilization such that FDA would depart from DBRUP’s 2016 findings and recommend adding quinacrine to the section 503B Bulks List for this use.

B. Giardiasis

The 2016 DAIP review regarding quinacrine’s use to treat infectious disease found that use of quinacrine is predominantly for cases of giardiasis that are refractory to other treatments and that these cases occur predominantly outside of the U.S., in Europe. FDA conducted a literature review of PubMed to identify articles published between January 1, 2016 and October 8, 2020 that provided updates from 503A review and 2016 PCAC about quinacrine’s use in this indication. FDA reached the decision not to nominate quinacrine for this use based on both the 2016 503A reviews and the 2020 literature update, as summarized here. The literature update review identified five articles regarding the use of quinacrine in the treatment of nitroimidazole (such as metronidazole) refractory giardiasis (Carter et al. 2018; Escobedo et al. 2017; Lalle and Hanevik 2018; Laynez-Roldan et al. 2017; Requena-Mendez et al. 2017). Two articles describe the use of a variety combination drug therapies, some combinations including quinacrine, for use in treating refractory giardiasis (Cañete et al. 2020; Escobedo et al. 2016). Consistent with the 2016 DAIP review, this literature update does not provide information on which to base a recommendation that quinacrine is clinically needed to treat refractory giardiasis in the U.S.

Because these indications have not been nominated by FDA, we do not consider them in our evaluation of quinacrine for placement on the 503B Bulks list.

II. Evaluation

A. Physical and Chemical Characterization

We agree with the conclusions in the February 3, 2016 memorandum to the PCAC that there are no chemistry or physical characterization issues that would preclude quinacrine from being compounded, and that quinacrine can be obtained in a highly pure form and is stable when

protected from light.11 Although the 503A review did not specify any proposed dosage forms, it does identify that quinacrine is mutagenic and genotoxic, and its potential impurities may be as well. An updated review of relevant information related to the physical and chemical characterization of quinacrine as an oral dosage form to treat CLE did not identify any further concerns.12

B. Safety Issues Raised by Use of the Substance in Compounding

We believe that the safety profile of quinacrine is essentially unchanged since the record developed for the March 2016 PCAC meeting. The 2016 DAIP 503A review described safety information from labeling of the previously marketed single ingredient Atabrine (quinacrine) tablet, which was not FDA approved and was discontinued by the manufacturer due to lack of sales in 1995. Additional information from the published literature was provided for most adverse events.13

The 2016 review from DPARP provided a detailed discussion of the safety of quinacrine when used to treat cutaneous and/or systemic lupus.14

The most frequently reported adverse reactions associated with quinacrine HCl include diarrhea, nausea, vomiting, abdominal pain, headache, and yellowing of the skin and mucous membranes. Rare cases of transient lupus-associated quinacrine HCl-induced hepatitis and peritonitis have been reported, although these were attributed to doses three-fold higher than the generally recommended dose of 100 mg daily. At higher doses, patients have reported restlessness, vertigo, insomnia, nightmares, hyperirritability, and convulsions. Several publications have reported quinacrine HCl-induced psychosis ranging from 0.1-0.4% of patients. Although rare, the most serious potential toxicity associated with quinacrine HCl is aplastic anemia, which was observed at a rate of between 0.66-2.84 cases/100.000 soldiers treated with quinacrine HCl during World War II. One third of these cases were determined to be due to quinacrine HCl overdose or concomitant drugs known to be associated with aplastic anemia. Approximately 70% of the remaining cases were associated with patients presenting with lichenoid tissue reactions several months prior to the onset of aplastic anemia. Therefore the rate of aplastic anemia in patients treated with quinacrine HCl who did not present with a lichenoid reaction is approximately 1 case/500,000 patients.

Like quinacrine, hydroxychloroquine and chloroquine, which are also used in the treatment of cutaneous and/or systemic lupus, have been associated with serious side effects such as hematologic effects (e.g. reversible agranulocytosis and aplastic anemia) and neurologic effects (e.g. psychosis, seizures). Because quinacrine does not appear to cause retinopathy, which is

11 See OND memo at 2, DAIP memo at 4. 12 Currently, neither a drug substance nor a Compounded Preparation Monograph (CPM) for quinacrine HCl is available in the United States Pharmacopeia (USP-NF). The USP-NF previously contained a drug substance monograph for quinacrine HCl and a drug product monograph for quinacrine HCl oral tablets (USP-NF 1990), but those monographs were deleted from the USP-NF after Atabrine, an unapproved quinacrine tablet, was withdrawn from the U.S. market in 1995. Quinacrine HCl does not appear on the list of drug products that were withdrawn for reasons of safety or effectiveness (21 CFR 216.24). 13 The appendix includes an excerpt of the safety summary from the DAIP review memo. 14 Appendix B: DPARP Review at 3. 6

dose-related and irreversible with hydroxychloroquine and chloroquine, it is not uncommon for rheumatologists to add quinacrine when a patient appears to require additional antimalarial therapy and increasing the dosage of hydroxychloroquine or chloroquine is not desirable due to the concern for retinal toxicity.

In October 2020, FDA conducted a literature search of PubMed using the search term “quinacrine” to update the safety information contained in the 503A reviews prepared for the 2016 PCAC meeting and the 2016 PCAC discussions. That search identified 155 articles published between January 1, 2016 and October 8, 2020. Of these, 22 pertaining to safety or effectiveness of quinacrine use in CLE are discussed in this review. Most of the adverse events identified in recent literature have been previously linked to quinacrine use, including the following:

Transitory psychosis – Pedapudi et al. (2020) described a case of psychiatric symptoms in a patient treated for giardia. The symptoms resolved when the drug was stopped, recurred when the drug was reintroduced and finally resolved when the drug was discontinued. Another case report was of a patient with CLE who received quinacrine therapy and experienced a change in her mental status with auditory hallucinations and other symptoms after 8 months of use (Al Osiami et al. 2017). Resolution of her primary symptoms occurred by approximately 3 months after discontinuation of quinacrine.

Dermal effects – A case of hyperpigmentation induced by hydroxychloroquine and quinacrine was reported in a patient with systemic lupus erythematosus and a literature review was conducted (Kwak and Grimes 2020).

General – Mittal et al. (2018) conducted a retrospective cohort study of 532 patients with either CLE or dermatomyositis, treated at the Hospital of the University of Pennsylvania beginning treatment between January 2007 and January 2008, and continuing through August 2016. Treatment with quinacrine only (i.e., not in combination with hydroxychloroquine or chloroquine) was associated with few adverse effects. Those reported were gastrointestinal upset and dyspigmentation. There were no reports of retinal toxicity. The authors directly address concerns expressed at the 2016 PCAC regarding the occurrence of aplastic anemia and hepatitis, indicating that these were not observed in the study.

There were several adverse events identified in FDA’s 2020 literature review that may not have been previously associated with quinacrine. Each adverse event not previously associated with quinacrine is based on a single patient case report. We intend to consider these for inclusion in any safety communications that are made available to healthcare practitioners and patients if quinacrine is included on the 503B Bulks List.

o Mepacrine-induced interstitial lung disease in discoid lupus erythematosus (Waas and Meggitt 2018) o Chloroquine neuromyotoxicity case report in a patient with refractory discoid lupus erythematosus potentiated by concomitant use of mepacrine (Winn et al. 2018) o Quinacrine-associated punctate palmar keratoderma (Haag et al. 2018)

There was no review of FAERS data described in the 503A reviews for quinacrine prepared for the 2016 PCAC meeting. A search of the FAERS public dashboard returned 112 cases associated with “quinacrine” or “quinacrine hydrochloride” between 1970 and June 30, 2020. The most frequently reported “reaction”15 was psychotic disorder (n = 16), followed by headache (n = 10), diarrhea (n = 9) and pyrexia (n = 8). Of the 112 cases, 89 reactions were reported to have been severe and death was the reported outcome in seven cases. Quinacrine was listed as the only suspect product active ingredient in two cases for which death was the reported outcome. In one case reactions were reported to be pseudolymphoma, sepsis, hepatomegaly and abdominal pain. In the second case, there were no reactions listed other than death. Quinacrine is known to be associated with aplastic anemia, but this reaction was not reported among the FAERS cases. Reported reactions in the reaction group “blood and lymphatic symptom disorders” included pancytopenia (n = 13), leukopenia (n = 4), bone marrow failure (n = 6), lymphopenia (n = 5), methemoglobinemia (n = 1), hemolytic anemia (n = 1), pseudolymphoma (n = 2), anemia (n = 1) and coagulopathy (n = 1).

In light of the foregoing, it is FDA’s view that the safety profile of the quinacrine is essentially the same as when quinacrine was evaluated and discussed at 2016 PCAC.

Due to the safety concerns outlined above, if FDA places quinacrine on the 503B Bulks List, FDA intends to make safety information about the use of quinacrine HCl available to prescribers, pharmacists, outsourcing facilities, and the public through information on FDA’s website, in a safety guide, or through other mechanisms, as appropriate. The warnings to enhance safe use and the adverse events identified in the DAIP’s 2016 review (referenced above and at Appendix A) would be included in this safety information.

C. Available Evidence of Effectiveness or Lack of Effectiveness

We agree with the conclusions in the 2016 DPARP review that there is evidence supporting the effectiveness of quinacrine as adjunctive treatment to other commonly used FDA-approved drugs for the treatment of CLE or as a single agent to treat patients who are intolerant of FDA- approved drugs. Clinical data that have become available since the 2016 DPARP review provide additional support for that conclusion.

CLE16 is an autoimmune disease affecting the skin. Hejazi and Werth (2016) state that CLE has “a broad range of dermatologic manifestations, which may or may not be associated with systemic disease.” The incidence of CLE has recently been reported for the population of Olmsted County, Minnesota between 1964 and 2005 as 4.30 per 100,000 (Durosaro et al. 2009).

15 Reaction is a suspected side effect, adverse event or adverse drug reaction reported by the reporter. Cases may contain more than one reaction. https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event- reporting-system-faers-public-dashboard 16 Because quinacrine HCL was only nominated by FDA for use in CLE, FDA has not evaluated the clinical need for compounded quinacrine HCl to treat systemic lupus erythematosus, including articular manifestations, lupus erythematosus tumidus, dermatomyositis, or other conditions. This should not be interpreted as FDA’s assessment of the safety or effectiveness of the use of quinacrine in treating conditions that were not raised in the nomination. 8

The studied population is predominantly white, but CLE affects all races and both sexes. CLE is generally separated into three types: acute, subacute and chronic (predominantly discoid) lupus, each of which can be exacerbated by exposure to ultraviolet radiation (Eastham and Vleugels 2014). The pathophysiology is not fully characterized, but CLE is known to be a heterogeneous disease resulting from a combination of genetics, environmental exposure, including certain drugs, and immune dysregulation (Achtman and Werth 2015).

The 2016 DPARP review described case series and observational studies that supported the effectiveness of quinacrine in CLE, including the discoid LE subtype. In many cases, patients who have not achieved a satisfactory clinical response to FDA approved hydroxychloroquine are prescribed quinacrine and find better treatment response by taking both drugs simultaneously. The following is an excerpt from the DPARP memo.17

Several review articles report a large case series involving 771 patients with discoid lupus erythematosus who were enrolled from 1940 to 1961 and described improvement with quinacrine HCl in 73% to 85% of patients (Dubois 1978; Wallace 1989). More recent data support the use of quinacrine HCl in combination with hydroxychloroquine in patients with cutaneous lupus erythematosus. Chang et., al (2011) conducted a prospective analysis in 128 patients with cutaneous lupus erythematosus and concluded that the addition of quinacrine HCl 100 mg/d with standard doses of hydroxychloroquine was associated with an improved clinical response in patients who failed hydroxychloroquine monotherapy. Similarly, Cavazzana et., al (2009) evaluated the efficacy of hydroxychloroquine and quinacrine HCl combination therapy in the treatment of lupus skin lesions in patients refractory to hydroxychloroquine monotherapy. Thirty-four patients were treated with hydroxychloroquine 5 mg/kg/d (n=34) and either quinacrine HCl 100 mg/d (n=29) or quinacrine HCl 50 mg/d (n=5). A total of 29 of the 34 (85%) of patients demonstrated a clinical improvement with a more rapid response seen in patients receiving quinacrine HCl 100 mg/d compared to the 50 mg/d group. The authors concluded that the combination of hydroxychloroquine and quinacrine HCl was an effective therapy in the treatment of lupus skin lesions unresponsive to hydroxychloroquine alone. Three additional studies supporting the use of quinacrine HCl in combination with chloroquine or hydroxychloroquine were referenced in review articles. but these were not readily available for independent review (Chung et al., 1997; Feldmann et al., 1994; Von Schmiedeberg et al., 2000).

The 2016 DPARP review noted that quinacrine has not been evaluated in prospective, well- controlled, double-blinded studies with prespecified endpoints, although the use of quinacrine is recommended in “the scientific literature, major rheumatologic text books, and online medical reference sites.”

The 2016 DPARP review also noted the recommendation by some in the rheumatology community to add quinacrine HCl to hydroxychloroquine therapy to prevent ocular toxicity of hydroxychloroquine.18

17 Appendix B: DPARP Memo at 5-6 18 Id. at 6. 9

Most recently, McCune and Gonzalez-Rivera (2015) have proposed that the addition of quinacrine HCl to hydroxychloroquine therapy should be seriously considered as long-term maintenance therapy of remission in patients with systemic lupus to reduce ocular toxicity.

FDA’s 2020 literature review update identified several articles that provided additional information about the effectiveness of quinacrine in the treatment of CLE.

Mechanism of action – As discussed above, CLE is characterized as a heterogeneous disease whose pathology has not been fully worked out. Ongoing efforts to understand the disease include assessment of drug actions on the disease. Quinacrine has been shown to suppresses tumor necrosis factor-α and IFN-α, proinflammatory cytokines in CLE, to a greater degree than hydroxychloroquine suggesting that the two drugs may have different mechanisms of action (Alves et al. 2017). Further investigation from this group suggests that patients with increased myeloid dendritic cell population, and higher TNF-α expression, “may contribute to hydroxychloroquine refractoriness and a better response to quinacrine” (Zeidi et al. 2019). This information emphasizes the complexity of CLE pathogenesis and quinacrine’s pharmacologic activity and supports the utility of quinacrine in the treatment of CLE.

Clinical use of quinacrine for CLE – Several articles were identified in FDA’s 2020 literature review update that reported use of quinacrine in treatment of CLE. Articles reviewed by FDA also included positive outcomes and guidelines for selecting drug treatments for CLE among numerous options, none of which are FDA approved for that indication.

 Pathogenesis of CLE is an area of active research and is expected to guide future drug development (Patel et al. 2020; Stannard and Kahlenberg 2016).

 Yan et al. (2020) states, “Antimalarials have played a central role in the treatment of CLE over the past several decades. Quinacrine in particular has been an important adjuvant therapy when a single antimalarial agent is unable to control CLE”. The authors review the use of alternatives to quinacrine given that the API has not been available for importation into the U.S. since early 2019 and is not currently manufactured in the U.S. While identifying targeted therapies that are currently being developed and are not yet FDA- approved, the authors conclude that “it would greatly benefit patients with CLE to have access to quinacrine as a potential treatment again”.

 A recently published guideline includes quinacrine in the treatment options for the treatment of CLE (Kuhn et al. 2017). This guideline was developed by the European Dermatology Forum in cooperation with the European Academy of Dermatology and Venereology. It describes in general that CLE treatment, depending on disease severity, may be treated initially with topical corticosteroids. If inadequate response is observed, hydroxychloroquine or chloroquine are added, followed by quinacrine. All of these are considered to be “first- line” treatments. Second and third line treatments may or may not continue the use of quinacrine.

 The addition of mepacrine (quinacrine) to hydroxychloroquine, in patients with and without corticosteroids for treatment of refractory CLE, was found to increase therapeutic response and, in some patients, reduce the need for corticosteroid use (Ugarte et al., 2018a, Ugarte et al., 2018b).

 An international survey of practitioners who treat CLE patients resulted in 83 completed questionnaires from Japan, Europe, the U.S., Canada and the Republic of South Africa (Reich et al. 2016). The survey data established that a wide variation of drugs from over 13 drug classes may be selected to treat CLE. Practitioners worldwide use personal experience to guide their selections and disease subtype is a major factor in their decisions. The authors concluded that more effort is needed to “harmonize treatment strategies for CLE in order to improve the quality and efficacy of medical care for patients with this disease.”

 Rios-Fernandez et al. (2019) analyzed the clinical response of 38 patients who had been treated with quinacrine between March 2014 and June 2016 at the Hospital San Cecilio in Granada, Spain. Of these, 5 patients were reported to have had clinical symptoms of discoid lupus (DL), a type of CLE, alone. Another 10 patients had discoid lupus, or subacute cutaneous lupus, with other related photosensitive autoimmune diseases. Of the 5 patients with DL alone, 3 responded to treatment with 100 mg/day quinacrine (n = 1) or 100 mg/day quinacrine plus hydroxychloroquine, corticosteroid and methotrexate therapies (n = 2). The other two patients with DL alone did not respond to a therapeutic regimen that included quinacrine. The authors considered outcomes for the all 38 patients and concluded that quinacrine is a useful antimalarial to avoid ocular toxicity with hydroxychloroquine, can be used when other antimalarials are not tolerated, or can be used as an add-on therapy when response to antimalarials therapy is sub-optimal.

 Garcia-Montero et al. (2016) described a case of a 45 year old female who was diagnosed with CLE at age 38 and developed systemic LE in the following 6 years. Treatment with topical and systemic drugs including prednisone, hydroxychloroquine, methotrexate and cholchicine at various times had not controlled her disease. She was started on quinacrine 100 mg/day, added to her existing regimen of cholchicine and hydroxychloroquine. By seven months of treatment she experienced “marked improvement in her skin lesions and a decrease in the frequency and severity of disease flares.”

In FDA’s view, the 2016 DPARP review, as supplemented by the 2020 FDA literature search provides support for the effectiveness of quinacrine, in combination with other therapies, as appropriate, in the treatment of CLE.

D. Historical and Current Use in Compounding

1. Overview of the historical and current use of quinacrine HCl Quinacrine (quinacrine HCl also marketed as Atabrine or mepacrine oral tablets) has historically been used in the treatment of giardiasis, malaria, cutaneous lupus erythematosus (CLE) with or without concurrent systemic lupus, rheumatoid arthritis, and cancer, as well as for female sterilization. Quinacrine is an antimalarial agent that was originally produced in the 1920s. In the 1940s, oral quinacrine, marketed as Atabrine, became heavily used as a malaria treatment

and prophylaxis agent, particularly for U.S. soldiers and Allies in World War II, due to the limited availability of quinine. By the end of World War II, the use of quinacrine in malaria had declined because of the development and efficacy of chloroquine. Atabrine marketing in the United States was discontinued in 1995.19 An injectable formulation of quinacrine was approved in the United States in 1964 for treatment of ascites due to various cancers but marketing of this drug product was discontinued in 1977, and the NDA was withdrawn in 2003.20

In 2019, quinacrine from the only foreign manufacturer shipping the bulk drug substance that was used in compounding in the United States was listed on FDA’s import alert 66-40 because of the firm’s significant deviations from current good manufacturing practices (cGMP) for active pharmaceutical ingredients (API). There has been a lack of availability of quinacrine in the U.S. since importation from that API manufacturer ceased. Based on reported outsourcing facility data from January 2018 to December 2019, one outsourcing facility reported compounding quinacrine HCl 100 mg oral capsules in the six months preceding the January 2018 reporting period.21

2. Length of time the substance has been used in pharmacy compounding

In 1995, Sanofi-Winthrop discontinued the production of quinacrine in the United States (FDA 2016a). Since then, quinacrine drug products have been compounded using the bulk drug substance (Mittal et al. 2018). Werth (2001) describes using quinacrine bulk drug substance to compound oral capsules. Specifically, “for six years dermatologists and rheumatologists have been using these preparations; the Panorama Pharmacy in California will prepare this and actually perform an additional purification step in the process.” Similarly, Smith (2017) reported that “quinacrine is no longer manufactured commercially as a finished drug product but is available in a powder that compounding physicians put into 100-mg capsules.”

The FDA provided a grant to the University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI) to research current and historical use in compounding of various drugs, including quinacrine. M-CERSI completed their review of quinacrine in February 2020 and identified 206 studies for their qualitative synthesis including 72 descriptive, 110 experimental and 24 observational studies.22 Of these, 80 studies were published in the U.S. Compounded products were identified as having been used in 13 of these studies for a variety of uses, but no studies in CLE were described. All 13 studies were published between 1947 and 1983 and provide no information about current quinacrine use. In addition, two of 12 individual professionals who responded to an M-CERSI survey reported that they have recommended or prescribed quinacrine for lupus vulgaris (tuberculosis luposa, a skin infection unrelated to CLE).

19 Atabrine was never approved by FDA for sale in the United States, and it was withdrawn from the market by the sponsor voluntarily. It does not appear on the list of drug products that were withdrawn by FDA for reasons of safety or effectiveness. 21 CFR 216.24. 20 Federal Register /Vol. 68, No. 159 /Monday, August 18, 2003 /Notices, Page 49483, Docket 2003N-0335. 2003. Quinacrine does not appear on the list of drug products that were withdrawn for reasons of safety or effectiveness. See 21 CFR 216.24. 21 See https://www.accessdata.fda.gov/scripts/cder/outsourcingfacility/index.cfm. 22 Appendix H: M-CERSI Report on Quinacrine.

3. The medical condition(s) it has been used to treat

FDA nominated quinacrine for treatment of CLE due to its long history of use in this condition and the safety and effectiveness profile, as discussed above.23 Quinacrine is also used worldwide for the treatment of both infectious and noninfectious diseases, as discussed in the 503A reviews prepared for the 2016 PCAC meeting. For infectious diseases, quinacrine is primarily used as an agent to treat refractory or chronic giardiasis.24 It has also been used as an anti-tapeworm agent. Regarding noninfectious diseases, quinacrine has been used to treat CLE, systemic lupus dermatomyositis, rheumatoid arthritis, refractory pulmonary effusion and pneumothorax. As discussed in the 2016 DBRUP review, intrauterine administration of quinacrine has been used for female sterilization.25

4. How widespread has its use been?

Mittal and Werth (2017) surveyed providers from various institutions within the United States to determine quinacrine prescribing practices and to evaluate the need for continued access to compounded quinacrine. Two rheumatologic skin disease specialists from Texas, “estimated having seen 96 and 30 patients on quinacrine within the last year.” According to the authors, “an academic dermatologist from Utah, prescribed quinacrine to 98 patients over a 3-year period.”

Using retrospective methodology, the authors examined the extent of quinacrine use at the Hospital of the University of Pennsylvania (HUP) (Mittal and Werth 2017). From June 2015 to May 2016, it was found that, out of 899,990 active patients, 241 (0.027%) were prescribed quinacrine and “most prescriptions were ordered by dermatology (n=177) and rheumatology (n=75) with 18 individuals prescribed by multiple departments.” The same authors retrospectively analyzed two NIH-funded prospective longitudinal databases that began in 2007 of patients with cutaneous lupus erythematosus (CLE) (n=421) and dermatomyositis (DM) (n=215). The extent of quinacrine use in these patients was evaluated and approximately half of the patients who used antimalarials (n = 538) were prescribed quinacrine.

5. Recognition of the substance in other countries or foreign pharmacopeias

Availability of quinacrine has been found to be limited in France, Spain, and Germany (Brasseur et al. 2012, Pérez-López et al. 2016 and Benoit and Goebler 2015).

A compendial monograph is not available for quinacrine hydrochloride in the European, British, and Japanese Pharmacopeias.

Conclusion: There is evidence of the historical and current use of quinacrine in compounding as an oral formulation for the treatment of CLE in the U.S. at least since 1995 when the marketing of Atabrine was discontinued. There are no FDA approved products in the U.S.

23 See supra sections I-II.C. See also DPARP Review at Appendix B 24 Appendix A: DAIP Review at 13. 25 Appendix C: DBRUP review. Because the intrauterine dosage form was not nominated, FDA has not addressed it here. 13

IV. Conclusion and Recommendation

FDA nominated quinacrine HCl for the 503B Bulks List to compound drug products for oral use in the treatment of cutaneous lupus erythematosus in patients who are not fully clinically responsive to, or are intolerant of, treatment with FDA approved products alone. The nominated bulk drug substance is not a component of an FDA-approved drug product. We evaluated quinacrine HCl for potential inclusion on the 503B Bulks List under the clinical need standard in section 503B of the FD&C Act, considering data and information regarding the physical and chemical characterization of quinacrine HCl, safety issues raised by the use of this substance in compounding, available evidence of effectiveness, and historical use in compounding.

Quinacrine is well characterized. Although there are concerns about its safety profile in certain patient populations, we believe these risks are well known within the rheumatology and dermatology specialties that most often treat CLE, and the known risks could be controlled with appropriate dosing and monitoring. Quinacrine has been used for several decades to treat systemic and cutaneous lupus, and there is a significant body of experience, documented in the scientific literature, that quinacrine may be effective in the treatment of patients with cutaneous lupus, and patients who are not fully clinically responsive to, or are intolerant of, treatment with FDA approved products alone. These patients may respond to the addition of quinacrine to their existing therapy, or to the use of quinacrine alone. This is a well-defined patient population whose medical needs do not appear to be fully met by any of the approved products.

On balance, the physical and chemical characterization, safety, effectiveness, and historical and current use of quinacrine weigh in favor of including this substance on the 503B Bulks List. Accordingly, we propose adding quinacrine HCl to the 503B Bulks List for oral use only. We have not identified significant evidence to support its use in other routes of administration.

Due to the safety risks referred to above, if quinacrine is placed on the 503B Bulks List, FDA intends to make safety information about the use of quinacrine HCl available to prescribers and patients through information on FDA’s website, in a safety guide, or through other mechanisms, as appropriate.

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APPENDICES

Table of Contents:

Appendix A: Final DAIP Quinacrine Review for 2016 PCAC……………………………….….19 Appendix B: Final DPARP Quinacrine Review for 2016 PCAC………………………………. 36 Appendix C: Final DBRUP Quinacrine Review for 2016 PCAC ……………………...…….….47 Appendix D: OND Quinacrine Summary Memorandum for 2016 PCAC……………...…….… 54 Appendix E: Safety Information from Withdrawn Atabrine (quinacrine) Labeling………....…. 62 Appendix F: Comments Submitted for the March 8 and 9, 2016 PCAC Meeting………….……66 Appendix G: FDA’s Nomination of Quinacrine for the 503B Bulks List ………………….…. 131 Appendix H: M-CERSI Report on Quinacrine…………………...………………………….….136

APPENDIX A:

Final DAIP Quinacrine Review for 2016 PCAC

DEPARTMENT OF HEALTH & HUMAN SERVICES

Food and Drug Administration Silver Spring, MD 20993-0002

DATE: February 3, 2016

FROM: Shrimant Mishra, MD Medical Officer, Division of Anti-Infective Products

Chunchun Zhang, PhD Chemistry Reviewer, Office of New Drug Products Office of Pharmaceutical Quality

Wendelyn Schmidt, PhD Pharmacology/Toxicology Supervisor Division of Anti-Infective Products

THROUGH: Edward Cox, MD MPH Director, Office of Antimicrobial Products

Sumathi Nambiar, MD MPH Director, Division of Anti-Infective Products

Dmitri Iarikov, MD PhD Clinical Team Leader, Division of Anti-Infective Products

Ramesh Sood, PhD, Senior Scientific Advisor (acting), Office of New Drug Products, Office of Pharmaceutical Quality

TO: Pharmacy Compounding Advisory Committee

SUBJECT: Review of Quinacrine Hydrochloride for Inclusion on the 503A Bulk Drug Substances List

I. INTRODUCTION

Quinacrine hydrochloride (HCl) has been nominated for inclusion on the list of bulk drug substances for use in compounding under section 503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act) for use in the treatment of rheumatoid arthritis, lupus, as an antimalarial and an antiprotozoal. This review is focused on the use of quinacrine HCl in infectious disease indications. The use of quinacrine HCl for other indications will be addressed separately.

We have reviewed available data on the physicochemical characteristics, safety, effectiveness, and historical use in compounding of this drug substance related to use as an antimalarial, an antiprotozoal, and an anti-tapeworm drug. For the reasons discussed below, we do not recommend that quinacrine HCl be added to the list of bulk drug substances that can be used to compound drug products in accordance with section 503A of the FD&C Act for use in infectious diseases.

II. HISTORICAL BACKGROUND

Quinacrine HCl is an antimalarial agent that was originally produced in the 1920’s. In the 1940’s, oral quinacrine HCl, marketed as Atabrine, became heavily used as a malaria treatment and prophylaxis agent, particularly for U.S. soldiers and Allies in World War II, due to the limited availability of quinine. By the end of World War II, its use in malaria had declined because of the development and efficacy of chloroquine. Atabrine marketing was discontinued in 1995. An injectable formulation of quinacrine HCl was approved in the United States in 1964 for treatment of ascites due to various cancers but marketing of this drug product was discontinued in 1977, and the NDA was withdrawn in 2003 (Health Hazard Evaluation, 1998; Federal Register 2003).

III. EVALUATION CRITERIA

A. Is the substance well-characterized, physically and chemically, such that it is appropriate for use in compounding?

This information was obtained via searches of the Micromedex database followed by cross-references with the Physician’s Desk Reference.

Quinacrine HCl is 6‐Chloro‐9‐(4‐diethylamino‐1‐methylbutylamino)‐2‐methoxyacridine dihydrochloride dihydrate; its structure differs only slightly from chloroquine (Wallace, 1989).

1. Stability of the API and likely dosage forms

Literature cited below indicates that quinacrine HCl, also known as quinacrine dihydrochloride dihydrate, is stable when protected from light. The PCCA Certificate of

Analysis (CoA) provided with the nomination indicates that quinacrine dihydrochloride dihydrate is stable for five years (Rotival, 2011; Material Safety Data Sheet, 2006).

2. Probable routes of API synthesis

Quinacrine hydrochloride (also called quinacrine dihydrochloride dihydrate) is commercially available and patented. As described in the patents, the compound is prepared by condensing 1-diethylamino-4-aminopentane with 3,9-dichloro-7- methoxyacridine (Winthrop Chemical Company 1938; Abbot Laboratories, 1944).

3. Likely impurities

Quinacrine HCl appears to be available in a highly pure form. According to the PCCA CoA provided with the nomination, it can be obtained in a purity of 99.6%. We also identified another source of the substance available in a purity of 97%. Four impurities (SI1-SI4) are likely present in the drug substance under recommended storage conditions. The proposed degradation pathways of quinacrine HCl in solid state and aqueous solution are shown below (Rotival, 2011).

4. Toxicity of those likely impurities

Literature references indicate quinacrine HCl is mutagenic, as discussed further below, and clastogenic in vitro. The identified potential impurities are also possible genotoxins and mutagens (Rotival, 2011; Clarke et al., 2001).

5. Physicochemical characteristics pertinent to product performance, such as particle size and polymorphism

Quinacrine HCl is a yellow powder with a melting point of 248-250 °C. The water solubility is 2.8 g/100 mL. The particle size distribution and polymorphism have not been reported.

6. Any other information about the substance that may be relevant, such as whether the API is poorly characterized or difficult to characterize

There is no other relevant information.

Conclusions: Quinacrine HCl (also called quinacrine dihydrochloride dihydrate) is well characterized, physically and chemically. It can be obtained in a highly pure form and is very stable when protected from light. As indicated above, quinacrine dihydrochloride dihydrate and related impurities are potentially mutagenic.

B. Are there concerns about the safety of the substance for use in compounding?

1. Nonclinical Assessment

The following information is summarized from the references listed below, which are the results of a search of Google, EMBASE, and Micromedex.

a. Pharmacology of the drug substance

Quinacrine HCl (marketed as Atabrine or Mepacrine) has been used in the treatment of giardiasis, malaria, lupus, rheumatoid arthritis, and cancer, as well as for female sterilization. Proposed mechanisms of action include DNA intercalation interference with RNA transcription and translation, inhibition of succinate oxidation interference with electron transport, inhibition of cholinesterase, and inhibitor of phospholipase A2.

b. Safety pharmacology

No safety pharmacology data are available for quinacrine HCl.

c. Acute toxicity

By the oral route, the median lethal dose (LD50) in the mouse was 1000 mg/kg while the LD50 in the rat was 900 mg/kg.

d. Repeat dose toxicity

Fischer 344 rats were fed a diet with 1000, 500, or 250 ppm quinacrine HCl for up to 2 years. The rats at 1000 and 500 ppm died with atrial thrombosis in combination with focal myocardial degeneration and congestion of lungs, liver and other organs. Hypertrophied myocardial cells with vacuoles and fibrosis were also noted. Necrosis of central liver parenchymal cells was also observed. Serum chemistries were not reported (Reuber, et.al., 1984).

e. Mutagenicity

Quinacrine HCl is a DNA intercalator. It was positive for mutagenicity in the AMES TA 1537, TA98 and WP2 strains (negative in TA100 and TA 1535). Quinacrine HCl was positive in the mouse lymphoma cell line and positive for chromosomal aberrations (but not polyploidy) in Chinese hamster ovary (CHO) cells. In vivo, the mouse micronucleus assay was negative ( Clarke et al., 2001).

f. Developmental and reproductive toxicity

Quinacrine HCl was administered subcutaneously to rats at 120 mg/kg/day on gestation days 13 through 19. Increased fetal death, but no teratogenic changes were observed. Levels of quinacrine HCl in the liver were 549 mcg and 9 mcg in dams and fetii respectively (de RB, 1950). Blake et al. reported that intrauterine instillation of 0.4 to 4 mg of quinacrine HCl during pregnancy in the rat resulted in dose dependent increases in fetal mortality (In Zatuchni et al., 1983). Fetal death was also noted with intrauterine instillation in pregnant monkeys at 3 mg. Goodman and Gilman 1980 notes that quinacrine HCl should not be given to pregnant women as the drug readily crosses the placenta to the fetus (Goodman et al., 1980).

g. Carcinogenicity

A non-traditional carcinogenicity study is discussed in a separate consult, prepared by the Division of Bone, Reproductive, and Urologic Products.

h. Toxicokinetics

Quinacrine HCl by the oral route is rapidly absorbed in the rat. Distribution is primarily to the liver (concentration may be over 20,000 times higher than in plasma) and minimally to the cerebrospinal fluid (1-5% of plasma levels). Urinary excretion accounts for approximately 10% of the dose/day. Detectable levels may still be found in urine two months after cessation of therapy. The half-life is 5 to 14 days.

Conclusions: The nonclinical data for quinacrine HCl are scarce, particularly when limited to administration by the oral route using a tablet formulation. A rat study by Reuber et al., suggests that heart and liver are primary targets of toxicity, which correlates with liver accumulation (Reuber et al., 1984). Positive results were seen in mutagenic and clastogenic assays, but not in a mouse micronucleus assay. The Atabrine label and Goodman and Gilman note that the use of quinacrine is not recommended during pregnancy as the drug crosses the placenta. The evidence of mutagenicity, carcinogenicity, and developmental/ reproductive toxicity raise concerns about the safety of quinacrine HCl.

2. Human Safety

a. Reported adverse reactions

The safety profile of oral quinacrine HCl is well described in the various sources cited below. Safety of the use of quinacrine HCl is in part dependent on dose and duration.

i. Label of Discontinued Quinacrine HCl Product

As of the date of its discontinuation in 1995, the prescribing information for Atabrine included a boxed warning stating that “[p]hysicians should completely familiarize themselves with complete contents of this leaflet before prescribing Atabrine.”

The warnings section of the prescribing information indicated, among other adverse reaction, the following:

• Quinacrine may occasionally cause a transitory psychosis and should be used with special caution in patients over 60 years of age or in those with a history of psychosis. • Use of quinacrine in patients with psoriasis may precipitate a severe attack of psoriasis. • Quinacrine may exacerbate porphyria.

The warnings section concluded that the drug should not be used in patients with psoriasis and porphyria unless in the judgment of the physician, the benefit outweighs the possible hazard (Physician's Desk Reference, 1985).

The precautions section of the quinacrine HCl prescribing information stated that the drug should be used with caution in patients with hepatic disease of alcoholism or in conjunction with known hepatotoxic drugs. The Precautions section also indicated that quinacrine HCl should be administered with caution to patients with G-6-PD deficiency (Physician's Desk Reference, 1985). Quinacrine HCl was not recommended for use in pregnancy (Physician's Desk Reference, 1985).

ii. Adverse Reactions Described in Literature and the Atabrine Package Insert

Adverse reactions associated with quinacrine HCl use include the following:

Dermatologic effects Yellowish discoloration of the skin, mucous membranes, and conjunctiva as well as a bluish- black discoloration of the nails has been observed. Discoloration generally occurs within 1 to 2 weeks after initiation of therapy and persists for 2 weeks to 4 months. Quinacrine HCl can be associated with significant rashes, including eczematous and exfoliative rashes as well as worsening of psoriasis (Wallace, 1989; Physician's Desk Reference, 1985). Among 120,000 Australian soldiers who received quinacrine HCl, the incidence of lichen planus (a skin disease) was 1 in 2,000 in those receiving 100 mg/day (Wallace, 1989).

Gastrointestinal disorders Nausea, diarrhea, vomiting, and abdominal cramps have been commonly associated with quinacrine HCl use (Physician's Desk Reference, 1985).

Hematologic effects Aplastic anemia is one of the most serious adverse reactions associated with quinacrine HCl use. The incidence of quinacrine HCl -associated aplastic anemia was assessed based on the rates of aplastic anemia in soldiers who received quinacrine HCl for prophylaxis of malaria. There was almost a five-fold rise in the incidence of aplastic anemia within two years of introduction of quinacrine, from 0.66 to 2.84 cases per 100,000 soldiers (Wallace, 1989; Brio, 1965). One third of these cases were determined to be due to quinacrine HCl overdose or concomitant drugs known to be associated with aplastic anemia. Aplastic anemia developed after patients received quinacrine HCl at 100 mg daily for 3 months or longer and was often heralded by a lichen planus rash (Wallace, 1989; Physician's Desk Reference, 1985; Brio, 1965). Approximately 70% of the above cases were associated with patients presenting with lichenoid tissue reactions several months prior to the onset of aplastic anemia. When quinacrine HCl was used in patients with lupus with additional safety precautions, including monitoring of complete blood count (CBC), drug discontinuation after 8 weeks if no effect was seen or lichen planus developed or hemoglobin/reticulocyte count dropped, and in a daily dose not exceeding 100 mg, the incidence of aplastic anemia was assessed at 1: 500,000 patients (Wallace, 1989).

Scoazec et al., 2003). In a comparative trial of quinacrine HCl in the treatment of Creutzfeldt-Jakob disease elevation in liver tests were noted at a higher rate in the quinacrine HCl arm (3/26 patients) as compared to the placebo arm (0/28 patients (Geschwind et al., 2013). In another trial in the treatment of Creutzfeldt-Jakob disease 16 out 40 patients treated with quinacrine HCl discontinued the drug due to alanine aminotransferase elevation (Collinge et al., 2009). The rate of liver test abnormalities in the control arm in this trial was not reported.

Neurologic and Psychiatric effects Quinacrine HCl can also have significant psychiatric effects including restlessness, insomnia, and psychosis (Physician's Desk Reference, 1985; Lally et al., 2012). One large study of 7,604 U.S. soldiers in the Second World War found an incidence of 0.4% for quinacrine HCl -induced psychosis (Wallace, 1989). Convulsions have occurred after administration of quinacrine HCl (Rockwell, 1968).

Ophthalmic effects Reversible corneal edema or deposits, manifested by visual halos, difficulty focusing and blurred vision have been reported in patients taking quinacrine HCl long-term for malaria suppression (Physician's Desk Reference, 1985; Rockwell, 1968). Retinopathy has been reported in patients who received quinacrine HCl even for a short-term treatment of parasitic diseases. However, in comparison to chloroquine or hydroxychloroquine, quinacrine HCl -associated retinal toxicity appears to be less frequent (Zuehlke et al., 1981; Cox et al., 1994).

iii. Safety issues associated with non-oral use of quinacrine HCl.

As a female sterilizing agent, quinacrine HCl was originally studied using a slurry formulation that was instilled into the uterine cavity (Zipper et al., 1970). However, three deaths were reported (in the US and Bangladesh). It is unclear whether the deaths were due to erosion of the uterus and subsequent spillage of quinacrine HCl into the peritoneum or to effects of systemic exposure to quinacrine HCl. Quinacrine HCl pellets were subsequently used for female sterilization.

As regards the pellet formulation, on August 26, 1998, a safety assessment and Health Hazard Evaluation was conducted by FDA on a kit for uterine insertion of quinacrine HCl pellets for female sterilization [see Appendix 1]. In this evaluation, FDA raised concerns in three areas based on results from previously conducted toxicology studies on the oral formulation and the lack of adequate toxicology testing on the intrauterine pellet formulation:

(1) possible carcinogenicity of quinacrine; specifically, quinacrine is a known mutagen and had tested positive in several genotoxicity tests, and the intrauterine administration of quinacrine pellets would result in significant tissue damage and the presence of known mutagen could result in development of cancer of the reproductive tract;

(2) lack of sufficient pharmacokinetic data, specifically, concerns exist on the possible continuous exposure of the endometrium to the drug following intrauterine insertion; and (3) pharmacodynamic issues, specifically, that intrauterine instillation of the cytotoxic agent had been noted to be unsuccessful for complete destruction of the endometrium and had resulted in neoplastic transformation of residual endometrial cells.

The evaluation noted that drugs with positive mutagenicity and cytotoxicity profiles, such as quinacrine HCl, were of concern with regard to increased cancer risks in humans. FDA concluded that the potential and known risks may outweigh any proposed advantages this procedure may have over surgical sterilization in the United States.

On October 14, 1998, FDA issued a warning letter regarding unapproved quinacrine HCl pellets labeled for non-surgical female sterilization [see Appendix 2]. In this letter, FDA highlighted many of the same safety concerns identified in the August 1998 Health Hazard Evaluation summarized above and concluded that non-surgical female sterilization is an unsafe use of quinacrine HCl pellets. Citing safety concerns, FDA requested that the unapproved quinacrine HCl pellets for non-surgical female sterilization be immediately removed from the market. In October 2008, a WHO Panel recommended that “until the totality of safety, effectiveness and epidemiological data has been reviewed, quinacrine HCl should not be used for non-surgical sterilization of women in either clinical or research settings.” To date, this interim statement has not been updated or removed.

Oral formulations of quinacrine HCl have also been used for pleurodesis. When used for pleurodesis, quinacrine HCl has been associated with chest pain (Dikensoy et al., 2005).

b. Clinical trials assessing safety

Please refer to section B (2) (a) of this review. Given the amount of public information available, analyses of safety data are based on the cumulative analyses of literature rather than on particular clinical studies of quinacrine HCl.

c. Pharmacokinetic data

When administered orally, quinacrine HCl is rapidly absorbed from the GI tract, even in the presence of severe diarrhea. Plasma levels increase in 2 to 4 hours and reach a peak in 8 to 12 hours. Quinacrine HCl is distributed widely in tissues and can accumulate over time, particularly in the liver (Wallace, 1989; Physician’s Desk Reference, 1985). Due to accumulation in body tissues, quinacrine HCl is eliminated slowly from the body, primarily through urine with less than 11% of elimination daily. As noted above, quinacrine HCl can cross the placenta and reach the fetus (Wallace, 1989).

d. The availability of alternative approved therapies that may be as safe or safer

Safer first line alternative therapies are available for all infectious disease indications for which quinacrine HCl would be utilized.

While quinacrine HCl was once considered a first-line treatment for giardiasis, an intestinal protozoal infection presenting as diarrhea and abdominal discomfort, tinidazole and nitazoxanide have been approved and replaced quinacrine HCl for this indication. In addition, metronidazole is commonly used off-label for the treatment of giardiasis.

However, recently, there has been some increase in the use of quinacrine HCl for the treatment of cases nonresponsive to nitroimidazoles. These cases are commonly described as refractory giardiasis and present as recurrent episodes of diarrhea which may be associated with weight loss and malnutrition.

A recent case series supplemented by a literature review described 110 cases of giardiasis that failed treatment with nitroimidazoles (Meltzer et al., 2014). The cases were reported between 1962 and 2013. In 21 out of 110 cases, patients were retreated with quinacrine HCl monotherapy and 19 out of 21 were cured. In 2 cases, subjects were cured with quinacrine HCl after failure of several courses of nitroimidazoles, albendazole, and nitazoxanide. In 14 out of 110 cases, patients were retreated with a combination of quinacrine HCl and a nitroimidazole and all 14 patients were cured.

Another literature review reported successful treatment of refractory giardiasis with a quinacrine-nitroimidazole combination (Escobedo et al., 2014). The usual dosage of quinacrine HCl for the treatment of giardiasis was 300 mg a day in divided doses for 5-10 days. It should be noted that most of the quinacrine HCl use occurred outside of the United States.

In taeniasis (tapeworm infection), quinacrine HCl has been replaced by praziquantel and is no longer used in the United States to treat this condition.

Quinacrine HCl is no longer used as an anti-malarial drug because more effective and less toxic alternatives are available, such as chloroquine, mefloquine, atovaquone- proguanil, and artemether-lumefantrine.

As noted above, quinacrine HCl’s effect on prion disease is being explored in two recently completed trials; they do not appear to show positive findings (Geschwind et al, 2013; Collinge et al., 2009).

Conclusions: The well-known safety profile of quinacrine HCl presents significant concerns about the use of this substance in compounded drug products, which do not carry the same labels and warnings as approved products. Quinacrine HCl is known to be mutagenic and is not recommended for use in pregnancy. Adverse effects related to the use of quinacrine HCl include aplastic anemia, hepatitis, severe dermatitis, and exacerbation of psoriasis and psychosis. Several FDA-approved drugs have demonstrated safety for use as anti-malarials and anti-protozoals. 10

C. Are there concerns about whether a substance is effective for a particular use?

1. Reports of trials, clinical evidence, and anecdotal reports of effectiveness, or lack of effectiveness, of the bulk drug substance

As indicated above, although the evidence is limited to analyses of case reports/series and no controlled trials of quinacrine HCl in treatment of refractory giardiasis were identified, quinacrine HCl has been successfully used in the treatment of giardiasis that was nonresponsive to other anti-protozoal drugs (Zipper et al., 1970; Dikensoy et al., 2005).

2. Whether the product compounded with this bulk drug substance is intended to be used in a serious or life-threatening disease

No. Giardiasis and tapeworm infection would not be considered serious or life threatening. Quinacrine HCl is no longer used for the treatment of malaria.

3. Whether there are any alternative approved therapies that may be as effective or more effective.

Yes, there are more effective first-line alternatives for the majority of infectious diseases where quinacrine HCl may be potentially used. Please see comments to section B (2) (d).

Conclusions: There are more effective first-line alternative drugs for the majority of infectious diseases where quinacrine HCl may be potentially used. However, limited literature data suggest that quinacrine HCl might be effective in patients with giardiasis refractory to commonly used agents. Quinacrine HCl is not currently used for the other indications reviewed in this consult, including for no serious or life-threatening conditions.

D. Has the substance been used historically in compounding?

1. Length of time the substance has been used in pharmacy compounding

Given the recent unavailability of quinacrine HCl by traditional avenues since the discontinuation of atabrine in 1995, there has been moderate experience using this drug in its compounded form. However, it’s unclear how much of that use occurs in the United States, particularly with regard to use in refractory giardiasis (most such cases appeared to occur in Europe). The use associated with compounding in the US is more likely to be associated with treatment of rheumatologic conditions, which are addressed in a separate consult.

2. The medical condition(s) it has been used to treat

At the time of its discontinuation in 1995, the oral quinacrine HCl product label included the following indication statement: “ATABRINE is indicated for the treatment of

11 giardiasis and cestodiasis” (Physician’s Desk Reference, 1985). Currently, quinacrine HCl is being used in a variety of ways worldwide for treatment of both infectious and noninfectious diseases. In terms of infectious disease uses, quinacrine HCl currently is used primarily as an agent to treat refractory or chronic giardiasis. It has also been used as an anti-tapeworm agent and is currently being explored as an agent to treat prion diseases (Geschwind et al., 2013; Collinge et al., 2009). In terms of noninfectious uses, quinacrine HCl has been used to treat lupus (particularly cutaneous lupus), rheumatoid arthritis, refractory pulmonary effusion and pneumothorax, induce female sterilization, and is being explored for use as an adjuvant treatment for particular tumors.

Quinacrine HCl’s noninfectious disease uses appear to outstrip its infectious disease uses in both diversity of usage and prevalence. Quinacrine HCl pellets were used in many developing countries in the 1980’s and early 1990’s as a nonsurgical contraceptive agent. The pellets were delivered through an IUD and found to induce scarring in the endometrial wall/fallopian tubes. Though the rate of current usage of this method is unclear because of safety concerns related to the medication, there is evidence of at least some relatively recent usage (Afzal, 2014; Jensen, 2014).

Quinacrine HCl has recently reemerged for use in cutaneous lupus erythematosus, particularly refractory cases in combination with the other antimalarials (Chang et al., 2011; Kuhn et al., 2011). Generally, the dose is around 100 mg a day (though higher doses can be given), and it is given for a prolonged period of potentially several months; its maximal effect takes 6-8 weeks (Kuhn et al., 2011). It can also be used instead of the other antimalarials in subjects with preexisting retinopathy. The supply appears to come from compounding pharmacies. Quinacrine HCl may also be useful in other rheumatologic illnesses such as dermatomyositis (Ochsendorf, 2010). Quinacrine HCl is being explored for use against several tumor types due to particular anti-neoplastic activities noted in vitro (Hede, 2011). Quinacrine HCl is also used for the treatment of pleurodesis though its use may be more targeted to non US regions (particularly Scandinavia)

3. How widespread its use has been

It is difficult to estimate how widespread the compounding of quinacrine HCl has been. In infectious diseases its use seems to be rather limited.

Though quinacrine HCl has been used to treat a wide variety of medical conditions, it is still unclear how frequently such usage occurs, particularly in the United States. Indeed, its use in Spain was noted to be minimal due to lack of availability and information on its use (Gonzalez-Sixto et al., 2010).

4. Recognition of the substance in other countries or foreign pharmacopeias

It appears that quinacrine HCl is still used in some countries for the treatment of giardiasis and tapeworm infections in a limited number of patients. Quinacrine HCl also has been used as a sterilization agent in females more recently. It is unclear, however, 12

whether quinacrine HCl in other countries is used in compounded or manufactured formulations.

Conclusions: We cannot estimate the use of quinacrine HCl through compounding and have not found evidence to indicate that for infectious diseases indications more than a limited amount of quinacrine HCl has been compounded in the United States.

III. RECOMMENDATION

Although quinacrine HCl was initially used as an antimalarial agent, its current usage in infectious diseases is limited to rare cases of refractory giardiasis, mostly outside the United States. Quinacrine HCl is now primarily used for noninfectious indications including systemic lupus erythematosus (SLE), nonsurgical female sterilization, pleurodesis, and exploratory treatment of prion diseases and various tumors. Much of this usage also occurs outside the United States.

We have evaluated quinacrine HCl, as an antimalarial and an anti-tapeworm agent, for use in compounding based on its physicochemical characteristics, safety, effectiveness, and evidence of historical use in compounding. It is well-characterized, physically and chemically, and there is some evidence of its historical use in compounding, at least since the marketed version of the drug was discontinued. Regarding safety, however, quinacrine HCl is a known mutagen and is associated with serious adverse reactions such as aplastic anemia, hepatitis, severe dermatitis, exacerbation of psoriasis, and psychosis. Furthermore, when quinacrine HCl was marketed, its use was not recommended during pregnancy, and the label warned that special caution should be exercised when it was used in patients over 60 years of age. All these safety concerns resulted in the inclusion of a boxed warning in the quinacrine HCl label. Regarding efficacy, there is some limited evidence related to its use for giardiasis but not for the treatment of malaria or tapeworms. There are FDA-approved products available for these indications that have demonstrated safety and effectiveness.

Therefore, the use of quinacrine HCl without providing complete prescribing information presenting directions for use, risks, and warnings, as would be the case if the drug is allowed for compounding, may be associated with increased risks to the patients. For infectious disease indications, these risks are not outweighed by the benefits of quinacrine HCl, given the limited evidence of efficacy and the availability of other alternative treatments for anti-malarial and anti-protozoal uses. Given all the above considerations, we do not recommend that quinacrine HCl be added to the list of drug substances that can be used for compounding for the treatment of infectious diseases. In a limited setting, whether for an individual patient or for research purposes, it would be more appropriate to obtain quinacrine HCl though the expanded access IND process, where the provision of safety information may be secured. However, the risk-benefit considerations for this substance might be weighed differently for other treatment areas.

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Afzal S, Bukhari MH. Endometrial abnormalities on transvaginal ultrasonography and histopathology in women after quinacrine sterilization. Pak J Med Sci 2014 Jul; 30(4):778-83.

Biro L, Leone N. Aplastic anemia induced by quinacrine. Arch Dermatol 1965 Nov; 92(5):574-6.

Chang AY, Piette EW, Foering KP, Tenhave TR, Okawa J, Werth VP. Response to antimalarial agents in cutaneous lupus erythematosus: a prospective analysis. Arch Dermatol 2011 Nov; 147(11):1261-7.

Clarke JJ, Sokal DC, Cancel AM, et al. Re-evaluation of the mutagenic potential of quinacrine dihydrochloride dihydrate. Mutat Res 2001 Jul 25; 494(1-2):41-53.

Collinge J, Gorham M, Hudson F, et al. Safety and efficacy of quinacrine in human prion disease (PRION-1 study): a patient-preference trial. Lancet Neurol 2009 Apr; 8(4):334-44.

Cox NH, Paterson WD. Ocular toxicity of antimalarials in dermatology: a survey of current practice. Br J Dermatol 1994 Dec; 131(6):878-82. de RB, LEVY G. [Effect of quinacrine on gestation in the rat]. C R Seances Soc Biol Fil 1950 Oct; 144(19-20):1350-2.

Dikensoy O, Light RW. Alternative widely available, inexpensive agents for pleurodesis. Curr Opin Pulm Med 2005 Jul; 11(4):340-4.

Escobedo AA, Hanevik K, Almirall P, Cimerman S, Alfonso M. Management of chronic Giardia infection. Expert Rev Anti Infect Ther 2014 Sep; 12(9):1143-57.

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Fishman AP, Kinsman JM. Hypoplastic anemia due to atabrine. Blood 1949 Aug; 4(8):970-6.

Geschwind MD, Kuo AL, Wong KS, et al. Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease. Neurology 2013 Dec 3; 81(23):2015-23.

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Goodman, Luis S., and Alfred Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics: 6th Ed. New York, NY : Macmillan, 1980:1078.

Health Hazard Evaluation Summary of a kit for intrauterine insertion of Quinacrine Hydrochloride pellets for female sterilization; August 26, 1998. 1998.

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APPENDIX B

Final DPARP Quinacrine Review for 2016

DEPARTMENT OF HEALTH & HUMAN SERVICES

Food and Drug Administration Silver Spring, MD 20993-0002

DATE: February 5, 2016

FROM: Keith M Hull, MD, PhD Medical Officer, Division of Pulmonary, Allergy, and Rheumatology Products

THROUGH: Nikolay P. Nikolov, MD Clinical Team Leader, Division of Pulmonary, Allergy, and Rheumatology Products

Sarah Yim, MD Associate Director, Division of Pulmonary, Allergy, and Rheumatology Products

Badrul Chowdhury, MD, PhD Division Director, Division of Pulmonary, Allergy, and Rheumatology Products

TO: Pharmacy Compounding Advisory Committee

SUBJECT: Review of Quinacrine Hydrochloride for Inclusion on the 503A Bulk Drug Substances List

I. INTRODUCTION

Quinacrine hydrochloride (HCl) has been nominated for inclusion on the list of bulk drug substances that can be used in compounding under section 503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act). The substance was nominated for use in the treatment of rheumatoid arthritis and lupus as an antimalarial and an antiprotozoal. This consult is limited to an assessment of the Division of Pulmonary, Allergy, and Rheumatology Products (DPARP) assessment of the appropriateness of including quinacrine HCl on the 503A bulk drug substances list as it pertains to the lupus and rheumatoid arthritis uses.

We have reviewed available data on the physicochemical characteristics, safety, effectiveness, and historical use in compounding of this substance. For the reasons discussed below, we recommend that quinacrine HCl be added to the list of bulk drug substances that can be used to compound drug products in accordance with section 503A of the FD&C Act.

II. EVALUATION CRITERIA

Please see the review prepared by the Division of Anti-Infective Products (DAIP) and the Office of Pharmaceutical Quality for information on the physical and chemical characteristics and non-clinical safety of quinacrine HCl.

A. Are there concerns about the safety of the substance for use in compounding?

We have reviewed the following available relevant information specific to the use of quinacrine hydrochloride for rheumatoid arthritis or lupus:

• Reported adverse reactions • Clinical trials assessing safety • Pharmacokinetic data • The availability of alternative approved therapies that may be as safe or safer, including approved products used off-label

This information is discussed in detail below.

Lupus

1. Background

Literature searches were conducted using the National Library of Medicine’s PubMed database with the search terms quinacrine and lupus and quinacrine and rheumatoid arthritis. Searches identified a total of 170 and 31 publications, respectively. A general assessment of abstracts and electronically available publications were reviewed to evaluate for the general safety and efficacy of quinacrine HCl in patients with lupus or rheumatoid arthritis. The majority of the data assessing the safety of quinacrine HCl were derived from clinical studies conducted from the 1940s through the 1960s, and as a result, many of the individual publications were not readily available for review. Consequently, much of the safety data for this review was obtained from more recent review articles summarizing the overall safety of quinacrine HCl. However, when possible, more recent studies were reviewed and found to be consistent with the overall safety profile described in earlier studies.

The use of antimalarial drugs for the treatment of rheumatologic diseases began in 1894 when Payne (Payne 1894) reported that quinine was effective for treating cutaneous lupus. However, its widespread use was limited due to substantial toxicity at therapeutic doses. Synthetic antimalarial drugs were subsequently developed over the next five decades and determined to also be effective at treating the manifestations of cutaneous and systemic lupus erythematosus. These synthetic antimalarials included quinacrine (a.k.a. mepacrine), chloroquine, and hydroxychloroquine, all of which are the current antimalarials most commonly used for systemic and/or cutaneous lupus.

Quinacrine HCl was initially developed in the 1930s and used extensively for malaria prophylaxis and treatment. In 1951, the first report of its use for the treatment of lupus was published in Lancet (Page 1951) and was subsequently followed with over 30 additional reports over the next eight years further supporting its efficacy for lupus and rheumatoid arthritis (Wallace 1989). A 1959 issue of The New England Journal of Medicine (Tye et al., 1959) reported improvement in 44 of 45 lupus patients treated with Triquin, a combination product containing quinacrine HCl, chloroquine, and hydroxychloroquine. Triquin was later approved in 1955 by FDA for the treatment of lupus but was subsequently removed from the market in 1973 as detailed in the Review of Quinacrine for the Withdrawn or Removed List consult.

2. Reported Adverse Reactions

Because quinacrine HCl has a long history of clinical use, especially in the treatment of malaria, its safety profile is well understood (Wallace 2000; Canete et al., 2006; Ehsanian et al., 2011; Collinge et al., 2009). The most frequently reported adverse reactions associated with quinacrine HCl include diarrhea, nausea, vomiting, abdominal pain, headache, and yellowing of the skin and mucous membranes. Rare cases of transient lupus-associated quinacrine HCl-induced hepatitis and peritonitis have been reported (Gibb et al., 1985), although these were attributed to doses three-fold higher than the generally recommended dose of 100 mg daily (See et al., 1998). At higher doses, patients have reported restlessness, vertigo, insomnia, nightmares, hyperirritability, and convulsions. Several publications have reported quinacrine HCl-induced psychosis ranging from 0.1-0.4% of patients (Lidz et al., 1946; Gaskill et al., 1945). Although rare, the most serious potential toxicity associated with quinacrine HCl is aplastic anemia, which was observed at rate of between 0.66-2.84 cases/100,000 soldiers treated with quinacrine HCl during World War II (Gonzalez-Sixto et al., 2010; Custer 1946; Palmer et al., 1953; Paton et al., 1955). One third of these cases were determined to be due to quinacrine HCl overdose or concomitant drugs known to be associated with aplastic anemia. Approximately 70% of the remaining cases were associated with patients presenting with lichenoid tissue reactions several months prior to the onset of aplastic anemia. Therefore, the rate of aplastic anemia in patients treated with quinacrine HCl who did not present with a lichenoid reaction is approximately 1 case/500,000 patients (Wallace 1994).

Like quinacrine, hydroxychloroquine and chloroquine have been associated with serious side effects such as hematologic effects (e.g., reversible agranulocytosis and aplastic anemia) and neurologic effects (e.g., psychosis, seizures). Because quinacrine does not appear to cause retinopathy, which is dose-related and irreversible with hydroxychloroquine and chloroquine, it is not uncommon for rheumatologists to add quinacrine when a patient appears to require additional antimalarial therapy and increasing the dose of hydroxychloroquine or chloroquine is not desirable due to the concern for retinal toxicity.

3. Pharmacokinetic Data

Quinacrine HCl is most commonly administered orally, where it is rapidly absorbed from the gastrointestinal tract with plasma levels increasing 2 to 4 hours after administration and peaking in 8 to 12 hours (Campbell 1986; Joint Report 1946; Wallace 1989). Plasma concentrations increase rapidly during the first week of administration and plateau by the fourth week. In general, tissue concentrations of quinacrine HCl are many fold higher compared to plasma levels. The highest concentrations are found in the liver, spleen, lungs, integument, and adrenal glands while the lowest concentrations are found in the brain, heart, and skeletal muscle (Shannon et al., 1944; Goodman et al., 1954). The half- life of quinacrine HCl varies between 5 to 14 days depending on the therapeutic dosing regimen and is approximately 80-90% bound to plasma proteins (Looareesuawan et al., 1988; Bjorkman et al., 1989). The major route of elimination is via renal excretion (Gaskill et al., 1945; Palmer et al., 1953)..

4. Alternative Treatments

Although there are numerous drugs available for treating lupus, the most relevant for this discussion is the antimalarial drug hydroxychloroquine, which is FDA approved for the treatment of lupus and rheumatoid arthritis. Hydroxychloroquine was approved by FDA in 1955 and soon replaced the use of quinacrine HCl. However, quinacrine HCl is still prescribed primarily for the treatment of refractory cutaneous lupus or in conjunction with hydroxychloroquine for systemic lupus erythematosus. The rheumatology community has continually recommended the use of quinacrine HCl for the treatment of lupus, and it is listed as a treatment alternative in the scientific literature, major rheumatology text books, and online medical reference sites.

Rheumatoid Arthritis

Although monotherapy and combination therapy with antimalarial drugs have been demonstrated to be effective in treating rheumatoid arthritis, no individual study specifically evaluating quinacrine HCl could be identified using the currently available databases. However, the safety profile of quinacrine HCl would not be expected to be different in patients with rheumatoid arthritis compared to lupus patients given the overall similar safety profiles of chloroquine and hydroxychloroquine in the two diseases.

There are multiple approved therapies for rheumatoid arthritis. Medications used to slow disease progression are referred to as nonbiologic and biologic disease-modifying antirheumatic drugs (DMARDs). Since 1998, FDA has approved the following drugs for rheumatoid arthritis: leflunomide, etanercept, infliximab, anakinra, adalimumab, abatacept, rituximab, certolizumab, golimumab, tocilizumab, tofacitinib, golimumab intravenous (IV), and methotrexate subcutaneous injection.

Although each drug has its own specific safety profile, all of these drugs are associated with an increased risk of infection. In addition, oral glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs) are approved for the treatment of rheumatoid arthritis.

Similar to DMARDs, glucocorticoids are associated with an increased risk of infection. NSAIDs are associated with gastrointestinal, renal, and cardiovascular adverse effects.

Conclusions

Millions of people have been treated with multiple doses of quinacrine HCl since the 1940s. Consequently, the safety profile has been well described in the medical literature. The most common adverse reactions involve headache, gastrointestinal symptoms, and yellowing of the skin, which are all reversible by lowering the dosage or discontinuation of the drug. The more serious adverse reactions, which include hepatitis, psychosis, and aplastic anemia, occur rarely and are typically associated with higher doses than the 100 mg/d used to treat rheumatic diseases. Performing a complete blood count and thorough skin exam every three months in quinacrine HCl-treated patients is recommended in the medical literature to screen for potential cases of aplastic anemia. Given the potential benefits of therapy in patients with refractory cutaneous lupus, discussed further below, the safety profile of quinacrine hydrochloride is acceptable considering the relative safety of other lupus treatments.

B. Are there concerns about whether the substance is effective for a particular use? If there are no data regarding effectiveness available, is the substance used to treat a serious or life-threatening condition for which there are approved alternative therapies available?

In developing our response to this question, we have considered the following, to the extent available:

• Reports of trials demonstrating effectiveness of the bulk drug substance as it is used in drug products • Any clinical evidence of effectiveness, or lack of effectiveness, of drug products with the bulk drug substance • Any anecdotal reports of effectiveness, or lack of effectiveness, of drug products with the bulk drug substance • Whether the product compounded with this bulk drug substance is intended to be used in a serious or life-threatening disease • Whether there are any alternative approved therapies that may be as effective or more effective, including approved products used off-label

Lupus

The efficacy of quinacrine HCl in treating patients with lupus was first established in 1951 (Page 1951). However, as discussed above, since the late 1950s, it has largely been replaced by hydroxychloroquine, which FDA approved in 1955 with a better characterized efficacy and safety profile.

data support the use of quinacrine HCl in combination with hydroxychloroquine in patients with cutaneous lupus erythematosus. Chang et., al (2011) conducted a prospective analysis in 128 patients with cutaneous lupus erythematosus and concluded that the addition of quinacrine HCl 100 mg/d with standard doses of hydroxychloroquine was associated with an improved clinical response in patients who failed hydroxychloroquine monotherapy. Similarly, Cavazzana et., al (2009) evaluated the efficacy of hydroxychloroquine and quinacrine HCl combination therapy in the treatment of lupus skin lesions in patients refractory to hydroxychloroquine monotherapy. Thirty- four patients were treated with hydroxychloroquine 5 mg/kg/d (n=34) and either quinacrine HCl 100 mg/d (n=29) or quinacrine HCl 50 mg/d (n=5). A total of 29 of the 34 (85%) of patients demonstrated a clinical improvement with a more rapid response seen in patients receiving quinacrine HCl 100 mg/d compared to the 50 mg/d group. The authors concluded that the combination of hydroxychloroquine and quinacrine HCl was an effective therapy in the treatment of lupus skin lesions unresponsive to hydroxychloroquine alone. Three additional studies supporting the use of quinacrine HCl in combination with chloroquine or hydroxychloroquine were referenced in review articles, but were not readily available for independent review (Chung et al., 1997; Feldmann et al., 1994; Von Schmiedeberg et al., 2000). In 1996, the American Academy of Dermatology included quinacrine hydrochloride (100 to 200mg/d) on a list of first-line system treatments for lupus (Guidelines of Care for Cutaneous Lupus Erythematosus, 1996). Most recently, McCune and Gonzalez-Rivera have proposed that the addition of quinacrine HCl to hydroxychloroquine therapy should be seriously considered as long- term maintenance therapy of remission in patients with systemic lupus to reduce ocular toxicity (McCune et al., 2015). Furthermore, the use of quinacrine HCl is recommended in the most-recent algorithm for treatment of systemic lupus erythematosus (Muangchan et al., 2015).

Lupus is a systemic autoimmune disease considered a serious condition with increased morbidity and mortality. It can affect virtually any organ system; the more commonly involved organ systems are mucocutaneous, musculoskeletal, renal, nervous, cardiovascular, pleura, and lungs. The mucocutaneous and musculoskeletal systems are involved in over three-fourths of lupus patients. The current standard of care for treatment of mild-to-moderate manifestations of lupus includes non-steroidal anti- inflammatory drugs (NSAIDs), antimalarial drugs like hydroxychloroquine, and corticosteroids like prednisone. Life-threatening manifestations of lupus, such as those involving the kidneys, central nervous system, or blood vessels are treated more aggressively with drugs like high dose corticosteroids, or immunosuppressive agents like cyclophosphamide, azathioprine, and mycophenolate mofetil. Of these drugs, only prednisone and hydroxychloroquine have FDA approved labeling for use in lupus. FDA approved belimumab, a B-lymphocyte stimulator (BLyS)-specific inhibitor in 2011 for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus who are receiving standard therapy (BENLYSTA Prescribing Information Highlights, accessed September 2015). Currently, there is no approved treatment of lupus that has been shown to prolong survival or reverse the course of the disease. Lupus remains a disease with unmet medical need, especially for patients with active and life- threatening manifestations.

Rheumatoid Arthritis

Although monotherapy and combination therapy with antimalarial drugs have been demonstrated to be effective in treating rheumatoid arthritis, no individual study specifically evaluating quinacrine HCl could be identified using the currently available databases. Reports from the 1950s regarding quinacrine HCl’s efficacy in rheumatoid arthritis were noted in several review articles. However, independent verification of the studies was not possible for this review.

Rheumatoid arthritis can be a serious condition. Approved alternatives are discussed above. Although quinacrine has also been used historically for rheumatoid arthritis, the availability of many highly effective FDA-approved treatments for RA has made the use of quinacrine uncommon for RA today.

Conclusions

Despite its well-documented antirheumatic properties, quinacrine HCl has never been carefully evaluated in prospective, well-controlled, double-blinded studies with prespecified endpoints. Nevertheless, the overall evidence suggests that quinacrine HCl fulfills a therapeutic need and is currently prescribed, albeit to a limited extent, for the treatment of cutaneous lupus and as an add-on therapy to patients who are refractory to hydroxychloroquine monotherapy. In our view, there is a body of evidence in the scientific literature that supports its effectiveness, especially as related to cutaneous lupus and patients who are refractory to hydroxychloroquine monotherapy. Additionally, given its lower retinal toxicity as compared to the FDA-approved antimalarials, quinacrine HCl may be an option for patients with lupus who respond to antimalarial therapy but have retinal disease. Furthermore, the rheumatologic community has continually recommended the use of quinacrine HCl for the treatment of lupus, and it is listed as a treatment alternative in the scientific literature, major rheumatologic text books, and online medical reference sites.

There is insufficient evidence to support the use of quinacrine HCl for the treatment of rheumatoid arthritis, especially in the context of numerous therapies that have established efficacy and the risk of irreversible structural damage with ineffective therapies.

C. Has the substance been used historically in compounding?

In developing our response to this question, we have considered the following, to the extent available:

• Length of time the substance has been used in pharmacy compounding • The medical condition(s) it has been used to treat • How widespread its use has been • Recognition of the substance in other countries or foreign pharmacopeias

Please see DAIP's review for information on the historical use of quinacrine HCl in compounding. 7

III. RECOMMENDATION

In light of the information set forth above and in DAIP's consult, we recommend that quinacrine HCl be placed on the list of bulk drug substances allowed for use in compounding under section 503A for oral administration. This recommendation is based on the data supporting its efficacy in the treatment of cutaneous and systemic lupus and its overall safety profile, which has important differences compared to the approved antimalarials typically used for SLE (especially hydroxychloroquine); this allows it to be used in conjunction with other antimalarials. The safety concerns with quinacrine are well known, and are monitored for by clinicians who choose to use quinacrine. The most concerning of these is aplastic anemia, which is a very rare idiosyncratic reaction, which may be reversible but also may be life-threatening and may require bone marrow transplant. For those patients who require additional anti-malarial therapy, but are at risk of irreversible retinopathy and blindness with an increased dose of an approved antimalarial, or who are at risk of life-threatening lupus flares if not adequately treated, adding 100 mg or less of quinacrine to lower doses of hydroxychloroquine or chloroquine has been a valuable therapeutic alternative.

As discussed in the DAIP consult, quinacrine HCl is well characterized physically and chemically and has been used since the 1940s as an antimalarial and antiprotozoal agent and for the treatment of patients with refractory cutaneous lupus erythematosus. Because quinacrine HCl has a long history of clinical use, especially in the treatment of malaria, its safety profile is well understood. Quinacrine HCl is used to treat lupus in a manner similar to chloroquine and hydroxychloroquine, FDA-approved products that are used in the treatment of lupus. In comparison with chloroquine or hydroxychloroquine, quinacrine HCl has lower retinal toxicity. In 1996, the American Academy of Dermatology included quinacrine HCl (100 to 200mg/day) on a list of first-line system treatments for lupus.

Of note, DPARP acknowledges DAIP’s recommendation not to include quinacrine HCl on the 503A bulk drug substances list for anti-malarial and anti-protozoal uses and DBRUP's recommendation not to include quinacrine HCl on the 503A bulk drug substances list for use in intrauterine administration. However, this consult is limited to DPARP’s assessment of the appropriateness of including quinacrine HCl on the 503A bulk drug substances list as it pertains only to lupus and rheumatoid arthritis indications.

BIBLIOGRAPHY

BENLYSTA Prescribing Information Highlights, accessed September 2015, http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125370s016lbl.pdf Bjorkman S, Elisson LO, Gabrielsson J. Pharmacokinetics of quinacrine after intrapleural instillation in rabbits and man. J Pharm Pharmacol 1989; 41:160-63. Campbell WC. The chemotherapy of parasitic infections. J Parasitol 1986; 72:45-61. Canete R, Escobedo AA, Gonzalez ME et al. Randomized clinical study of five days therapy with mebendazole compared to quinacrine in the treatment of symptomatic giardiasis in children World J Gastroenterol 2006; 12:6366-70. Cavazzana I, Sala R, Bazzani C, et al. Treatment of lupus skin involvement with quinacrine and hydroxychloroquine. Lupus 2009; 18:735-39. Chang AY, Piette EW, Foering KP. Response to antimalarials in cutaneous lupus erythematosus A Prospective Analysis. Arch Dermatol 2011; 147:1261-67. Chung JS, Hann SK. Lupus panniculitis treated by a combination therapy of hydroxychloroquine and quinacrine. J Dermatol 1997; 24:569-72. Collinge J, Gorham M, Hudson F et al. Safety and efficacy of quinacrine in human prion disease (PRION-1 study): a patient-preference trial. Lancet Neurol 2009; 8:334-44. Dubois EL. Antimalarials in the management of discoid and systemic lupus erythematosus. Semin Arthritis Rheum 1978; 8:33-51. Ehsanian R, van Waes C, Feller SM. Beyond DNA binding- a review of the potential mechanisms mediating quinacrine’s therapeutic activities in parasitic infections, inflammation and cancers. Cell Commun and Signalling 2011; 9:13-31. Feldmann R, Saolmon D, Saurat JH. The association of the two antimalarials chloroquine and quinacrine for the treatment-resistant chronic and subacute cutaneous lupus erythematosus. Dermatology 1994; 189:425-27. Gaskill HS, Fitz-Hugh T. Toxic psychosis following Atabrine. Bull US Army Med Dept. 1945; 86:63-9. Gibb W, Isenberg DA, Snaith ML. Mepacrine induced hepatitis. Ann Rheum Dis 1985; 44:861-2. Goodman, LS, Gilman, A (Eds), Goodman and Gilman’s the Pharmacological Basis of Therapeutics, New York, Macmillan 1954. Gonzalez-Sixto B, Garcia-Doval I, Oliviera R, et al. Quinacrine in the treatment of cutaneous lupus erythematosus: practical aspects and a case series. Actas Dermosifiliogr 2010; 101:54-58. Custer RP. Aplastic anemia in soldiers treated with Atabrine (quinacrine). Am J Med Sci 1946; 212:211-24. “Guidelines of Care for Cutaneous Lupus Erythematosus” J Am Acad Dermatol. 1996 May;34(5 Pt 1):830-6. 9

Joint Report of the Armored Medical Research laboratory and Commission on Tropical Diseases AEB. Preventive Medicine Service, Office of the Surgeon General, US Army. Plasma quinacrine concentration as a function of dosage and environment. Arch Intern Med 1946; 78:64-107. Lidz T, Kahn RL. Toxicity of quinacrine (Atabrine) for the central nervous system. Arch Neurol 1946; 56:284-9. Looareesuawan S, Phillips RE, Edwards G, et al. Mepacrine accumulation during treatment of chloroquine-resistant falciparum malaria. Ann Trop Med Parasitol 1988; 82:107-112. McCune WJ, Gonzalez-Rivera T. Should very low doses of hydroxychloroquine and quinacrine be employed in combination for long-term maintenance of remission in systemic lupus to reduce the risk of ocular toxicity? Curr Opin Rheumatol 2015; 27:213- 15. Muangchan C, van Vollenhoven RF, Bernatsky SR, et al. Treatment Algorithms in Systemic Lupus Erythematosus, Arthritis Care Res (Hoboken). 2015 Mar 16. doi: 10.1002/acr.22589. [Epub ahead of print] Page F. Treatment of lupus erythematosus with mepacrine. Lancet 1951; 2:755-8. Palmer LG, Sawitsky A. Fatal aplastic anemia follwonig quinacrine therapy in chronic discoid lupus erythematosus. J Am Med Assoc 1953; 153:1172-4. Paton MD, Riddell MJ, Stong JA. Aplastic anemia following mepacrine treatment of lupus erythematosus. Lancet 1955; 268: 281-2. Payne JF. A postgraduate lecture on lupus erythematosus. Clin J 1894; 4:223-9. Shannon JA, Earle DP, Brodie BB et al. The pharmacological basis for the rational use of Atabrine in the treatment of malaria. J Pharmacol Exp Ther 1944; 81:307-30. See, e.g., Petri, M. Treatment of Systemic Lupus Erythematosus: An Update. Am Fam Physician. 1998 June 1;57(11):2753-2760. Tye MJ, White H, Appel B et al. Lupus erythematosus treated with a combination of quinacrine, hydroxychloroquine and chloroquine. New Engl J Med 1959; 260:63-66. Von Schmiedeberg s, Ronnau AC, Schuppe HC, et al. Combination of antimalarial drugs mepacrine and chloroquine in therapy refractory cutaneous lupus erythematosus. Hautarzt 2000; 51: 82-85. Wallace DJ. Antimalarial agents and lupus. Rheum Dis Clin North Am 1994; 20:243-63. Wallace DJ. Is there a role for quinacrine (Atabrine) in the new millennium? Lupus 2000; 9:81-2. Wallace DJ. The use of quinacrine (Atabrine) in rheumatic disease, a reexamination. Semin Arthritis Rheum 1989; 18:282-97.

APPENDIX C

Final DBRUP Quinacrine Review for 2016 PCAC

DEPARTMENT OF HEALTH & HUMAN SERVICES

Food and Drug Administration Silver Spring, MD 20993-0002 DATE: February 9, 2016 FROM: Lisa Soule, MD, Clinical Team Leader Division of Bone, Reproductive, and Urologic Products

THROUGH: Christine Nguyen, MD, Deputy Director for Safety Division of Bone, Reproductive, and Urologic Products

Julie Beitz, MD, Director Office of Drug Evaluation III

SUBJECT: Review of Quinacrine Hydrochloride for Intrauterine Administration

TO: Pharmacy Compounding Advisory Committee

I. INTRODUCTION

Quinacrine hydrochloride (quinacrine HCl) has been nominated for inclusion on the list of bulk drug substances that can be used in compounding under section 503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act). The substance was nominated for use in the treatment of rheumatoid arthritis, lupus, as an antimalarial and an antiprotozoal. FDA’s Division of Anti- Infective Products (DAIP) evaluated quinacrine HCl for inclusion on the 503A list for the proposed antimalarial and antiprotozoal uses. The Division of Pulmonary, Allergy and Rheumatology Products (DPARP) evaluated quinacrine HCl for the section 503A list for the proposed lupus and rheumatoid arthritis uses.

In addition to the nominated uses, the Agency is aware that an intrauterine form of quinacrine HCl has been used for non-surgical female sterilization. Safety concerns about this procedure have been identified in the literature and by public health organizations over the past 40 years. In light of this information, the Division of Bone, Reproductive, and Urologic Products (DBRUP) was asked to prepare a secondary review addressing the safety of the intrauterine use.

We have reviewed available data on the physicochemical characteristics, effectiveness, and historical use in compounding of this substance discussed in the DAIP and DPARP reviews, as well as the safety information set forth below. For the reasons discussed below, we do not recommend that quinacrine HCl be added to the list of bulk drug substances that can be used to compound drug products in accordance with section 503A of the FD&C Act.

II. EVALUATION CRITERIA

Please refer to the review prepared by DAIP on the physical and chemical characteristics, the non-clinical safety of quinacrine HCl and the historical use of quinacrine HCl in compounding.

A. Are there concerns about the safety of the substance for use in compounding?

Quinacrine HCl is a derivative of acridine, and belongs to a class of compounds that are well known to have mutagenic properties (Ferguson et al., 1991). Compounds of this class have a planar structure and can intercalate into DNA and cause various types of mutations (Nasim et al., 1979).

Quinacrine HCl was studied as a female sterilizing agent initially using a slurry formulation that was instilled into the uterine cavity (Zipper et al., 1970). However, three deaths were reported (in the United States and Bangladesh). It is unclear whether the deaths were due to erosion of the uterus and subsequent spillage of quinacrine HCl into the peritoneum or to effects of systemic exposure to quinacrine HCl. The slurry formulation was discontinued, and subsequently, a pellet formulation was developed in 1977 and studied initially by Dr. Jaime Zipper in Chile (Zipper et al., 1980). In this method, quinacrine HCl pellets are placed inside the uterine cavity with the aim of creating fibrosis and occlusion of the Fallopian tubes.

During the latter part of the 20th century, investigators and practitioners in a number of countries used intrauterine quinacrine HCl as a sterilizing agent. The World Health Organization (WHO) estimated that over 140,000 quinacrine sterilizations were performed in 34 countries over the period from 1977-2000. However, the procedure was banned in Vietnam in 1993, in Indonesia in 1994, and in India and Chile in 1998, following reports of women being sterilized without their consent and due to concerns about potential long-term safety (Hieu et al., 2003; Mudur, 1998; Meeting report: The quinacrine debate and beyond, 2001).

On June 17, 1997, an FDA Talk Paper was issued warning consumers not to purchase certain unapproved products that pose significant, possibly life-threatening health risks (See Appendix 1). One of the two products in question, which was offered for sale on the Internet, was a female self-sterilization kit, formerly marketed as Femestra kit. The kit, which used pellets of quinacrine HCl, was described in the FDA Talk Paper as “an unapproved drug, which can cause ectopic pregnancy, abnormal pregnancies, and permanent damage to a woman’s reproductive organs.”

On August 26, 1998, a safety assessment and Health Hazard Evaluation were conducted by FDA on the kit for uterine insertion of quinacrine HCl pellets for female sterilization (see Appendix 2). In the August 1998 Health Hazard Evaluation, FDA raised concerns in three areas based on results from previously conducted toxicology studies on the oral formulation and the lack of adequate toxicology testing on the intrauterine pellet formulation:

1) Possible carcinogenicity of quinacrine: specifically, quinacrine is a known mutagen and had tested positive in several genotoxicity tests, and the intrauterine administration of quinacrine HCl pellets would result in significant tissue damage and the presence of known mutagen could result in development of cancer of the reproductive tract; 2) Lack of sufficient pharmacokinetic data: specifically, concerns exist on the possible continuous exposure of the endometrium to the drug following intrauterine insertion; and 2

3) Pharmacodynamic issues: specifically, that intrauterine instillation of the cytotoxic agent had been noted to be unsuccessful for complete destruction of the endometrium and had resulted in neoplastic transformation of residual endometrial cells.

The August 1998 Health Hazard Evaluation noted that drugs such as quinacrine HCl with positive mutagenicity and cytotoxicity profiles were of concern with regard to increased cancer risks in humans. Several safety concerns were also identified, including uterine perforation during insertion, possible intraperitoneal leakage of dissolved drug product, formation of hematometra, increased risk for reproductive tract cancers, development of abnormal uterine lesions, and ectopic pregnancy. FDA concluded that the potential and known risks may outweigh any proposed advantages this procedure may have over surgical sterilization in the United States.

On October 14, 1998, FDA issued two warning letters regarding unapproved quinacrine HCl pellets labeled for non-surgical female sterilization (see Appendix 3, 4). In these letters, FDA highlighted many of the same safety concerns identified in the August 1998 Health Hazard Evaluation summarized above and concluded that non-surgical female sterilization is an unsafe use of quinacrine HCl pellets. Citing safety concerns, FDA requested that the unapproved quinacrine HCl pellets for non-surgical female sterilization be immediately removed from the market.

Due to the product’s known mutagenicity, a rat carcinogenicity study was conducted in the 2000’s by a U.S. research organization interested in developing quinacrine HCl as a sterilizing agent. Results of this study were published (Cancel et al., 2010). The stated conclusion of the authors was:

We conclude that two doses of quinacrine administered approximately 21 days apart into the uterus of young sexually mature rats at dose levels ≥ 70 mg/kg increased the lifetime risk of tumor development in the reproductive tract. The types of tumors that developed were mostly uncommon for this strain of rat. The incidence of these tumors was dose- related and was significantly increased at a local quinacrine dose that was a small multiple (8x based on a mg quinacrine/g uterus basis) of the human dose of quinacrine used for non-surgical female sterilization.

This U.S. research organization decided in late 2006 not to continue development of quinacrine HCl for female sterilization, explaining in a journal publication (Sokal et al., 2007) the findings of concern and its reason for discontinuing work on the product:

FHI’s research plan included a “go/no-go” decision point when data became available from a rat carcinogenicity study, at which time results would be reviewed along with other data on quinacrine's safety and effectiveness. Preliminary results became available in November 2006, and FHI subsequently notified the FDA. We followed a consultative process within FHI and with outside experts, stakeholders and FHI’s advisory committee, of women’s health advocates regarding our decision and its dissemination. FHI's 2-year rat carcinogenicity study showed a clear, dose-related increase in reproductive tract tumors following intrauterine administration of quinacrine. After

careful review of these data with outside experts, and taking into account earlier test results indicating quinacrine is mutagenic in vitro, and lower-than-desired effectiveness, a “no-go” decision was made. We shared our decision with other researchers and stakeholders, prior to publication of the rat study. Most appreciated our notification, and the news of our decision did not result in alarmist or inappropriate publicity in the media.

In October 2008, the World Health Organization (WHO) convened a technical panel (WHO, Interim statement, accessed 2016) to discuss the safety of quinacrine sterilization. The panel of experts concluded the following:

• Currently available genetic toxicity data are sufficient to support the conclusion that quinacrine is genotoxic in vitro. No additional in vivo studies are recommended, “because negative results would not negate positive in vitro study results.” • In the two-year rat carcinogenicity study, a dose-related increased incidence of both benign and malignant tumors of the vagina, cervix and uterus was observed in the quinacrine-exposed animals. However, changes such as inflammation, necrosis and cystic dilation of the uterus were also observed. As the panel report noted, “Thus, the findings did not allow the Panel to distinguish between a direct genotoxic effect of quinacrine, a secondary effect of inflammation and tissue regeneration, or a combination of the two, in the genesis of observed tumors in rats.” • The available epidemiologic studies showed no excess risk of reproductive tract cancer but were limited in statistical power. Thus, the report noted that “the Panel could not exclude a modest increased risk in gynecologic cancers.” • Safety outcomes other than cancer were not reviewed.

Overall, the WHO Panel recommended that “until the totality of safety, effectiveness and epidemiological data has been reviewed, quinacrine should not be used for non-surgical sterilization of women in either clinical or research settings.” To date, this interim statement has not been updated or removed.

Conclusions: In light of the risk of carcinogenicity and potentially life-threatening risks discussed above, we have significant concerns about the safety of quinacrine HCl for intrauterine use.

DBRUP has reviewed the literature on the effectiveness of intrauterine administration of quinacrine HCl for female sterilization. The majority of efficacy data are based on follow up of women in developing countries, and there are almost no randomized or controlled clinical trials. Where follow-up data on pregnancy are available, they are typically collected only on a subset of sterilized women; where reported, typically 10-20% of subjects have been lost to follow up.

Pregnancy data are not consistently based on serum or urine pregnancy. In addition, the available data do not rely upon a single standard method of sterilization, so the data may not be pooled or compared across studies.

Reported (Sokal et al., 2008) pregnancy rates range from:

• 0.3 to 3.3% in first year • 1.1 to 10% over five years • 4.3 to 12.1% over 10 years • These rates compare unfavorably with surgical sterilization or intrauterine devices, which provide long-term contraception.

III. RECOMMENDATION

As discussed in the DAIP review, quinacrine HCl is well characterized physically and chemically and there is some evidence of its historic use in compounding. However, quinacrine HCl is a known carcinogen, it is genotoxic and cytotoxic. Female sterilization, the main indication for intrauterine administration of quinacrine HCl, can be done surgically. We have considered the physical and chemical characteristics, and the historical use set forth in DAIP’s and DPARP’s reviews. Due to the serious safety concerns discussed above, and the lack of compelling evidence of efficacy that is at least comparable to currently available methods of female sterilization, we recommend that quinacrine HCl for intrauterine administration not be included on the list of drugs that can be used in compounding under section 503A of the FD&C Act. Furthermore, we recommend that quinacrine HCL for intrauterine administration be placed on the 503A List 2 – Bulk Drug Substances That Raise Safety Concerns, because of the serious risk of female reproductive tract cancer. Drugs on 503A List 2 may not be used in compounding under section 503A unless and until FDA publishes a final rule authorizing their use under section 503A.

BIBLIOGRAPHY

Cancel AM, Dillberger JE, Kelly CM, et al. A lifetime cancer bioassay ofquinacrine administered into the uterine horns of female rats. Regul Toxicol Pharmacol. 2010; 56:156-65.

Ferguson LR, Denny WA. The genetic toxicology of acridines. Mutat Res. 1991; 258:123-60.

Hieu DT, Luong TT. The rate of ectopic pregnancy for 24,589 quinacrine sterilization (QS) users compared to users of other methods and no method in 4 provinces in Vietnam, 1994-1996. Int J Gynaecol Obstet. 2003; 83(Suppl 2):S35-43.

Meeting report: The quinacrine debate and beyond: Exploring the challenges of reproductive health technology development and introduction. Report of a meeting held April 20-22, 2001. Available at http://www.rhtp.org/news/publications/documents/Pub.QS.pdf (accessed April 16, 2015).

Mudur G. India to ban female sterilisation with malaria drug. BMJ. 1998; 316:958.

Nasim A, Brychcy T. Genetic effects of acridine compounds. Mutat Res. 1979; 65:261-88.

Sokal DS et al. Comparative effectiveness of two insertions of quinacrine: Results from 10-year follow-up in Vietnam. Contraception. 2008; 78: 61-5.

Sokal D, Haneke K, Robinson E, et al. FHI’s decision to halt development of quinacrine: Why and how. Contraception. 2007; 76:173-4 (Abstract P48).

World Health Organization. The safety of quinacrine when used as a method of non-surgical sterilization in women. Interim statement. Available at http://apps.who.int/iris/bitstream/10665/70085/1/WHO_RHR_09.21_eng.pdf (accessed February 10, 2016).

Zipper JA, Stachetti E, Medel M. Human fertility control by transvaginal application of quinacrine on the fallopian tube. Fertil Steril. 1970; 21:581-9.

Zipper J, Cole LP, Goldsmith A, et al. Quinacrine hydrochloride pellets: preliminary data on a nonsurgical method of female sterilization. Int J Gynaecol Obstet. 1980; 18:275-9.

APPENDIX D

OND Quinacrine Summary Memorandum for 2016 PCAC

DEPARTMENT OF HEALTH & HUMAN SERVICES

Food and Drug Administration Silver Spring, MD 20993-0002

DATE: February 8, 2016

FROM: Charles J. Ganley, MD Director, Office of Drug Evaluation (ODE) IV Center for Drug Evaluation and Research

THROUGH: John Jenkins, MD Director, Office of New Drugs Center for Drug Evaluation and Research

TO: Pharmacy Compounding Advisory Committee

SUBJECT: Office of New Drugs (OND) Recommendation that Quinacrine Hydrochloride Not Be Placed on the 503A Bulk Drug Substances List

I. Reviews Conducted by OND Review Divisions

Fagron, Professional Compounding Centers of America, and National Community Pharmacists Association nominated quinacrine hydrochloride (“quinacrine”) for inclusion on the list of bulk drug substances that can be used in compounding under section 503A of the Federal Food, Drug, and Cosmetic Act (section 503A bulks list). Reviews of the uses of quinacrine proposed in the nominations were completed by the Division of Anti- Infective Products (DAIP) and the Division of Pulmonary and Allergy Drug Products (DPARP).

In addition to the reviews conducted by DAIP and DPARP, the Division of Bone, Reproductive, and Urologic Drug Products (DBRUP) conducted a review to discuss the concerns that the FDA has with the intrauterine administration of quinacrine. DBRUP recommended that if quinacrine were to be added to the list of bulk drug substances that can be used in compounding under section 503A, it should not be permitted to be compounded for intrauterine administration.

DAIP recommended that quinacrine not be placed on the section 503A bulks list. DAIP found that the availability of quinacrine to treat refractory giardiasis, which may be associated with treatable weight loss and malnutrition but is not considered life threatening, is not advised under section 503A. For this indication, DAIP is concerned about the substantial safety issues associated with the use of quinacrine and the absence of approved labeling to inform the practitioner and patient community regarding those substantial safety issues.

DPARP recommended that quinacrine be placed on the list. This recommendation was based on the data supporting the efficacy of quinacrine in the treatment of cutaneous and

systemic lupus and its overall safety profile relative to alternative treatments, of which the most serious adverse reactions can be monitored and some are reversible following discontinuation of the drug.

Because of the disparate recommendations from DAIP, DBRUP, and DPARP as to whether quinacrine should be placed on the section 503A bulks list, the Director of OND ODE IV reviewed the information in each division memorandum and is making a recommendation that, with the concurrence of the Director of OND, will represent the position of OND on this issue.

II. Evaluation Criteria

Four criteria have been developed for evaluating whether a substance should be included on the section 503A bulks list:

1) The physical and chemical characterization of the substance; 2) Any safety issues raised by the use of the substance in compounded drug products; 3) Historical use of the substance in compounded drug products, including information about the medical condition(s) the substance has been used to treat and any references in peer-reviewed medical literature; and 4) The available evidence of effectiveness or lack of effectiveness of a drug product compounded with the substance, if any such evidence exists.

To reach an overall recommendation regarding whether quinacrine should be added to the section 503A bulks list, OND considered the information presented in the three reviews that accompany this document and each of the four criteria described above.

Physical and Chemical Characterization

The Office of Pharmaceutical Quality review of the chemical and physical properties of quinacrine identifies that quinacrine “can be obtained in a highly pure form and is stable when protected from light.” There are no chemistry or physical characterization issues that would preclude quinacrine from being compounded.

Nonclinical and Clinical Safety

DAIP surveyed the published literature and tertiary reference information regarding quinacrine and found that it is a DNA intercalator, with positive results in mutagenic and clastogenic assays. DNA intercalators perturb DNA structure and stability and by definition are mutagens, which can in turn influence DNA-processing by proteins. A clastogen is a mutagenic agent that results in breakages of chromosomes. Because mutations can lead to carcinogenicity, many mutagens are considered potentially tumorigenic. There were no safety pharmacology data available and a no observed effect level has not been established for quinacrine toxicity or tumorigenicity. In the rat, oral quinacrine is readily absorbed, concentrates in the liver, crosses the blood brain barrier to a limited extent (1 – 5% of plasma levels) and has a half-life of 5 – 14 days. Intrauterine 2

administration in pregnant rats and monkeys has been shown to lead to increased fetal death.

Adverse events in humans were described in prescription labeling or literature for the previously marketed injectable (trade name Atabrine) and oral forms of quinacrine and the oral combination of quinacrine, chloroquine phosphate, and hydroxychloroquine sulfate (NDA 11-234, trade name Triquin). The most serious adverse event described is aplastic anemia, estimated to occur in 1:500,000 lupus patients taking doses of 100 mg/day maximum, despite monitoring of hematologic parameters and visual inspection for the development of lichen planus, which has been known to manifest prior to aplastic anemia. Labeling of the approved product Atabrine (Atabrine [package insert], 1994) warned that the drug could cause transitory psychosis, precipitate an occurrence of psoriasis, or exacerbate porphyria. Precautions in the label stated the drug should not be used in patients with hepatic disease or those taking other hepatotoxic drugs, due to the potential for hepatotoxicity, in patients with G-6-PD deficiency, or in pregnancy. Adverse effects of the gastrointestinal and ophthalmic system events have also been described. It is noted that the U.S.-approved drug hydroxychloroquine sulfate (trade name Plaquenil) bears labeling that describes a safety profile similar to quinacrine’s known safety concerns, including a boxed warning.

As DBRUP described in its review, quinacrine has been used as an unapproved female sterilization agent, in pellet form or as a solution for intrauterine instillation, to scar the endometrial wall and Fallopian tubes and prevent pregnancy. Female sterilization via this route has never been an approved indication for quinacrine in the United States, and multiple alternative methods of female contraception and sterilization are approved. In addition to quinacrine’s positive mutagenic and clastogenic effects, the results of a non- traditional carcinogenicity study published in 2010 concluded that a dose related increase in lifetime risk of reproductive tract tumors was observed in rats following administration of two intrauterine quinacrine doses. Based on an August, 1998 Health Hazard Evaluation, FDA issued an October 1998 warning letter regarding the unapproved products, citing mutagenicity, cytotoxicity and possible carcinogenicity of quinacrine and lack of sufficient pharmacokinetic data with which to determine a safe and effective intrauterine dose.

Historical Use of the Substance

• Atabrine tablets were available during World War II for the treatment and prophylaxis of malaria in troops. Use declined with the development of chloroquine. Marketing was discontinued in 1995. • Atabrine as an injectable was approved in 1964 for the treatment of ascites associated with several types of cancer. The NDA was withdrawn in 2003. • Triquin (quinacrine hydrochloride, chloroquine, hydroxychloroquine) tablet was marketed in the United States until its approval was withdrawn in 1973. • An unapproved pellet dosage form of quinacrine for transcervical delivery was marketed in the late 1990’s for female sterilization. FDA issued warning letters to the firms in 1998 and marketing was discontinued.

• The DPARP review cites peer-reviewed medical literature that discusses the use of quinacrine to treat lupus dating as far back as 1940. However, the extent to which quinacrine is used in the treatment of cutaneous lupus erythematosus (CLE), discoid lupus erythematosus (DLE), or systemic lupus erythematosus (SLE) is unclear. • As noted in the DAIP review, due to the recent unavailability of quinacrine by traditional avenues since the discontinuation of Atabrine in 1995, there has been experience using this drug in its compounded form.

Available Evidence of Effectiveness or Lack of Effectiveness

Areas of therapeutic use were evaluated consistent with the nomination. The published literature describes a number of cases of giardiasis refractory to nitroimidazoles (e.g., tinidazole) alone having been successfully treated with quinacrine monotherapy or a quinacrine-nitroimidazole combination therapy (Nash et al., 2001). DAIP’s review states that the option to treat giardiasis with quinacrine continues to be reported in the literature, although no treatment algorithms were identified that define quinacrine’s specific place in a sequence of treatment options. DAIP also notes that quinacrine is no longer used in clinical practice for malaria or taeniasis (tapeworm) infections because other more effective and less toxic drugs have been approved in the United States for these conditions.

DPARP was asked to consider quinacrine’s nomination for uses in rheumatoid arthritis and lupus. While antimalarial drugs have been used to treat rheumatoid arthritis in the past, DPARP concludes that the numerous approved biologic and nonbiologic therapies for rheumatoid arthritis provide sufficient treatment options.

Current rheumatology and dermatology treatment algorithms recommend quinacrine to improve symptoms of CLE, particularly the severely disfiguring subtype DLE that is refractory to hydroxychloroquine monotherapy and other therapies (Kuhn et al., 2011; Okon et al., 2013). In addition, some literature identifies use of quinacrine with hydroxychloroquine in the treatment of SLE, particularly in cases with extensive skin manifestation. Quinacrine is also recommended for use in combination with hydroxychloroquine to allow for a reduction in the dose of hydroxychloroquine to lower the overall risk of retinal toxicity (Zuehlke et al., 1981). However, no controlled clinical trials evaluating the efficacy of quinacrine in CLE, DLE or SLE could be identified. As the DPARP review points out, prednisone, hydroxychloroquine, and belimumab are approved in the treatment of lupus. Neither the approved treatments nor quinacrine have been shown to prolong survival or reverse the course of the disease.

III. Weighing of the Four Criteria and OND Recommendation

Based on weighing the four criteria, OND recommends that quinacrine hydrochloride not be added to the list of bulk drug substances that may be compounded under section 503A of the FD&C Act.

Physical and Chemical Characterization • There are no chemistry or physical characterization issues that would preclude quinacrine from being compounded.

Historical Use of the Substance • Quinacrine has a long compounding history.

Effectiveness • For CLE, SLE and DLE, there is a long history of use for these conditions and some evidence that it is an effective therapy. • As an antimalarial, an anti-protozoan and an anti-tapeworm therapy, quinacrine is effective but there are newer more effective and less toxic therapies available.

Safety • As noted in the DAIP review, quinacrine is associated with serious adverse events both acutely and with prolonged use. • Quinacrine’s adverse effect profile is similar to other antimalarial drugs (hydroxychloroquine, chloroquine) currently approved with the exception that it does not appear to be associated with retinal toxicity. • Quinacrine has been associated with the development of aplastic anemia. This was first reported during World War II when the rate of aplastic anemia increased in the Pacific war theater. The incidence of aplastic anemia increased from 0.66 / 100,000 prior to the use of quinacrine to 2.84 / 100,000 cases after its introduction (Custer, 1946). The occurrence of lichen planus while on therapy may be a predictor of the development of aplastic anemia. Approximately one-half of the cases of aplastic anemia were preceded by a lichen planus rash. o If a patient develops a lichen planus rash, quinacrine should be stopped. o Patients should be monitored for hypoplastic anemia while on quinacrine.

The Office of New Drugs does not recommend quinacrine for the 503A bulks list because of the serious side effects associated with the use of quinacrine. The DPARP review notes that the safety concerns with quinacrine are known to the clinicians who treat lupus patients. OND is not aware of information to support this, but suspects many rheumatologists are familiar with quinacrine’s serious adverse effects. Placing quinacrine on the section 503A bulks list, however, would allow any prescribers, not just rheumatologists, to prescribe it for any use, not just for lupus, and at any dose. Compounding pharmacies and websites could promote the use of quinacrine for many conditions without much FDA oversight. In addition, because of the possibility for developing serious side effects with quinacrine, an approved package insert should be available to inform both practitioner and patient of the serious side effects and provide recommendations for appropriate follow up. Such package inserts are not required for compounded drugs, and an approved package insert will not be available for a compounded drug containing quinacrine. Therefore, the FDA recommends that quinacrine not be included on the 503A bulk list.

FDA recognizes that in some circumstances, clinicians would choose to prescribe quinacrine for some patients who are either unresponsive to approved alternative 5 therapies or have discontinued approved alternative therapies because of adverse effects. For these situations, the best mechanism for availability is through an expanded access Investigational New Drug (IND) application. An expanded access IND application provides safeguards for patients because under an IND, an investigational brochure containing safety information is prepared, information on the safety of the drug is provided to the patient through informed consent, consistent follow up for patients is required, and a consistently manufactured product is provided to patients. As it would for any drug, FDA is willing to work with sponsors if they should choose to submit an IND application or develop the drug for marketing.

BIBLIOGRAPHY

Atabrine® [package insert]. New York, NY: Sanofi Winthrop Pharmaceuticals; 1994 (discontinued).

Custer RP. Aplastic anemia in soldiers treated with atabrine (quinacrine). Am J Med Sci. 1946 Aug; 212(2):211-24.

Kuhn, A., Ruland, V, Bonsmann G. Cutaneous lupus erythematosus: update of therapeutic options, part 1. J Am Acad Dermatology 2011; 65:e195-e213.

Nash, TE, et al. Treatment of patients with refractory giardiasis. CID 2001; 33:22-28

Okon, LG, Werth, VP. Cutaneous lupus erythematosus: diagnosis and treatment. Best Pract Res Clin Rheumatol 2013; 27:391-404.

Zuehlke, RL, Lillis, PJ, Tice, A. Antimalarial therapy for lupus erythematosus: an apparent advantage of quinacrine. Int J Derm 1981; 20:57-60.

APPENDIX E

Safety Information from Withdrawn Atabrine (quinacrine) Labeling

This text is taken directly from the 2016 DAIP review, regarding the safety of oral use of quinacrine. Much of it was extracted by DAIP from the labeling for the single ingredient Atabrine (quinacrine) tablet product marketed until it was discontinued by the manufacturer in 1995 for lack of sales. This may serve as a basis for safety information that FDA may choose to convey to healthcare practitioners and patients should quinacrine be added to the 503B list.

2. Human Safety

a. Reported adverse reactions

The safety profile of oral quinacrine HCl is well described in the various sources cited below. Safety of the use of quinacrine HCl is in part dependent on dose and duration.

i. Label of Discontinued Quinacrine HCl Product

The warnings section of the prescribing information indicated, among other adverse reaction, the following:

 Quinacrine may occasionally cause a transitory psychosis and should be used with special caution in patients over 60 years of age or in those with a history of psychosis.  Use of quinacrine in patients with psoriasis may precipitate a severe attack of psoriasis.  Quinacrine may exacerbate porphyria.

ii. Adverse Reactions Described in Literature and the Atabrine Package Insert

Adverse reactions associated with quinacrine HCl use include the following:

weeks after initiation of therapy and persists for 2 weeks to 4 months. Quinacrine HCl can be associated with significant rashes, including eczematous and exfoliative rashes as well as worsening of psoriasis (Wallace, 1989; Physician's Desk Reference, 1985). Among 120,000 Australian soldiers who received quinacrine HCl, the incidence of lichen planus (a skin disease) was 1 in 2,000 in those receiving 100 mg/day (Wallace, 1989).

Gastrointestinal disorders Nausea, diarrhea, vomiting, and abdominal cramps have been commonly associated with quinacrine HCl use (Physician's Desk Reference, 1985).

Hepatic effects Elevated liver function tests and, rarely, hepatitis have occurred during long-term and short- term quinacrine HCl therapy (Physician's Desk Reference, 1985; Eshleman et al., 1970; Scoazec et al., 2003). Hepatitis was associated with therapeutic doses of quinacrine HCl and was considered an idiosyncratic unpredictable reaction similar to that caused by halothane (Gibb et al., 1985). Changes in liver tests were detected from 7 to 42 days after initiation of quinacrine HCl. Histological changes in the liver of patients who developed quinacrine HCl associated hepatitis included cytolysis, cholangitis characterized by marked duct wall fibrosis mimicking primary sclerosing cholangitis, and portal inflammatory infiltrates containing lymphocytes, plasma cells, and eosinophils (Scoazec et al., 2003). In a comparative trial of quinacrine HCl in the treatment of Creutzfeldt-Jakob disease elevation in liver tests were noted at a higher rate in the quinacrine HCl arm (3/26 patients) as compared to the placebo arm (0/28 patients (Geschwind et al., 2013). In another trial in the treatment of Creutzfeldt-Jakob disease 16 out 40 patients treated with quinacrine HCl discontinued the drug due to alanine aminotransferase elevation (Collinge et al., 2009). The rate of liver test abnormalities in the control arm in this trial was not reported.

Neurologic and Psychiatric effects

Quinacrine HCl can also have significant psychiatric effects including restlessness, insomnia, and psychosis (Physician's Desk Reference, 1985; Lally et al., 2012). One large study of 7,604 U.S. soldiers in the Second World War found an incidence of 0.4% for quinacrine HCl -induced psychosis (Wallace, 1989). Convulsions have occurred after administration of quinacrine HCl (Rockwell, 1968).

APPENDIX F

Comments Submitted for the March 8 and 9, 2016 PCAC Meeting

THE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE and THE JOHNS HOPKINS HOSPITAL

RHEUMATOLOGY FACULTY PRACTICE Mailing Address: Division of Molecular 1830 E. Monument Street and Clinical Rheumatology Suite 7500 Baltimore, MD 21205 Tel: (410) 955-3823 Telefax: (410) 614-0498 Email: [email protected]

February 17, 2016

Cindy Hong, PharmD Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Avenue WO31-2417 Silver Spring, MD 20993-0002

Re: Quinacrine and Chloroquine

Dear Dr. Hong,

I am providing this written statement for consideration at the March 8, 2016 meeting of the FDA Pharmacy Compounding Advisory Committee.

As the Director of the Lupus Center at Johns Hopkins Hospital, I depend on compounding pharmacists for both quinacrine and chloroquine. These are essential medications for SLE patients in whom hydroxychloroquine is insufficient or cannot be continued due to allergy.

I ask the Committee to recommend inclusion of Quinacrine on the section 503A bulk drug substances list.

Sincerely,

Michelle Petri, M.D., M.P.H. Professor of Medicine From: To: PCAC; Subject: Quinacrine is used in Lupus Date: Thursday, February 18, 2016 11:03:51 PM

To: Cindy Hong, PharmD Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Avenue WO31-2417 Silver Spring, MD 20993-0002

------Please do not take this drug off the market. It makes no sense to propose the removal of this drug. There are a number of articles on quinacrine in peer reviewed journals showing how it helps lupus. Just because the drug is old should not be a reason to ban it.

Why remove access to a drug from people whom it helps?

Thank you for your time,

Sincerely, From: To: PCAC Subject: Quinacrine Date: Wednesday, February 24, 2016 1:53:55 PM

Can you please put Quinacrine on the positive list? I’ve been on this for many years and never had a problem. Definitely been on it at least 10 years.

Don’t know why the FDA wouldn’t be positive.

From: To: PCAC Subject: Quinacrine Date: Friday, February 19, 2016 7:40:58 AM

I am a practicing rheumatologist in(b) (6) Because of the marked escalation of price for generic hydroxychloroquine in the past year (>400%), compounded quinacrine, which has been used to treat rheumatoid arthritis and lupus for at least since my internship in 1978- has become a cost effective alternative. I understand the FDA is having hearings to consider prohibiting compounding of the drug for such treatment. I implore you leave quinacrine still available for compounding.

(b) (6) MD Daniel J Wallace MD FACP MACR Clinical Professor of Medicine Associate Director, Rheumatology Fellowship Program Cedars-Sinai Medical Center David Geffen School of Medicine at UCLA 8737 Beverly Blvd #302 West Hollywood, CA 90048 (310) 652 0920 (b) (6) e mail:

February 21, 2016

Cindy Hong, Pharm D Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Avenue W031-2417 Silver Spring, MD 20993-0002

Re: FDA Proposed Ban of Quinacrine Compounding

Dear Dr. Hong:

I have been contacted on behalf of the American College of Rheumatology, Dr Michelle Petri (Johns Hopkins), Dr Victoria Werth (U of Penn), and Dr David McLain (University of Alabama) to comment on the FDA Proposed Ban on Quinacrine Compounding in preparation for the hearing next month.

In preparation for this correspondence, I reviewed pages 9-64 of the 412 page document put together by the FDA. It includes correspondence from the PCCA, Fagron and the National Community Pharmacology Association recommending that it remain on the compounding list. Further included is the FDA conclusion that quinacrine pellets not be allowed to be compounded (no argument). There is a report from Drs Mishra and Zhang at the FDA that this agent is EFFECTIVE as an antimalarial and antiprotozoal agent, there are other alternatives given its “genotoxic and mutagenic” findings in non human studies. Dr Huff at the FDA acknowledged that quinacrine is safe and effective, has a 70 year history and is recommended in treatment algorithms by lupus experts and the American Academy of Dermatology. Finally, Dr Ganley at the FDA, while acknowledging the probable efficacy and utility of quinacrine had concerns about the lack of adequate safety studies, related that there are alternative agents for lupus and rheumatoid arthritis that can be used, and that if prescribed by physicians without the proper safety admonitions, the agent will ‘fall into the wrong hands’ and be used outside of its appropriate indications.

By way of background, I actively treat 2000 lupus patients, run a fellowship program, have 3 NIH grants, and supervise 30 IRB approved clinical trials and studies. I have written extensively on the use of quinacrine and have had experience with more than 1000 patients on the drug over the last 35 years. The papers include:

1. DJ Wallace, Antimalarial agents and lupus, Rheum Dis Clin North America 1994; 20: 243-263 2. DJ Wallace, Antimalarials—the ‘real’advance in lupus, Lupus 2001; 10: 385-387. 3. DJ Wallace, The use of quinacrine (Atabrine) in rheumatic diseases: A reexamination, Seminars Arth Rheumatism 1989; 18:282-296. 4. DW Wallace, Is there a role for quinacrine (Atabrine) in the new millennium, Lupus 2000; 9:81-82. 5. Antimalarial chapters in editions 2-7 of Dubois’ Lupus Erythematosus, the principal lupus textbook.

Based on the following, I have the following comments:

1. Three million US, UK, Australian, Canadian, and New Zealand soldiers stationed in the South Pacific theater during World War II took Quinacrine EVERY DAY from 1943-1945. No drug in the history of pharmacology has ever been studied for safety issues this thoroughly. I had the pleasure of reading the Surgeon General’s 3000 page summary published in several volumes at the UCLA Medical Library of this incredible experience. The basic conclusions were summarized in my 1989 article and also in detail in the 1954 Goodman gold- standard pharmacology textbook (Goodman LS, Gilman A, The pharmacologic basis of therapeutics (ed 2), New York, Macmillan, 1954, pp 1167-1173). Bottom line: Of the 64 deaths where quinacrine could have played a role, almost all could be attributed to overdoses in soldiers with psychological issues or those who took more than 100 mg a day for months by accident. The rate of aplastic anemia in those taking the correct dose was 1:500,000. No subsequent reports could be attributed to mutagenicity or genotoxicity. 2. The FDA letter states that because of the large number of older articles, they were “not readily available for review”!!!! Table 3 of my 1989 article summarizes 771 patients studied in 20 trials with a 73% response rate. My files contain many of these “not readily available” articles. I just need to be asked. 3. Quinacrine was approved by the FDA for lupus erythematosus in the form of Triquin which was available from 1959 to 1973. In that year, the agency was concerned about combination drugs (Triquin contained hydroxychloroquine and chloroquine), so Winthrop decided to simply continue marketing the components separately. 4. The issue was raised concerning the availability of alternative treatments for lupus. All published treatment algorithms by lupus experts include quinacrine. First of all, it is safer than cyclophosphamide, azathioprine, methotrexate and mycophenolate mofetil, which are NOT FDA approved but widely used. Secondly, the FDA reviewers agree that the drug does not affect the eyes, which is a concern for some patients with disfiguring lupus who cannot take hydroxychloroquine and have the choice of going blind, taking high doses of steroids, chemotherapy or quinacrine. 5. Finally, there are circumstances where quinacrine is life-saving alone or in combination with other lupus therapies.

I agree with Dr Mc Lain that pursuing the IND route will make the drug unavailable for several years (causing flares, hospitalizations and perhaps deaths), and not preclude its off label use by predatory companies who will charge thousands of dollars annually for a drug based on a small study showing what we all know: the drug is works and its safe.

Let me conclude with an anecdote. Quinacrine has clear cut effects on cognitive function, which is often diminished with lupus. I had the opportunity to have a delightful dinner with Dr Stanley Prusiner, a nobel laureate at UC San Francisco (for discovery of prions), who uses quinacrine for certain dementias with some amazing results and is working on trying to accrue a particular isomer of it for future study.

Thank you for your time and attention and feel free to contact me if you have any questions.

Daniel J Wallace MD

February 21, 2016

Cindy Hong, Pharm D Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Avenue W031-2417 Silver Spring, MD 20993-0002

Re: FDA Proposed Ban of Quinacrine Compounding

Dear Dr. Hong:

I am a Professor of Dermatology and Internal Medicine (Rheumatology) at the University of Pennsylvania in Philadelphia, Pennsylvania. I am also Chief of Dermatology at the Philadelphia Veterans Administration Medical Center. I am a previous President and a founding member of the Rheumatologic Dermatology Society. My practice at the University of Pennsylvania is devoted to autoimmune skin disease, with a majority of my patients have lupus erythematosus, dermatomyositis, and other autoimmune diseases. I am thus very aware of the importance of quinacrine to this population.

I have been funded by NIH to conduct prospective database studies in the area of lupus and dermatomyositis over the fifteen years. Among my many patients, I have over 400 patients with lupus and over 200 patients with dermatomyositis who have enrolled in these databases. The data I have obtained has been published in numerous publications over that period of time. One of the articles we published looked at patient outcomes with quinacrine and was cited repeatedly in the FDA Briefing Document for the upcoming PCAC meeting (Chang AY et al, Response to Antimalarials in Cutaneous Lupus Erythematosus: A Prospective Analysis. Arch Dermatol 147, 1261-7, 2011). Between 25 and 50% of my lupus patients require treatment with quinacrine because hydroxychloroquine, the only antimalarial now available without compounding, is not sufficiently effective. In our study we found that nearly 2/3’s of lupus patients not responding to plaquenil do respond to the combination of plaquenil and quinacrine. Many patients find the effects of quinacrine so helpful that they now pay for it out of pocket since insurance companies frequently no longer pay for this compounded medication. There is no other similar medication available, and alternatives such as oral prednisone and immunosuppressives carry many more serious side effects.

We know the quality of life of autoimmune skin disease patients is quite poor, and we have published data about the effects of this chronic, disfiguring, pruritic skin disease on these patients (Klein RS, et al. Quality of Life in Cutaneous Lupus Erythematosus. J Am Acad Dermatol 64, 649-58). Quinacrine has made a huge difference for many of my patients, and positive effects include improvement in arthritis, fatigue, pleuritic chest pain, as well as skin disease.

I have dispensed quinacrine for 3 decades and have not had any patient suffer an irreversible side effect. The side effects are easily monitored, particularly since there is no eye toxicity associated with the drug. Previous reports of aplastic anemia have been related to higher doses previously used for malaria prophylaxis, and I have not seen this with the lower doses used in my autoimmune patients. I have not had a single patient among many hundreds I have treated develop this complication.

As an active member of both the American College of Rheumatology, the American Academy of Dermatology, and the Rheumatologic Dermatology Society, I participate in frequent discussions at national and international meetings that emphasize the importance of quinacrine. With my large population of over 1000 autoimmune patients, it is clear that removing quinacrine as a medication that can be compounded will prevent my treating many patients with a safe and effective therapy. Other therapies we may have to substitute have many more side effects and are often less effective.

There is a need to represent the impact of the removal of quinacrine on the patients with autoimmune disease and on the practitioners who are advocating for optimal care of these patients at the upcoming PCAC meeting. I look forward to sharing my perspective with the group.

Sincerely,

Victoria P. Werth, MD. Professor of Dermatology University of Pennsylvania

Chief, Dermatology Philadephia VAMC

Dept of Clinical Pharmacology 825 NE 13th St. Oklahoma City, OK 73104

Joan T Merrill MD OMRF Professor of Medicine University of Oklahoma Health Sciences Center Member, Oklahoma Medical Research Foundation 825 NE 13th St Oklahoma City, OK 73104 e mail: [email protected]

February 22, 2016

Cindy Hong, Pharm D Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Avenue W031-2417 Silver Spring, MD 20993-0002

Re: FDA Proposed Ban of Quinacrine Compounding

Dear Dr. Hong:

The American College of Rheumatology has made the Community Aware of the Potential FDA Ban on Quinacrine Compounding in preparation for the hearing next month.

I was previously the Medical Director of the Lupus Foundation of America (2002-2016) and am currently the Chief Advisor for Clinical Development at that organization. I am also a widely experienced clinical trial investigator in lupus. As the initiator of the lupus cohort at the Oklahoma Medical Research Foundation and before that, as the Chief of Rheumatology at St. Lukes Roosevelt Hospital in New York City, I have cared for more than a thousand lupus patients during my career.

Qunacrine is compounded safely and effectively by pharmacies all over the country and those of us who take care of lupus patients have been relying on this source for many years. The only side effect that is of any consequence has been some discoloration of skin, which rapidly reverses on stopping the treatment. Quinacrine does not have the ocular toxicity that is (albeit rarely) associated with the use of chloroquine and hydroxychloroquine. Furthermore, the increasing shortage and expense of hydroxychloroquine means that eliminating our source of Quinacrine, a medication that is known to be safe and effective, will cause a serious hardship to patients in an already unacceptably underserved chronic, life threatening disease.

The last thing that will serve the safety and wellbeing of lupus patients is even less treatment options!

Sincerely,

Joan T. Merrill, M.D.

From: To: Hong, Cindy Subject: Quinicrine Date: Wednesday, February 24, 2016 5:16:53 PM

I have just learned that the FDA is considering removing Quinicrine from the market. My daughter has suffered from lupus for 12 years, since she was 8 years of age. She has tried all of the other appropriate medications with no positive outcome. Last year she started quinicrine and after a couple of months was doing well enough to come off several medications. She is now able to go to college, go out with friends, and basically live a life that is not controlled by illness and pain.

Please do not remove quinicrine from the market. I'm sure it will affect the health, happiness, and lifespan of many people suffering from lupus.

I am sharing this information on social media and will continue to do so until this matter is resolved.

Thank you for your time, From: To: Hong, Cindy Subject: Quinicrine Date: Friday, February 26, 2016 9:26:07 AM

Please help us keep quinicrine, which is an excellent drug to help lupus victims!

Thank you for your time.

February 28, 2016

Cindy Hong, Pharm D Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Avenue W031-2417 Silver Spring, MD 20993-0002

Re: FDA Proposed Ban of Quinacrine Compounding

Dear Dr. Hong:

As a lupus patient, longtime advocate and leader of the Lupus and Allied Diseases Association, I would like to thank you for the opportunity to offer my comments on the FDA Proposed Ban on Quinacrine Compounding in preparation for the March 8-9 FDA Compounding Pharmacy Advisory Committee Meeting.

The Lupus and Allied Diseases Association, Inc., is a passion driven, all-volunteer patient advocacy organization dedicated to improving quality of life for those impacted by lupus and allied diseases and conditions of unmet need by fostering collaboration among all stakeholders and promoting innovative advocacy, awareness and biomedical research program initiatives.

Based on my experiences as both a lupus patient and advocate, I offer the following unique perspective. Currently, few therapies exist for patients like me as there are only four FDA-approved treatments for systemic lupus erythematosus: aspirin, antimalarials, corticosteroids, and belimumab. In 2011 the FDA approved the fourth treatment for lupus after many years of limited accepted therapeutic options, but these three older medications continue to be standard treatment for lupus today.

In addition, the FDA has acknowledged that immunosuppressives are a standard treatment for lupus, even though none are indicated. Belimumab, recently approved in 2011, is a biologic that is only approved in combination with standard treatments. Hydroxychloroquine, the most commonly used antimalarial drug, and corticosteroids, including prednisone were approved in the 1950s. Many of the companies that developed the brand name drugs used for lupus treatment discontinued production, resulting in mostly generic versions remaining on the market.

Due to the heterogeneous nature of autoimmune diseases like lupus, no two cases are alike and treatment is highly individualized; effectively treating patients like me is like balancing on a pinhead. Numerous times therapies have failed me over the years, forcing me and my physicians to take a step backwards and think outside of the box to treat my complicated medical picture. Many existing treatments for lupus are toxic and cause detrimental side effects with long-term use and since there are only so few drugs currently approved for lupus many therapies are off-label such as cancer treatments and transplant drugs.

Many treatments have significant side effects, especially with continuing use. For decades the “go to” drug for lupus patients has been prednisone, a corticosteroid. I call it, “the drug you love to hate.” It certainly saves your life and fights inflammation quickly, especially in an acute situation, but this comes at a high price with horrific side effects such as glaucoma, cataracts, hypertension, diabetes, acne, atherosclerosis, avascular necrosis, osteoporosis, an increased susceptibility to infections, elevated cholesterol, obesity, edema, fat deposition, manic feelings, and an appetite equal to that of 4 growing teenage boys. Other treatments include immunosuppressives that ablate the entire immune system and hydroxychloroquine and chloroquine which can cause retinal toxicity. Off-label therapies such as cancer treatments can cause infertility and miscarriages. Patients get numerous infections and many of us take drugs to treat the side effects of other medications which is ludicrous.

Individuals with complex care needs like me require unique strategies and personalized medicine to manage their care. When our disease status becomes stable through our current treatment regimen the last thing we want or need is for a drug to be discontinued; forcing us to an alternative treatment, disrupting continuity of care and causing us to go backwards in our care. For some lupus patients, quinacrine is the current successful treatment choice either by itself or in combination with other therapies.

For many lupus clinicians quinacrine has become the drug of choice in treating an unmet disease population with limited treatment choices and compounding pharmacies have safely provided the drug for years. Hydroxychloroquine has become more expensive with time and more difficult to obtain due to shortages. Quinacrine is safer than current off-label treatments that are not FDA-approved but widely used such as cyclophosphamide, azathioprine, methotrexate and mycophenolate mofetil. Quinacrine also does not cause ocular complications whereas hydroxychloroquine and chloroquine are known for adversely affecting the eye. We are in dire need of newer treatments for lupus but until more drugs are developed and approved, the current arsenal of treatments must continue to include quinacrine as an effective and vital treatment.

On behalf of the Lupus and Allied Diseases Association and the many individuals struggling to manage life-threatening and life-diminishing diseases like lupus as well as the physicians who treat them, we thank you for your former initiatives concerning lupus and commend you for including the patient perspective during the drug regulatory process.

Please feel free to contact me at(b) (6) if you have any questions. Thank you.

Sincerely-

Kathleen A. Arntsen President/CEO

· PO Box 170 Verona, NY 13478 · 315-829-4272 · www.NoLupus.org · [email protected] · February 29, 2016

Cindy Hong, Pharm D Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Avenue W031-2417 Silver Spring, MD 20993-0002 Via email: [email protected]

Re: FDA Proposed Ban of Quinacrine Compounding; Docket No. FDA-2016-N-0001

Dear Dr. Hong,

As the nation’s leading private lupus research organizations founded and supported by patients and their families, the Alliance for Lupus Research (ALR) and Lupus Research Institute (LRI) urge the FDA not to ban the compounding of Quinacrine.

Systemic lupus erythematosus (lupus) is a complex, chronic disease that disproportionately affects women and minorities, for which there is a lack of safe and effective therapies. There is no known prevention or cure for lupus. Current treatments address the symptoms but not the underlying disease and have problems with efficacy and toxicity. Only four treatments have been approved for lupus and only one of these, belimumab, was developed specifically for lupus. The other treatments are the antimalarial hydroxychloroquine, prednisone (a corticosteroid), and aspirin. Belimumab, the first drug ever developed specifically for lupus does not remove the need for other treatments.

Standard of care continues to rely on corticosteroids combined with immunosuppressant and chemotherapeutic agents approved for other indications. These treatments can be effective in alleviating symptoms but have toxicities and harmful side effects (including osteoporosis, sterility, and infections) that can be as debilitating as the disease itself.

Many patients find the antimalarial hydroxychloroquine is not effective. In addition, many patients fear the side effects, particularly eye problems such as sensitivity to light and vision changes. Quinacrine is a vital alternative.

It is incredibly important for physicians to have as many treatments at their disposal to manage the very complex care of lupus patients and we respectfully request that Quinacrine be allowed to continue to be compounded.

Sincerely,

Kenneth M. Farber Margaret G. Dowd President & CEO, Alliance for Lupus Research President & CEO, Lupus Research Institute [email protected] [email protected] 212-218-2840 212-685-4118

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1 Giardiasis Surveillance — United States, 2011–2012. Centers for Disease Control and Prevention. http://www.cdc.gov/mmwr/preview/mmwrhtml/ss6403a2.htm. Accessed 2-25-2016.

Comment Letter: FDA Pharmacy Compounding Advisory Committee March 1, 2016 Page 2

dehydration, and malabsorption of nutrients.2 Chronic cases of giardiasis that are refractory or resistant to approved drugs have been reported and have responded to quinacrine alone or in combination with metronidazole.

Given the low but still noteworthy incidence of refractory cases for which quinacrine appears to be an effective treatment, ASHP is concerned about eliminating access to this agent despite well-founded concerns about its adverse effects. If the agency has not already done so, we recommend reaching out to practicing providers in primary care, gastroenterology, infectious diseases (particularly tropical medicine and parasitology specialists), as well as the Centers for Disease Control and Prevention, to affirm that other equally or more effective and less toxic, readily available therapies preclude the continued need to use quinacrine in certain refractory cases of giardiasis.

Systemic and cutaneous lupus: ASHP agrees with the conclusion of the Division of Pulmonary, Allergy, and Rheumatology that quinacrine has an established position among antimalarials used to treat lupus due to its overall safety profile compared to existing approved agents. We also share the concern of the Office of New Drugs that placing quinacrine on the 503A list does not limit its use to this indication. However, considering the serious and disfiguring nature of lupus and its cutaneous symptoms as well as the broad acceptance of quinacrine as a therapeutic option, we have strong concerns about eliminating access to this drug.

If quinacrine is not added to the 503A list, we recommend that FDA establish a regulatory pathway for making quinacrine available to patients who may benefit from its use before taking action that prohibits compounding. The expanded access investigational new drug application process suggested by the Office of New Drugs and discussed in the June 2015 PCAC meeting will not facilitate access to quinacrine and other drugs available only from compounders without significant revision.

ASHP also supports adding metered dose inhalers and dry powders for inhalation to the list of drug products with demonstrable difficulties for compounding for reasons similar to those identified for these products in the 2014 letter from Public Citizen included in the meeting briefing.

ASHP appreciates the opportunity to comment on these issues. Please contact me if you have any questions or wish to discuss our comments further. I can be reached by telephone at 301-664-8796 or by e-mail at [email protected] .

Sincerely,

Bona E. Benjamin, B.S.Pharm. Director, Medication-Use Quality Improvement ASHP 7272 Wisconsin Avenue

2 Bad Bug Book – Foodborne Pathogenic Microorganisms and Natural Toxin. Food and Drug Administration. http://www.fda.gov/downloads/Food/FoodborneIllnessContaminants/UCM297627.pdf Accessed 2-25-2016

Comment Letter: FDA Pharmacy Compounding Advisory Committee March 1, 2016 Page 3

Bethesda, MD 20814 Phone: 301-664-8796 [email protected]

March 1, 2016

Submitted via email: [email protected]

Ms. Cindy Hong Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Avenue, Building 31 Room 2417 Silver Spring, MD 20993-0002

Re: Pharmacy Compounding Advisory Committee

Dear Ms. Hong:

The American College of Rheumatology, representing over 9,500 rheumatologists and health professionals, appreciates the opportunity to respond to the Pharmacy Compounding Advisory Committee on its review of whether to continue to permit compounding of quinacrine. The American College of Rheumatology strongly resists the suggestion that quinacrine be removed from the FDA-approved compounding list.

Rheumatologists provide ongoing care for patients with complex, chronic and acute conditions that require specialized expertise. Rheumatologists provide face-to-face, primarily non-procedure- based care, and serve patients with serious conditions that can be difficult to diagnose and treat. These conditions include rheumatoid arthritis, systemic lupus erythematosus and other debilitating diseases. Early and appropriate treatment by rheumatologists slows or halts disease progression, improves patient outcomes and reduces the need for costly downstream procedures and care that is complicated and made more expensive by advanced disease states.

Rheumatologists have long trusted and relied on quinacrine, which is often the only treatment available, to safely and effectively provide patients with relief from rheumatic diseases. We urge the Committee to not limit our ability to provide our patients with the benefits quinacrine provides when appropriately provided under safe compounding standards. a. Quinacrine’s Safety and Effectiveness is Well-Established and Unquestioned

Quinacrine’s effectiveness has been demonstrated over decades of clinical use, and all standard textbooks of rheumatology list quinacrine as an important member of the antimalarial drug class of rheumatologic pharmacotherapy. Quinacrine possesses no recently disclosed intrinsic toxicity that should result in withdrawal of its FDA-approved status. There have been no newly published safety concerns or reports of widespread morbidity associated with the use of this medication in rheumatology patients. In short, there is no justification for the withdrawal of this medication on the basis of safety concerns. Further, quinacrine has been proven safe and effective by many peer- reviewed articles.1

1 Rheum Dis Clin North Am. 1994 Feb; 20(1):243-63. Antimalarial agents and lupus. Wallace DJ; Lupus (2001) 10:148-151, Antimalarial Therapy: A panacea for mild SLE?, Cruz DD; Lupus (2002) 11:71-81, Antimalarials in cutaneous lupus erythematosus: mechanisms of therapeutic benefit, A. Wozniacka1, A. Carter and D.P. McCauliffe

Ms. Cindy Hong March 1, 2016 Page 2

b. Patients with Rheumatological Diseases Have Few FDA-Approved Treatments Available

The majority of rheumatic diseases have few or no FDA-approved treatments. PubMed catalogues dozens of articles that list quinacrine as an appropriate treatment for lupus but its chances of receiving FDA-approval are minimal. To withdraw or significantly restrict quinacrine would deprive many patients of the benefits they obtain from this safe and effective antimalarial.

Antimalarial drugs are a key component of drug regimens for the treatment of rheumatologic diseases such as rheumatoid arthritis, systemic lupus erythematosus, and discoid lupus erythematosus. Hydroxycloroquine (Plaquenil) is presently the only available FDA- approved antimalarial drug for rheumatology patients. But many patients cannot take hydroxycloroquine due to intolerance (including allergy and ocular side effects). Even for patients who can take hydroxychloroquine, its combination with quinacrine has provided very effective treatment.

As far as we are aware, quinacrine is the last readily available or acceptable antimalarial substitute for patients who cannot take hydroxycloroquine. For these patients, quinacrine has been a critically important therapy that provides the therapeutic benefits of hydroxycloroquine. As our members have attested, quinacrine is often the only treatment available that effectively controls symptoms of rheumatic diseases. c. Quinacrine is the Only Affordable Treatment for Many Patients

As it is, our patients pay exorbitant prices to obtain quinacrine because their insurance companies frequently fail to cover compounded medications. Despite this lack of coverage, patients continue to pay out-of-pocket for quinacrine because it is the only therapy that prevents flare-ups of rashes and arthritis. In addition, for patients who are able to take hydroxycloroquine, access is often limited by cost as this drug can cost patients up to $200 per month. For these patients, quinacrine is sometimes a more attractive option. All of these patients will suffer if quinacrine is prohibited.

The American College of Rheumatology appreciates the work that the FDA does and the opportunity to respond to the Request for Information. We look forward to being a resource to you and to working with the FDA and the Committee. Please contact Adam Cooper, Senior Director of Government Affairs, at [email protected] or (404) 633-3777 if you have questions or if we can be of assistance.

Sincerely,

Joan M. Von Feldt, MD, MSEd President, American College of Rheumatology

Lupus (2001) 10:385-387; Antimalarials--the 'real' advance in lupus, Wallace DJ; J. Antimicrob Chemother. 2015 Jun; 70(6):1608-1621; Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases. Al-Bari MA. Jill P. Buyon, MD Lady Va and Sir Deryck Maughan Professor of Rheumatology Director, Division of Rheumatology Director, NYU Lupus Center Director, Research Registry for Neonatal Lupus

February 29, 2016

Cindy Hong, PharmD Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Avenue WO31-2417 Silver Spring, MD 20993-0002

Dear Dr. Hong,

Priority is a very powerful driver in a busy person’s life. Despite the myriad of deadlines I face as the Director of the Rheumatology Division at New York University School of Medicine and Director and Founder of the Lupus Clinic at the Hospital for Joint Diseases, the greatest priority in my professional life is the well-being of patients. That said, the opportunity to voice a critical concern regarding the potential withdrawal of quinacrine from the compounding marketplace assumes the highest immediate priority. When Dr. Victoria Werth brought this to my attention, I considered this one of the greatest potential setbacks to the care of my lupus patients. Why should quinacrine be pulled because there have been negative issues related to other compounded medications?

It cannot be emphasized enough the hardship our lupus patients face every day: not only the fear of flares at any time, the threat of organ failure, pain, and fatigue, but also the shame of hair loss or a skin rash that makes it difficult to carry on personal relationships. Our “black bag” of lupus treatments still remains far behind so many other rheumatologic diseases. Quinacrine has served a critical role in helping our lupus patients with fatigue, arthralgia, arthritis and skin rashes. It has been a treatment available, albeit only in compounding pharmacies. We as lupologists have observed the ameliorating effects this drug has had on our patients.

While initial approaches to cutaneous manifestations of lupus often begin with avoidance of sun exposure followed by hydroxychloroquine and then perhaps chloroquine, refractory activity often calls for the addition of quinacrine. This is important since quinacrine does not result in additive macular toxicity. While there are other choices of medications, they often carry far greater risk such as immunosuppression, diabetes, high blood pressure, or bone loss to mention a few. Other choices may require intravenous administration and are beyond the financial means of some patients.

301 East 17th Street – Suite 1410, New York, NY 10003 · tel 212.598.6110 · fax 212.598.6246

In short, I am sure I join the list of my colleagues who have devoted careers to the care of patients with lupus. Please accept this letter as a formal request that quinacrine remain on the permissible list for compounding therapeutic medications.

Sincerely,

Jill P. Buyon, MD Lady Va and Sir Deryck Maughan Professor of Rheumatology Director, Division of Rheumatology Director, NYU Lupus Center Director, Research Registry for Neonatal Lupus NYU School of Medicine/NYU Langone Medical Center

301 East 17th Street – Suite 1410, New York, NY 10003 · tel 212.598.6110 · fax 212.598.6246

March 1, 2016

Submitted via email: [email protected]

Cindy Hong, PharmD Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Avenue, WO31-2417 Silver Spring, MD 20993-0002

Re: Pharmacy Compounding Advisory Committee and Quinacrine

Dear Dr. Hong:

The Lupus Foundation of America appreciates the opportunity to provide comment to the Pharmacy Compounding Advisory Committee on its review of quinacrine. Quinacrine is a life line for many people with lupus; and often times, the only tolerable substitute for hydroxychloroquine (Plaquenil). Eliminating patient access to quinacrine would be detrimental to their health and quality of life.

Lupus is a chronic autoimmune disease in which the immune system is unbalanced, causing inflammation and tissue damage to virtually any organ system in the body including the lungs, heart, kidneys, blood, skin, joints, and brain. The disease can cause seizures, strokes, heart attacks, miscarriages, disfiguring skin rashes, and kidney failure. Nearly 1.5 million Americans live with some form of lupus. Given the heterogeneity of the disease, people with lupus need and deserve an arsenal of safe and effective treatments in order to manage the wide variety of manifestations.

To date, few medications have been approved by the FDA for use in lupus and only one has been specifically designed and approved for lupus in 2011. Most medications used to treat the disease are prescribed off-label. Removing an effective agent from an already slim list of available therapeutic options would have a significant negative impact on patients suffering from lupus.

The literature and reviews presented to the Advisory Committee clearly document the important role quinacrine can play in treating people with lupus. The drug is as safe and effective as any other drug used to treat lupus. Quinacrine is an acceptable antimalarial substitute for patients who cannot tolerate hydroxychloroquine and is sometimes used in combination with hydroxychloroquine for refractory disease. Quinacrine does not have the ocular toxicity that is associated with hydroxychloroquine; and for these patients, quinacrine is a critically important alternative with similar therapeutic benefits.

Dr. Hong Pharmacy Compounding Advisory Committee Lupus Foundation of America Page 2

Below is a representative sampling of input from our constituents over the last month regarding the value of quinacrine.   t 2 weeks. I cannot take Plaquenil, because I have bad side effects involving my eyes. I also can't take prednisone because of bad side

 crine has worked wonders for me with few side effects (Florida)

In addition to providing similar therapeutic benefits as hydroxychloroquine, quinacrine plays a significant role in treating patients with chronic cutaneous lupus, helping to reduce and prevent the disfiguring consequences. One leader in the field notes that between 25 and 50% of her cutaneous lupus patients require treatment with quinacrine because hydroxychloroquine is not sufficiently effective. She notes that alternatives such as prednisone and immunosuppressants can carry many more serious side effects. In addition, common and often debilitating symptoms experienced by people with lupus.

Eliminating access to quinacrine would create an undue hardship and be disastrous to those living with this cruel disease, and people with lupus deserve better. To that end, the Foundation opposes removing quinacrine from the FDA-approved compounding list. Thank you in advance for your consideration, and please contact Kim Cantor, Vice President, Advocacy and Government Relations at (202) 349-1150 or at [email protected] with any questions.

Sincerely,

Sandra C. Raymond Susan Manzi, MD, MPH President and Chief Executive Officer Medical Director Lupus Foundation of America Lupus Foundation of America

**PLEASE NOTE: The FDA Division of Advisory Committee and Consultant Management has received From: Alliance for Natural Health USA on behalf of To: PCAC over 700 of the same form Subject: Please Approve the Compounding Bulk Ingredient Nominations letter as below, signed by Date: Tuesday, March 01, 2016 2:38:33 PM different people from the public. The majority of these were submitted after the written submission Mar 1, 2016 deadline. We are including Pharmacy Compounding Advisory Committee this sample in lieu of sending all received to Dear Advisory Committee, date. I see that the Pharmacy Compounding Advisory Committee is meeting on March 8-9 to consider a new group of nominations to the Compounding Bulk Ingredient list, and I'm writing to ask you to approve all of them for compounding.

Boswellia (Indian frankincense) is a tree resin that has been used for thousands of years to treat a variety of conditions, and recently has been shown to have anti-inflammatory properties. It also can be used to treat arthritis and osteoarthritis.

Aloe vera leaves have been used medicinally as far back as the 16th century BCE. It is widely used in both natural and traditional medicine for a variety of conditions, treating everything from burns to constipation, psoriasis, and herpes simplex virus.

D-ribose is a natural ingredient for increasing energy (ATP) production. Evidence indicates that d-ribose can rejuvenate heart muscles after a heart attack or other cardiac events.

Chondroitin sulfate is a structural component of the cartilage in joints. It stimulates the production of cartilage, improves blood circulation to the joints, and is used to treat osteoarthritis, among other things.

These are commonly available supplements. What puzzles me is that the committee seems to think that everyday supplements should be banned from compounding. This is completely illogical. You can buy them in stores! Yet you think my doctor cannot include them in personalized medicine he prescribes? What kind of crazy illogic is that?

All of these types of patients, and many more, will suffer if the PCAC continues to ban supplements from compounding. You MUST maintain patient access to compounded supplements -- some of our most vulnerable patients rely on them!

I am copying my representative and my senators on this request, so they can see for themselves how your agency is mangling the compounding law that Congress passed. Stop banning everyday supplements from the Compounding Bulk Ingredients list! Last year your committee absurdly voted to ban curcumin, which is widely used for its well-documented anti-inflammatory properties, among many other health benefits. Keep supplements on the Bulk Ingredients list!

Sincerely, From: Alliance for Natural Health USA on behalf of To: PCAC Subject: Please Approve the Compounding Bulk Ingredient Nominations Date: Wednesday, March 02, 2016 3:13:59 AM

Mar 1, 2016

Pharmacy Compounding Advisory Committee

Dear Advisory Committee,

D-ribose is a natural ingredient for increasing energy (ATP) production. Many of my patients with Chronic Fatigue and Epstein Barr have shown functional improvement while using this supplement. Yet, the medication Lyrica which is highly addictive and can seriously injure or harm people is now the GO To for use! Evidence indicates that d-ribose can rejuvenate heart muscles after a heart attack or other cardiac events. I don't think that Lyrica can do that!

Acetyl-L-carnitine is naturally produced by the body, functions as an antioxidant, and promotes the production of glutathione in cells. It is used for Alzheimer's disease, age-related memory problems, and a wide range of other conditions. One of my patients who was starting liver failure due to consumption of the recommended prescription dose of tylenol had improved liver function after taking Acetyl -L- carnitine and Milk Thistle. She is no longer on a a donor request list.

Sincerely,

To Whom it May Concern,

I am an academic dermatologist and heard the disturbing news that the FDA is reviewing the ability of pharmacies to compound quinacrine. This is am extremely important drug that we use in dermatology and rheumatology for our patients with lupus and other autoimmune diseases to help control their disease. It often is used to help decrease the amount of prednisone the patient needs, which is very important as prednisone has many dangerous and irreversible long term side effects. I am part of the Wake Forest Baptist Health Comprehensive Autoimmune Disease clinic which is a regional provider for patients with complex autoimmune disease, and compounded quinacrine is a vital part of our therapeutic armamentarium. Please consider continuing to allow us to use this medication.

Sincerely,

Lindsay C. Strowd, MD

Assistant Professor of Dermatology

Wake Forest Baptist Health From: Alliance for Natural Health USA on behalf of To: PCAC Subject: Please Approve the Compounding Bulk Ingredient Nominations Date: Friday, March 04, 2016 9:59:37 AM

Mar 2, 2016

Pharmacy Compounding Advisory Committee

Dear Advisory Committee,

I have personally used the ingredients aloe vera (for relief for my stomach) and boswellia (for muscle/joint aches) and find them superior to OTC options such as TUMs or Tylenol. These also don't have side effects like many OTC drugs do when taken for longer periods. Please do not take away my freedom to choose the best remedies for me. This is America, supposedly Land of the Free.

D-ribose is a natural ingredient for increasing energy (ATP) production. Evidence indicates that d-ribose can rejuvenate heart muscles after a heart attack or other cardiac events.

Sincerely, From: Alliance for Natural Health USA on behalf of To: PCAC Subject: Please Approve the Compounding Bulk Ingredient Nominations Date: Friday, March 04, 2016 9:59:37 AM

Mar 2, 2016

Pharmacy Compounding Advisory Committee

Dear Advisory Committee,

D-ribose is a natural ingredient for increasing energy (ATP) production. Evidence indicates that d-ribose can rejuvenate heart muscles after a heart attack or other cardiac events.

Sincerely, From: Alliance for Natural Health USA on behalf of To: PCAC Subject: Please Approve the Compounding Bulk Ingredient Nominations Date: Friday, March 04, 2016 9:15:10 AM

Mar 2, 2016

Pharmacy Compounding Advisory Committee

Dear Advisory Committee,

PLEASE Vote YES to approve compounding bulk ingredients.

D-ribose is a natural ingredient for increasing energy (ATP) production. Evidence indicates that d-ribose can rejuvenate heart muscles after a heart attack or other cardiac events.

The elimination of supplements from compounding has far-reaching implications. Sometimes patients don't even have the option of using any form other than the compounded one. Supplements are compounded for all types of patients -- such as those with environmental sensitivities who cannot have supplements with preservatives, or autistic children and other patients for whom swallowing pills is extremely difficult, or patients suffering from depression who rely on compounded amino acid solutions to manage their mood. All of these types of patients, and many more, will suffer if the PCAC continues to ban supplements from compounding. You MUST maintain patient access to compounded supplements -- some of our most vulnerable patients rely on them!

Sincerely, From: Alliance for Natural Health USA on behalf of To: PCAC Subject: Please Approve the Compounding Bulk Ingredient Nominations Date: Friday, March 04, 2016 7:14:52 AM

Mar 2, 2016

Pharmacy Compounding Advisory Committee

Dear Advisory Committee,

Stop messing with REAL MEDICINE. I see that the Pharmacy Compounding Advisory Committee is meeting on March 8-9 to consider a new group of nominations to the Compounding Bulk Ingredient list, and I'm writing to ask you to approve all of them for compounding.

D-ribose is a natural ingredient for increasing energy (ATP) production. Evidence indicates that d-ribose can rejuvenate heart muscles after a heart attack or other cardiac events.

Sincerely, From: Alliance for Natural Health USA on behalf of To: PCAC Subject: Please Approve the Compounding Bulk Ingredient Nominations Date: Friday, March 04, 2016 9:59:37 AM

Mar 2, 2016

Pharmacy Compounding Advisory Committee

Dear Advisory Committee,

PLEASE -Stop banning everyday supplements from the Compounding... I see that the Pharmacy Compounding Advisory Committee is meeting on March 8-9 to consider a new group of nominations to the Compounding Bulk Ingredient list, and I'm writing to ask you to approve all of them for compounding.

D-ribose is a natural ingredient for increasing energy (ATP) production. Evidence indicates that d-ribose can rejuvenate heart muscles after a heart attack or other cardiac events.

Sincerely, From: Alliance for Natural Health USA on behalf of To: PCAC Subject: Please Approve the Compounding Bulk Ingredient Nominations Date: Friday, March 04, 2016 11:26:11 AM

Mar 2, 2016

Pharmacy Compounding Advisory Committee

Dear Advisory Committee,

My tax dollars support outfits like the PCAC which uses it power to deny doctors and citizens everything that is NOT BIG PHARMA ENDORSED at the expense of public health. Stop it! Your objective is obviously another attempt to do away with Compounding Pharmacies AND natural health because you have prostituted yourselves to the DRUG CARTEL that drives American Medicine and funds politicians. Citizens deserve better. Try ethics!

D-ribose is a natural ingredient for increasing energy (ATP) production. Evidence indicates that d-ribose can rejuvenate heart muscles after a heart attack or other cardiac events.

Sincerely, From: Alliance for Natural Health USA on behalf of To: PCAC Subject: Please Approve the Compounding Bulk Ingredient Nominations Date: Friday, March 04, 2016 11:26:11 AM

Mar 2, 2016

Pharmacy Compounding Advisory Committee

Dear Advisory Committee,

I see that the Pharmacy Compounding Advisory Committee is meeting on March 8-9 to consider another new group of nominations to the Compounding Bulk Ingredient list, and I'm writing to ask you to approve all of them for compounding.

D-ribose is a natural ingredient for increasing energy (ATP) production. Evidence indicates that d-ribose can rejuvenate heart muscles after a heart attack or other cardiac events.

Sincerely, From: Alliance for Natural Health USA on behalf of To: PCAC Subject: Please Approve the Compounding Bulk Ingredient Nominations Date: Friday, March 04, 2016 11:26:13 AM

Mar 2, 2016

Pharmacy Compounding Advisory Committee

Dear Advisory Committee,

I see that the Pharmacy Compounding Advisory Committee is meeting on March 8-9 to consider a new group of nominations to the Compounding Bulk Ingredient list, and I'm writing to ask you to approve all of them for compounding. As an American citizen concerned about my health, I think these and other helpful substances should be available to me in compounding form.

D-ribose is a natural ingredient for increasing energy (ATP) production. Evidence indicates that d-ribose can rejuvenate heart muscles after a heart attack or other cardiac events.

Thank you for your consideration.

Sincerely, A Summary of World War II (WWII) – Era Publications on the Psychiatric Adverse Effects of Quinacrine1

Written Evidence Submitted to the March 8, 2016 Pharmacy Compounding Advisory Committee Meeting

Dr. Remington Nevin Johns Hopkins University Bloomberg School of Public Health

Quinacrine is a derivative of acridine dye first synthesized in the early 1930s [1], marketed initially under the names erion and atabrine [2], then later also under the name

Mepacrine [3] (Figures 1-2). The drug may be considered a ring substituted 4- aminoquinoline that is structurally closely related to chloroquine. The drug is a member of the quinoline class of antimalarials that also includes quinine and mefloquine.

In early reports of its use prior to WWII, quinacrine was noted to induce “definite cases of delirium and mental disturbances” [4], including symptoms of depression [5], and delusional insanity. Case reports described acute personality and behavioral, change, severe insomnia and anxiety described as an “impression of impending death” [6], visual hallucinations, and cognitive dysfunction. One patient complained that “a large part of his brain was out of action” [6], while another patient was described as manic, restless, disoriented, and suffering visual hallucinations that “snakes and fantastic animals were crawling on the floor” [7]. Early marketing materials for quinacrine drug acknowledged these “mental disturbances which have been observed in a few instances during treatment” [8].

1 Adapted from a review article currently under editorial review, co-authored by Dr. Ashley Croft.

1 With shortages of quinine during WWII, quinacrine was added to the U.S. pharmacopoeia in 1942 [9], and the drug was quickly prioritized for military use both as treatment and as a suppressive prophylaxis throughout the war [10]. Studies of the acute toxicity of quinacrine had been planned during a wartime antimalarial drug development effort [11], but these were soon deprioritized after they were declared to be of “minor importance” to military leadership [12]. Although early studies in the U.K. had suggested that quinacrine caused “troublesome dreams” [13], and independent studies in the U.S. had noted slight increases in nervousness [14], it was initially unclear whether toxic effects were actually due to quinacrine or merely to a contaminant [10,15].

Towards the end of the war, however, sufficient experience had accumulated, including from rechallenge experiments, for wartime researchers to conclude that quinacrine use was definitely associated with a toxic psychosis distinct from the effects of malaria, often of abrupt onset [16,17], described as including “mania, catatonia, and paranoid and hallucinatory states” [18], and typically developing only several days after the start of treatment [16]. Authors noted the psychosis was typically marked either by

“excitement, hallucinations, and delusions” with an affect of “euphoria and expansiveness” [19], or alternatively with “retardation, disorientation, and amnesia to recent events, together with confabulation” [19], where affect was predominantly “one of bewilderment and fearfulness” [19].

In controlled tests of intellectual functioning, a large proportion of subjects administered quinacrine were found to suffer significant subclinical impairment, and in 2 cases of psychosis that developed subsequently, tests of intellectual functioning had showed mild impairment prior to onset [20]. The authors concluded that “among a large

2 group” administered quinacrine, “some would show clinical confusion” [21]. A separate controlled study conducted among healthy U.S. military physicians clearly demonstrated quinacrine induced changes in the electroencephalograph [22], accompanied by apprehension, restlessness, insomnia, “awakening dreams which at times were of frightening and nightmare quality” [23], and symptoms of mania described as “an unusual push of activity” associated with “tension, irritability, and anxiety” [24]. One subject experiencing panic attack and flight of ideas noted he “felt so bombarded by stimuli that he could not deal with them effectively” [23]. The patient became very anxious, depressed, confused, and was thought to be suffering delirium, although his consciousness was in fact preserved [23,24].

With the publication of such research findings initially restricted due to wartime considerations, official documents acknowledged only that “psychological disturbances occasionally appear” with use [25], and that the drug could cause “mild excitement” and rarely, “acute maniacal psychoses” [26]. Despite the imprecision of these official military reports, quinacrine was nonetheless recognized by numerous wartime physicians as a potential cause of psychiatric disorders [27], and as the war ended and in subsequent years as restrictions were rescinded, numerous publications entered the literature describing psychiatric effects associated with the drug’s use.

One ecological study linked an increase in a combat unit’s rate of psychoses to their initiation of quinacrine for prophylaxis [28]. A case report described a previously healthy soldier suffering 3 distinct episodes of mania, each occurring with recurrent use of quinacrine both for prophylaxis and treatment [29]. Another detailed case report described a patient free of psychiatric history initially and thought to be suffering from

3 cerebral malaria, who following 5 days treatment with quinacrine developed excitement, talkativeness, and rambling, progressing to depression, impaired concentration, disorientation in time and place, anterograde and retrograde amnesia, and delusions; the symptoms lasted two weeks [30]. One case series of those treated with quinacrine reported psychoses developing 0—10 days after the last day of malarial fever [31]; another between 3 —12 days following the start of quinacrine [19]; while another reported an even wider latency of onset of 2—22 days, with a similarly wide range in time to satisfactory recovery of 1— 30 days. In at least 4 cases in the series, failure to recover and the development of chronic psychiatric disorders was noted [17].

In the immediate postwar years, a few additional studies and case reports of psychiatric effects with quinacrine were also published [32], including a series describing inappropriate sexual behavior associated with psychoses [33]. In a final published study of 31 previously healthy Army Medical Department officers who volunteered to take the drug experimentally at treatment doses [34], 77% suffered some form of mental disturbances: 71% complained of abnormal, anxious and disturbing and rarely terrifying dreams; 58% developed sleep disturbances, with loss of up to half of normal sleep, prompting sedative use to treat insomnia in two fifths of these, or 26% of the total; 39% went on to develop severe psychic disturbances, of which a quarter, of 10% of the total, suffered frank psychoses with delusions, hallucinations, and profound changes in mood, including mania; 35% complained of tension; 32% complained of restlessness, and 29% depression. During an earlier phase of the trial when the drug had been administered at lower prophylactic dose rates, 29% had complained of mild complaints, most notably

4 abnormal dreams and sleep disturbances, which were deemed “the most reliable warning sign” of the development of “more severe reactions” [34].

References

1. von Oettingen W. Acridine Dyes. In: The Therapeutic Agents of the Quinoline Group.

New York, NY: The Chemical Catalog Company;1933. p. 239–55.

2. Russell PF. Plasmochin, Plasmochin with Quinine Salts and Atabrine in Malaria

Therapy. Arch Intern Med. 1934;53:309–20.

3. British Medical Journal. Quinine and World War. Br Med J. 1942;1:152–3.

4. Froilano de Mello I. Chemoprophylaxis of Malaria in Portugese India. Suid-Afrikaanse

Tydskr vir Geneeskd. 1938;12:710–24.

5. Ad A, Needham DE. More Observations on Atebrin. Lancet. 1933;222:929–30.

6. Kingsbury AN. Psychoses In Cases of Malaria Following Exhibition of Atebrin.

Lancet. 1934;224:979–82.

7. Govindaswamy MV. Atebrin Poisoning. Lancet 1936;227:56–7.

8. Winthrop Chemical Company. Malaria: Chemotherapy with Atabrine. New York, NY:

Winthrop Chemical Company;1938.

9. The Science News-Letter. New Anti-Malarial Drugs Announced Ahead of Time. Sci

News-Letter. 1942;42:108.

10. Baxter JP. Antimalarials. In: Scientists Against Time. Boston, MA: Little, Brown and

Company;1946:299–320.

5 11. Committee on Medical Research of the Office of Scientific Research and

Development. Minutes of Meeting of Atabrine Conference Held at the National Academy of Sciences November 2, 1942. In: Bulletin of Malaria Research, Vol 1. Washington, DC:

Board for the Coordination of Malarial Studies;1942. p. 46a–f.

12. Clark WM. History of the Co-Operative Wartime Program. In: Wiselogle FY, editor.

A Survey of Antimalarial Drugs, 1941-1945, Vol 1. Ann Arbor, MI: J.W. Edwards;1946. p. 2–57.

13. Temkin O, Ramsey EM. Antimalarial Drugs: Summary of Classified Material on File.

Washington, DC: National Research Council; 1944.

14. Loughlin EH, Bennett RH, Santora E, Mattucci S. Clinical Toxicity of Atabrine

Dihydrochloride. War Med. 1943, 4:272–9.

15. Carden GA. Introduction. In: Malaria Reports, Vol 1. Washington, DC: Board for the

Coordination of Malarial Studies;1946. p. i–xx.

16. Newell HW, Lidz T. Malaria Report #180: A Clinical Study of the Toxicity of

Atabrine on the Central Nervous System. In: Malaria Reports, Vol 2. Washington, DC:

Board for the Coordination of Malarial Studies;1944. p. 1–2.

17. Newell HW, Lidz T. The toxicity of atabrine to the central nervous system. Am J

Psychiatry. 1946;102:805–18.

18. Sheppeck ML, Wexberg LE. Malaria Report #A-196: Abstract of Report on Toxic

Psychoses Associated with Administration of Atabrine From an Overseas Hospital. In:

Malaria Reports, Vol 2. Washington, DC: Board for the Coordination of Malarial

Studies;1944. p. 1–2.

6 19. Gaskill HS, Fitz-Hugh T: Toxic Psychoses Following Atabrine. Bull US Army Med

Dep. 1945;86:63–69.

20. Lidz T, Kahn RL. Toxicity of quinacrine (atabrine) for the central nervous system; an experimental study on human subjects. Arch Neurol Psychiatry. 1946;56:284–99.

21. U.S. Army Medical Deparment. Malaria Report #181: Experimental Study of the

Toxicity of Atabrine to the Human Central Nervous System. In: Malaria Reports, Vol 2.

Washington, DC: Board for the Coordination of Malarial Studies;1944:2–5.

22. Engel GL, Romano J, Ferris EB. Effect of quinacrine (atabrine) on the central nervous system; clinical and electroencephalographic studies. Arch Neurol Psychiatry.

1947;58:337–50.

23. Engel GL, Romeno J, Ferris EB, Schmidt LH. Malaria Report #212: The Effect of

Atabrine on the Central Nervous System. In: Malaria Reports, Vol 2. Washington, DC:

Board for the Coordination of Malarial Studies;1944:1–4.

24. Engel GL, Romano J, Ferris EB. Malaria Report #266: The Effect of Atabrine on the

Central Nervous System. In: Malaria Reports, Vol 3. Washington, DC: Board for the

Coordination of Malarial Studies;1944:1–4.

25. Lull GF. Reactions attributed to atabrine. J Mil Med Pac. 1945;1:1–4.

26. McIntire RT. Treatment of Clinical Malaria. Navy Dep BUMED News Lett.

1944;4:17–25.

27. Peal S. Psychiatric Experiences in a Tropical Theater of Operations. Bull US Army

Med Dep. 1944;73:68–78.

7 28. Greiber MF. Psychoses associated with the administration of atabrine. Am J

Psychiatry. 1947;104:306–14.

29. Shiers D. Cerebral Excitement Following Mepacrine Therapy. Br Med J. 1946;1:762–

30. Mergener JC. Psychosis following administration of quinacrine hydrochloride for malaria; neuropsychiatric study of a case. War Med. 1945;8:250–2.

31. Sheppeck ML, Wexberg LE. Toxic psychoses associated with administration of quinacrine. Arch Neurol Psychiatry. 1946;55:489–510.

32. Ocko FH. A case of atabrine psychosis in a civilian. Am J Psychiatry. 1947;103:833.

33. Kapur KB, Das Gupta PR. Sexual disorder in “mepacrine psychoses”. Ind Med Gaz.

1950;85:20–2.

34. Hoobler SW. Psychotic reactions to the ingestion of large doses of quinacrine in normal subjects. Am J Trop Med Hyg. 1947;s1-27:477–481.

8 Figure 1: Quinacrine Label. From: Captured German, Italian and Japanese Medical Supplies, World War II. NCP 13729/OHA 250. New Contributed Photographs Collection. Otis Historical Archives. National Museum of Health and Medicine.

Figure 2: Atebrin, Bayer. Captured German, Italian and Japanese Medical Supplies, World War II. NCP 13754 /OHA 250: New Contributed Photographs Collection. Otis Historical Archives. National Museum of Health and Medicine.

APPENDIX G

FDA’s Nomination of Quinacrine for the 503B Bulks List

131

What is the Quinacrine hydrochloride name of the nominated ingredient? Is the ingredient Quinacrine is an active ingredient as defined in § 207.3(a)(4) because it is an active intended for incorporation into a finished compounded drug product and is ingredient that intended to furnish pharmacological activity in the treatment of CLE. meets the definition of Alves, P, MM Bashir, M Wysocka, et al., 2017, Quinacrine Suppresses “bulk drug Tumor Necrosis Factor-Alpha and Ifn-Alpha in Dermatomyositis and substance” in Cutaneous Lupus Erythematosus, J Investig Dermatol Symp Proc, 18:S57- §207.3(a)(4)? S63.

National Center for Biotechnology Information. "PubChem Compound Summary for CID 237, Quinacrine" PubChem, https://pubchem.ncbi.nlm.nih.gov/compound/Quinacrine. Accessed 10 December, 2020. What is the 6-Chloro-9-(4-diethylamino-1-methylbutylamino)-2-methoxyacridine chemical name dihydrochloride of the substance? What is the Mepacrine Hydrochloride; Atabrine common name of the substance? Does the G6242H2NAA substance have a UNII Code? What is the Pharmaceutical grade chemical grade of the substance? What is the The nominated drug substance should have acceptable quality (e.g., strength, quality, identity, strength, purity, potency) that is suitable for a substance to be used stability and in a pharmaceutical product. purity of the substance? How is the Powder ingredient supplied? Is this substance No foreign pharmacopeia monographs. recognized in foreign pharmacopeias or registered in other countries?

132

Has information The USP-NF previously contained a drug substance monograph for been submitted quinacrine hydrochloride and a drug product monograph for quinacrine about the hydrochloride oral tablets (USP-NF 1990), but these monographs were substance to the deleted. USP for consideration of monograph development? What medical Cutaneous Lupus Erythematosus (CLE) condition(s) is the drug product compounded with the bulk drug substance intended to treat? Are there other There are no FDA-approved drug products indicated for the treatment of drug products Cutaneous Lupus Erythematosus (CLE). There are FDA-approved products approved by the indicated for the treatment of Systemic Lupus Erythematosus (e.g., FDA to treat the Plaquenil (hydroxychloroquine sulfate) NDA-009768 and Benlysta same medical (belimumab) (BLA 125370)). condition? If there are FDA Some patients who have CLE are not fully clinically responsive to, or are approved drug intolerant of, treatment with FDA-approved products, primarily products that hydroxychloroquine sulfate. Patients who have not achieved a satisfactory address the same clinical response to FDA-approved hydroxychloroquine sulfate may medical achieve a better treatment response by taking both quinacrine and condition, why hydroxychloroquine sulfate simultaneously. Patients who have CLE and is there a clinical are intolerant of hydroxychloroquine sulfate may achieve a satisfactory need for a clinical response by taking quinacrine alone. compounded drug product? Are there safety Yan, D, R Borucki, RD Sontheimer, and VP Werth, 2020, Candidate Drug and efficacy data Replacements for Quinacrine in Cutaneous Lupus Erythematosus, Lupus on compounded Sci Med, 7(1):e000430. drugs using the nominated Kuhn, A, E Aberer, Z Bata-Csorgo, et al., 2017, S2k Guideline for substance? Treatment of Cutaneous Lupus Erythematosus - Guided by the European Dermatology Forum (Edf) in Cooperation with the European Academy of Dermatology and Venereology (Eadv), J Eur Acad Dermatol Venereol, 31:389-404.

Ugarte, A, S Porta, R Ríos, et al., 2018, Combined Mepacrine– Hydroxychloroquine Treatment in Patients with Systemic Lupus Erythematosus and Refractory Cutaneous and Articular Activity, Lupus, 27:1718-1722.

133

Reich, A, VP Werth, F Furukawa et al., 2016, Treatment of Cutaneous Lupus Erythematosus: Current Practice Variations, Lupus 25(9):964-972.

García-Montero, P, J del Boz, F Millán-Cayetano, et al., 2016, Quinacrine: A Treatment Option That Should Not Be Overlooked, Actas Dermo- Sifiliográficas (English Edition), 107:867-870. If there is an There is no FDA approved product that contains quinacrine hydrochloride. FDA-approved drug product that includes the bulk drug substance nominated, is it necessary to compound a drug product from the bulk drug substance rather than from the FDA- approved drug product? What dosage Oral dosage forms form will be compounded using the bulk drug substance? What strength(s) 25-100 mg will be compounded from the nominated substance? What are the Oral anticipated route(s) of administration of the compounded drug product(s)?

134

Has the bulk In 1995, Sanofi-Winthrop discontinued the production of quinacrine in the drug substance United States (see FDA 2016 quinacrine hydrochloride review, been used https://www.fda.gov/media/95976/download). Since then, quinacrine drug previously to products have been compounded using the bulk drug substance (see Mittal, compound drug L, L Zhang, R Feng, et al., 2018, Antimalarial Drug Toxicities in Patients products? with Cutaneous Lupus and Dermatomyositis: A Retrospective Cohort Study, J Am Acad Dermatol, 78:100-106 e101.). In addition, based on reported outsourcing facility data from January 2018 to December 2019, one outsourcing facility reported compounding quinacrine HCl 100 mg oral capsules in the six months preceding the January 2018 reporting period (see https://www.accessdata.fda.gov/scripts/cder/outsourcingfacility/index.cfm).

135

APPENDIX H

M-CERSI Report on Quinacrine

136

Summary Report

Quinacrine

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

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 ...... 9 Summary of focus groups/interviews of medical experts and specialty organizations ...... 18 Summary of survey results ...... 19 CONCLUSION ...... 21 APPENDICES ...... 22 Appendix 1. References ...... 22 Appendix 2. Transcripts from focus groups/interviews ...... 35 Appendix 3. Survey instrument ...... 36 Appendix 4. Raw survey data ...... 40

Table of Tables

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

REVIEW OF NOMINATION Quinacrine (UNII code: 81A613ZZ6X) was not nominated for inclusion on the 503B Bulks List.

METHODOLOGY Background information The national medicine registers of 13 countries and regions were searched to establish the availability of quinacrine 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 quinacrine; name variations of quinacrine 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 quinacrine. 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 March 25, 2019. The search included a combination of (quinacrine[tiab] OR Acrichine[tiab] OR Atabrine[tiab] OR Atebrin[tiab] OR Mepacrine[tiab]) AND (treat*[tiab] OR therap*[taib] OR clinic*[tiab] OR malaria*[tiab] OR immuno*[tiab] OR leishmaniasis[tiab] OR malignant[tiab] OR giardiasis[tiab] OR cancer[tiab] OR tumor[tiab] OR carcinoma[tiab]) AND (humans[MeSH Terms] AND English[lang] NOT autism). Peer-reviewed articles as well as grey literature were included in the search. Search results from each database were exported to Covidence®, merged, and sorted for removal of duplicate citations. Study selection Articles were not excluded on the basis of study design. Articles were considered relevant based on the identification of a clinical use of quinacrine or the implementation of quinacrine 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 quinacrine 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 quinacrine compared to alternative therapies. Results Please refer to Figure 1.

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

Outreach to medical specialists and specialty organizations Using the indications from the results of the literature review, fourteen (14) medical specialties that would potentially use quinacrine were identified: cardiology, dermatology, endocrinology, gastroenterology, hematology, hepatology, infectious disease, neurology, obstetrics and gynecology, oncology, pain management, primary care, pulmonology, and rheumatology. 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. Five (5) experts were contacted for interviews, of which one (1) accepted. Two (2) experts provided their response via email, one (1) expert specializing in hepatology stated that quinacrine is not used and one (1) expert specializing in gastroenterology stated that quinacrine is rarely used to treat giardiasis and other parasitic infections of the gut but would not consider it to be first-line, no additional follow-up was warranted. Two (2) experts, one (1) specializing in neurology and one (1) specializing in oncology, failed to respond to the interview request. 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 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, hematology, hepatology, infectious disease, neurology, obstetrics and gynecology, oncology, pain management, primary care, pulmonology, and rheumatology, identified from the literature review, were contacted to facilitate distribution of an online survey. A Google™ search was conducted to identify relevant professional associations within each specialty. Associations were included if their members are predominantly practitioners, national associations, and organizations focused on practice within the US. Organizations without practicing 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 17 associations. If an association had more than one (1) substance with indications relevant to that specialty, substances were combined into one (1) survey with no more than 14 substances per survey. Table 1 highlights the associations that agreed to distribute the survey link and Table 2 includes the associations that declined to participate. Additionally, single substance surveys were created and posted on the project website which was shared with survey participants. Participation was anonymous and voluntary. The estimated time for completion was 30 minutes with a target of 50 responses per survey. The Office of Management and Budget (OMB) approved this project.

Table 1. Participating associations

Specialty Association

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

Pain Medicine American Academy of Pain Medicine (AAPM)

Primary Care American Academy of Environmental Medicine (AAEM)

Rheumatology American College of Rheumatology (ACR)

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

Hematology American Society of Hematology (ASM) 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

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

Oncology American Society of Clinical Oncology (ASCO) Declined

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

Pulmonology American Thoracic Society (ATS) Declined

CURRENT AND HISTORIC USE Summary of background information • Quinacrine is not available as an FDA-approved product. • Quinacrine is not available as an OTC product in the US. • There is no current United States Pharmacopeia (USP) monograph for quinacrine. • Quinacrine is not available in any of the twelve foreign registries.

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

Table 4. Currently approved products – select non-US countries and regions No approved products in the selected non-US countries and regions

Summary of literature review • Total number of studies included: 206 (72 descriptive, 110 experimental, and 24 observational). • Most of the studies were from the US (80). o Quinacrine was never formally approved by the FDA but it was used for a long time for malaria, especially during World War II. It was marketed until 1995 and was discontinued due to a decrease in demand.1 • The most common indications for the use of quinacrine in the US were malaria, giardiasis, and female sterilization. The most common indications from the non-US studies were female sterilization, lupus erythematosus, and giardiasis. • Compounded products were identified from both US and non-US studies.

Table 5. Types of studies

Types of Studies Number of Studies

Descriptive2-73 72

Experimental74-183 110

Observational184-207 24

Table 6. Number of studies by country

Country Number of Studies

Australia11,61,92,113,150 5

Bangladesh190 1

Belgium124,178 2

Cameroon94 1

Canada33,43,87,134,187 5

Chile73,183 2

China52,101,114,137 4

Costa Rica80 1

Cuba98 1

Denmark95,96,100,139 4

Egypt3,4,109,111 4

Finland131,148 2

France12,44,121 3

Germany189 1

Honduras123 1

India6,130,141,157,168,174,186 7

Indonesia65,66,74,75 4

Iran162,199 2

Israel51,170-172 4

Italy99 1

Japan146 1

Kenya27,120,138 3

Libya108 1

The Netherlands71 1

Nigeria97,126 2

Norway45,112,129,132,143 5

Pakistan84,90 2

Panama160 1

Philippines79 1

Russia169 1

Saudi Arabia7 1

Singapore147 1

South Africa59 1

South Korea17 1

Spain29,46,57,70,188,204-206 8

Sudan2 1

Sweden76-78,81,164,176,193 7

Switzerland115 1

Syria198 1

Thailand16,151,158,159 4

UK5,22,26,30,36-38,50,54,64,72,105,117,136,142,149,152,154,167,177,179,185,203 23

US8-10,13-15,18-21,23-25,28,31,32,34,35,39-42,47-49,55,56,58,60,62,63,67-69,82,83,86,88,89,91,93,102- 104,106,107,110,118,119,125,127,128,133,135,140,145,153,155,156,161,163,165,166,173,175,180,182,184,191,194,195,200- 75 202,207

West Africa116 1

Multiple Countries • Brazil, Cuba196 • Brazil, US197 • Chile, US181 • Egypt, US85 8 • India, US144 • Ireland, UK53 • Kenya, US122 • Norway, Sweden192

Total US: 80 Total Non-US Countries: 131 aStudies 84, 121, 143, 180, and 196 counted in both US and non-US total.

Table 7. Number of studies by combinations No combination product(s) were nominated

Table 8. Dosage by indication – US

Indication Dose Concentration Dosage Form ROA Duration of Treatment

0.4-1g – Solution Intravenous Once

Malaria, 0.4-0.7g/week – Tablet Oral 1 month-1 year treatment41,82,83,102,104,106,119,122,125,153,165,173,18 0,201 0.1-1.2g/day – – Oral 6 days-8 months

Daily – – – 2 years

Malaria, suppressive82,103,122,191,195 0.21g/4 days-3.4g/week – – – 4-7 days

Malaria, protective104,106 0.4-0.8g/day – – – 11-25 days

200-300mg/day – Tablet Oral 5 days-3 weeks Giardiasis8,10,19,21,35,47,48,55,85,145,166,207 6mg/kg/day – Suspension Oral 5-10 days

240-252mg/month – Pellets Intracervical, Intrauterine, Transvaginal 1-3 months Female 1.5g – Powder Intracervical – sterilization39,68,89,107,110,135,140,144,181,182,197 3g – Suspension Intrauterine Once

Solution, Pneumothorax15,40,42,58,62,133,163,202 25-100mg/day 0.1-2% Intrapleural 3-4 days Suspension

25-200mg/day – Tablet Oral 15 months Lupus erythematosus9,13,20,155,175,194,200 100-300mg/day – – – 3 weeks-12 months

Pleural effusion23,49,86,93,127,156 100-1500mg/day – Solution Intrapleural Once-3 months

Dermatomyositis14,18,184 100mg/day – – – At least 5 months

Sarcoidosis60,63,128 0.1-2.7g/day – – – –

Amebiasis56 0.4g/day – – – 15 days

Annular erythema of Sjogren’s syndrome34 100mg/day – – Oral –

Ascites23 200-400mg/day – Solution Intrapleural 4-6 days

0.6g 6% Solution Intramuscular Twice Auricular fibrillation31 0.1-0.3g/day – – Oral 6 days

Creutzfeldt-Jakob disease118 300mg/day – – Oral 2 months

Dipylidiasis69 150mg 7.5% – Nasogastric tube Once

HBsAg-positive chronic hepatitis91 100-400mg/day – Tablet Oral 3 months

Light sensitive eruptions155 25-75mg/day – Tablet – At least 6 weeks

Non-small cell lung cancer88 50-150mg/day – – Oral 84 days

Psoriasis20 100-300mg/day – – – 3 weeks-3 months

Reticular erythematous mucinosis67 100mg/day – – – 10 weeks

Supraventricular tachycardia31 0.1g – – Intravenous Once

Systemic sclerosis28 – – – – –

Teniasis161 0.2g/10 minutes – Tablet – 4 doses

0.2g/6 hours – – Intramuscular 30 hours Torula meningitis32 0.3-0.4g/day – – Oral 18 days

Trichomonas vaginitis24 7.3g/treatment – Powder Intravaginal 4 treatments over 2 days

Tularemia, undulant fever25 0.3g/day – Tablet Oral 5 days Abbreviations: “–“, not mentioned; ROA, route of administration.

Table 9. Dosage by indication – non-US countriesa

Indication Dose Concentration Dosage Form ROA Duration of Treatment

Pellet, Intracervical, Intrauterine, 180-500mg/month – 1-4 months Female sterilization65,66,73- Solution Transcervical, Transvaginal 75,79,80,84,87,90,108,109,137,141,144,147,157,162,168,181,183,190,197,198 50mg-1g 16-20% Suspension Intrauterine, Intravaginal Once

100mg/day – Tablet Oral 8 months Lupus erythematosus12,17,22,29,33,38,44,54,70,99,100,115,170- 50mg-1.4g/week – – – 2 weeks-11 months 172,189,204 – – – – 6 months-7 years

0.3-1.2g/day – Solution Intramuscular 1 day-5 weeks

5mL/day 4% Solution Intravenous 7 days Malaria, treatment2,30,45,71,92,94,97,113,116,120,154,169,174,179,186 0.1-1.2g/day – Tablet Oral 1-17 days

0.1-1g/day – – – Once-2 months

Pleural effusion36,76-78,81,129,134,139,164,167,176,185,187,192,193 180mg-28g/week 0.25-4% Solution Intrapleural 1 day-3 months

200-300mg/day – – Oral 5-14 days Giardiasis7,12,51,57,85,98,131,143,158,177,196,199,205,206 6-8mg/kg/day – – – 5 days-3 years

Tapeworm (Taenia101,114,130,138 saginata27,43,123 and 0.4-1.2g/day – Tablet Oral 1 day solium61, Hymenolepis nana123, Raillietina siriraji16)

300mg/day – Capsule Oral 3 weeks-26 months Prion disease50,105, Creutzfeldt-Jakob disease46,121,146, Fatal familial insomnia188 100-600mg/day – – – 15 days-3 months

0.1g – Solution Injection Once

Amebiasis3,4,52 0.9g/day – – Oral 10 days

0.3-0.9g/day – – – 7-15 days

150-800mg/day – Tablet Oral 7 days Malaria, chloroquine-resistant11,136,151 2.5g/5 days – – – 5 days

Rheumatoid arthritis112,117,148 100-300mg/day – Tablet Oral 1 year

Sarcoidosis72,203 100mg/day – – Oral 10 months

Annular elastolytic giant cell granuloma53 300mg/week – – Oral –

Collagenous colitis150 300mg/day – – Oral 10 days

Common variable hypogammaglobulinemia59 300mg/day – – – 1 month

Cutaneous sarcoid37 100-200mg/day – – – 8 months

Dermatomyositis5 200mg/day – – – A few weeks

Gastroenteritis26 0.3g/day – – – 5 days

Hymenolepis nana111 15mg/kg – Tablet Oral Once

Intestinal parasitism160 300mg/day – – – 5 days

Jessner-Kanof disease178 300mg/week-100mg/day – – – 7-10 months

Malaria, suppressive6 1 tablet/day – Tablet – 7 months

Non-insulin-dependent diabetes mellitus152 300mg/day – – Oral 7 days

Onchocerciasis126 400mg/day – – – 5-7 days

Opisthorchis viverrini159 0.4-2g/day – – Oral 5-8 days

Petit mal142 500mg/week – – – 3-24 months

Pneumothorax124 100mg/day – Solution Intrapleural 4 days

Polymorphic light eruptions, chronic96 25-200mg/day – – – 31 days

Prevention against UV rays132 1mL 5% Ointment Topical 1-4 days

Reticular erythematous64 100mg/day – – – A few weeks

Rosacea95 100-200mg/day – Tablet Oral At least 31 days

Vitiligo149 0.1-0.3g/day – – Oral – Abbreviations: “–“, not mentioned; ROA, route of administration. aStudy 11 had more than one indication.

Table 10. Compounded products – US

Publication Indication Compounding Method Dosage Form Final Strength Year

Pneumothorax40,42,62,133,202 1973-1983 • Quinacrine in 5% glucose water or saline Solution 0.1-2%

Pleural effusion23,86,93,156 1964-1978 • Quinacrine in saline or in pleural/ascitic fluids Solution 0.33-2%

Ascites23 1967 • Quinacrine 200mg in saline or in pleural/ascitic fluids Solution 2%

Auricular fibrillation and supraventricular tachycardia31 1947 • Quinacrine in 1% novocaine – 6%

Dipylidiasis69 1962 • Quinacrine in water – 7.5%

Female sterilization182 1976 • Quinacrine powder in 2% xylocaine – 30%

Giardiasis21 1981 • Quinacrine suspension in 1.5M sucrose solution Suspension 2%

Malaria201 1947 • Atabrine dissolved in distilled water and added to saline Solution –

Trichomonas vaginitis24 1948 • Atabrine with boric acid powder Insufflation – Abbreviation: “–“, not mentioned.

Table 11. Compounded products – non-US countries

Indication Compounding Method Dosage Form Final Strength

• Quinacrine dissolved in distilled water, saline, or pleural fluid Solution 0.25-4% Pleural effusion36,76- 78,129,134,167,176,185,193 • Quinacrine dissolved in 0.25% bupivacaine Solution 0.33%

• Quinacrine suspended in water Suspension 16.7%

• Quinacrine in 2% xylocaine Solution –

• Quinacrine with epinephrine in 2% xylocaine Solution –

• Quinacrine in water Solution – Female sterilization87,183 • Quinacrine with oxytocin in water Solution –

• Quinacrine with tetracycline in 2% xylocaine Solution –

• Quinacrine with cortisone in water Solution –

• Quinacrine with versenate in water Solution –

Giardiasis7 • Mepacrine suspended in water Solution 0.5%

• Quinacrine HCl tablets dissolved in distilled water, boiled for 3 minutes after adding 15mL distilled water Malaria186 Solution 3.3% to 700mL of solution and allowed to cool

Pneumothorax124 • Quinacrine dissolved in sterile saline solution Solution 0.2%

Taeniasis61 • Atabrine HCl dissolved in glass of water containing one teaspoonful of sodium bicarbonate Solution – Abbreviation: “–“, not mentioned.

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

Table 12. Overview of interviewee

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

Academic medical END_03 MD Endocrinology No • Not familiar with quinacrine. institution Abbreviation: MD, Doctor of Medicine.

Summary of survey results

Table 13. Characteristics of survey respondents [12 people responded to surveya]

Board Certification DO MD No Response

Anesthesiology 0 1 0

Dermatology 0 2 0

Neurology 0 1 0

Pain Medicine 0 3 0

Rheumatology 1 0 0

No Response 0 0 6 Abbreviations: DO, Doctor of Osteopathic Medicine; MD, Doctor of Medicine.

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

Types of Products Respondents, n (N=2a)

Compounded 2

FDA-approved 0

Over-the-counter 0

Dietary 0

Unsure 0

No Response 0 aOut of 12 respondents, 2 reported using, prescribing, or recommending quinacrine product.

Table 15. Compounded use of quinacrine in practicea

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

Lupus 100mg Daily Tablet Oral Indefinitely Adult vulgaris

Systemic – – – – – – lupus Abbreviations: “–“, not mentioned; ROA, route of administration. aTwo (2) respondents.

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

Standard Therapy Indication Compounded, n (N=2) Non-compounded, n (N=0)

Nonea 1 0

No Response 1 0 aOne (1) respondent wrote “adjunct to hydroxychloroquine in recalcitrant cutaneous lupus”.

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

Theme Reasons

Availability “Only available via compounding”

Intolerance “Intolerance to FDA approved product”

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

Respondents, n (N=2)

No–use has remained consistent 1

Yes–I use it LESS often nowa 1

Yes–I use it MORE often now 0 aOne (1) respondent wrote “shortage/unavailability”.

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

Respondents, n (N=2)

No 2

Yes 0

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

CONCLUSION Quinacrine (UNII code: 81A613ZZ6X) was not nominated for inclusion on the 503B Bulks List. From the literature review conducted, the most common indications for the use of quinacrine in the US were malaria, giardiasis, and female sterilization. The most common indications from the non-US studies were female sterilization, lupus erythematosus, and giardiasis. Compounded products were identified from both the US and non-US studies. From the interview, one (1) interviewee was not familiar with quinacrine. From the survey responses, 2 out of 12 respondents used quinacrine. Respondents most commonly used compounded quinacrine for lupus vulgaris and systematic lupus. Availability and intolerance were the reasons provided for use of a compounded quinacrine product over an FDA-approved product. Zero (0) out of two (2) respondents who used the compounded product reported stocking non-patient specific compounded quinacrine in their practice.

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135. Lippes J, Brar M, Gerbracht K, Neff P, Kokkinakis S. An FDA phase I clinical trial of quinacrine sterilization (QS). International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2003;83 Suppl 2:S45-49. 136. Looareesuwan S, Phillips RE, Edwards G, et al. Mepacrine accumulation during treatment of chloroquine-resistant falciparum malaria. Annals of tropical medicine and parasitology. 1988;82(2):107-112. 137. Lu W, Zhu J, Zhong C, Zhao Y. A comparison of quinacrine sterilization (QS) and surgical sterilization (TL) in 600 women in Guizhou Province, China. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2003;83 Suppl 2:S51-58. 138. McKinnon JA. The mass treatment of tapeworm with mepacrine. East African medical journal. 1957;34(1):15-18. 139. Mejer J, Mortensen KM, Hansen HH. Mepacrine hydrochloride in the treatment of malignant pleural effusion. A controlled randomized trial. Scandinavian journal of respiratory diseases. 1977;58(6):319-323. 140. Merchant RN, Doctor VM, Thaku SS, et al. Clinico-pathological study of fallopian tubes after transcervical insertion of quinacrine hydrochloride pellets. Advances in contraception : the official journal of the Society for the Advancement of Contraception. 1986;2(1):79-90. 141. Merchant RN, Prabhu SR, Kessel E. Clinicopathologic study of fallopian tube closure after single transcervical insertion of quinacrine pellets. International journal of fertility and menopausal studies.40(1):47-54. 142. Miller RA. Mepacrine therapy for children with petit mal. Scottish medical journal. 1958;3(11):441-444. 143. Mørch K, Hanevik K, Robertson LJ, Strand EA, Langeland N. Treatment-ladder and genetic characterisation of parasites in refractory giardiasis after an outbreak in Norway. The Journal of infection. 2008;56(4):268-273. 144. Mullick BC, Kessel E, Mumford SD. A potential single insertion protocol for quinacrine pellet non-surgical female sterilization. Advances in contraception : the official journal of the Society for the Advancement of Contraception. 1995;11(3):239-244. 145. Murphy TV, Nelson JD. Five vs ten days' therapy with furazolidone for giardiasis. American Journal of Diseases of Children. 1983;137(3):267-270. 146. Nakajima M, Yamada T, Kusuhara T, et al. Results of quinacrine administration to patients with Creutzfeldt-Jakob disease. Dementia and geriatric cognitive disorders. 2004;17(3):158-163. 147. Ng AY, Chen C, Ratnam SS. Hysteroscopic sterilization with quinacrine sulphate and electrocoagulation. The Australian & New Zealand journal of obstetrics & gynaecology. 1976;16(1):38-39. 148. Oka MJ. Treatment of rheumatoid arthritis with atebrin. Annales medicinae internae Fenniae. 1953;42(3):215-220. 149. Pegum JS. Vitiligo treated with mepacrine. The British journal of dermatology. 1953;65(9):324- 325. 150. Pieterse AS, Hecker R, Rowland R. Collagenous colitis: a distinctive and potentially reversible disorder. Journal of clinical pathology. 1982;35(3):338-340.

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167. Taylor SA, Hooton NS, Macarthur AM. Quinacrine in the management of malignant pleural effusion. The British journal of surgery. 1977;64(1):52-53. 168. Thakur PS. Quinacrine sterilization in Tripura, India. Contraception. 2001;64(5):277-279. 169. Tiburskaja NA, Vrublevskaja OS. Clinical and experimental studies on quartan malaria following blood transfusion and methods for preventing its occurrence. Bulletin of the World Health Organization. 1965;33(6):843-851. 170. Toubi E, Kessel A, Rosner I, et al. Quinacrine added to ongoing therapeutic regimens attenuates anticardiolipin antibody production in SLE. Lupus. 2003;12(4):297-301. 171. Toubi E, Kessel A, Rosner I, Rozenbaum M, Paran D, Shoenfeld Y. The reduction of serum B- lymphocyte activating factor levels following quinacrine add-on therapy in systemic lupus erythematosus. Scandinavian journal of immunology. 2006;63(4):299-303. 172. Toubi E, Rosner I, Rozenbaum M, Kessel A, Golan TD. The benefit of combining hydroxychloroquine with quinacrine in the treatment of SLE patients. Lupus. 2000;9(2):92-95. 173. Trager W. The rate of asymptomatic malarial infection in white and Negro service troops taking suppressive atabrine. American journal of hygiene. 1947;46(3):336-340. 174. Tyagi N. Chemotherapy in malaria. Journal of the Indian Medical Association. 1955;25(7):261- 262. 175. Tye MJ, White H, Appel B, Ansell HB. Lupus erythematosus treated with a combination of quinacrine, hydroxychloroquine and chloroquine. The New England journal of medicine. 1959;260(2):63-66. 176. Ukale V, Agrenius V, Hillerdal G, Mohlkert D, Widström O. Pleurodesis in recurrent pleural effusions: a randomized comparison of a classical and a currently popular drug. Lung cancer (Amsterdam, Netherlands). 2004;43(3):323-328. 177. Wright SG, Tomkins AM, Ridley DS. Giardiasis: clinical and therapeutic aspects. Gut. 1977;18(5):343-350. 178. Wuyts L, Dandelooy J, Siozopolou V, Lambert J, Aerts O. Mepacrine as successful monotherapy for refractory Jessner-Kanof disease: still an important drug in the dermatologic armamentarium. The Journal of dermatological treatment. 2017;28(3):276-278. 179. Wynne-Griffith G. Suppression of malaria by mepacrine. Journal of the Royal Army Medical Corps. 1947;89(3):112-121. 180. Young MD, Eyles DE. The efficacy of chloroquine, quinacrine, quinine and totaquine in the treatment of Plasmodium malariae infections (quartan malaria). The American journal of tropical medicine and hygiene. 1948;28(1):23-28. 181. Zipper J, Cole LP, Goldsmith A, Wheeler R, Rivera M. Quinacrine hydrochloride pellets: preliminary data on a nonsurgical method of female sterilization. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 1980;18(4):275-279. 182. Zipper J, Medel M, Goldsmith A, Edelman D, Pastene L, Rivera M. The clinical efficacy of the repeated transcervical instillation of quinacrine for female sterilization. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 1976;14(6):499-502. 183. Zipper J, Stacchetti E, Medel M. Transvaginal chemical sterilization: clinical use of quinacrine plus potentiating adjuvants. Contraception. 1975;12(1):11-21.

184. Ang GC, Werth VP. Combination antimalarials in the treatment of cutaneous dermatomyositis: a retrospective study. Archives of dermatology. 2005;141(7):855-859. 185. Banerjee AK, Willetts I, Robertson JF, Blamey RW. Pleural effusion in breast cancer: a review of the Nottingham experience. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 1994;20(1):33- 36. 186. Basumullick KL, Gupta JC. Parenteral quinacrine in malarial fevers. The Indian medical gazette. 1947;82(4):193-195. 187. Beaudoin EL, Dumoulin E, Carrier N, Cantin AM, Poulin Y. Pleurodesis in spontaneous pneumothorax, a retrospective study comparing quinacrine to TALC and mechanical pleurodesis. American Journal of Respiratory and Critical Care Medicine. 2012;185((Beaudoin E.-L.; Dumoulin E.; Carrier N.; Cantin A.M.; Poulin Y., [email protected]) Centre Hospitalier, Universitaire De Sherbrooke, Sherbrooke, QC, Canada). 188. Benito-León J. Combined quinacrine and chlorpromazine therapy in fatal familial insomnia. Clinical neuropharmacology.27(4):201-203. 189. Benoit S, Goebeler M. Mepacrine in Recalcitrant Cutaneous Lupus Erythematosus: Old- fashioned or Still Useful? Acta dermato-venereologica. 2015;95(5):596-599. 190. Bhuiyan SN, Begum R. Quinacrine non-surgical female sterilization in Bangladesh. Contraception. 2001;64(5):281-286. 191. Bianco AA, Saunders GM, Levine AS, Cohn R. Long-term observation of Plasmodium vivax malaria in the returned serviceman. (Relapses). US Naval Medical Bulletin. 1947;47(3):550-567. 192. Bjermer L, Gruber A, Sue-Chu M, Sandstrom T, Eksborg S, Henriksson R. Effects of intrapleural mitoxantrone and mepacrine on malignant pleural effusion - A randomised study. European Journal of Cancer Part A: General Topics. 1995;31(13-14):2203-2208. 193. Bjorkman S, Elisson LO, Gabrielsson J. Pharmacokinetics of quinacrine after intrapleural instillation in rabbits and man. Journal of Pharmacy and Pharmacology. 1989;41(3):160-163. 194. Chang AY, Piette EW, Foering KP, Tenhave TR, Okawa J, Werth VP. Response to antimalarial agents in cutaneous lupus erythematosus: a prospective analysis. Archives of dermatology. 2011;147(11):1261-1267. 195. Downs WG, Harper PA, Lisansky ET. Malaria and other insect-borne diseases in the South Pacific campaign 1942-1945. II. Epidemiology of insect-borne diseases in army troops. American Journal of Tropical Medicine. 1947;27(SUPPL. OF NO. 3):69-89. 196. Escobedo AA, Almirall P, Alfonso M, et al. Hospitalization of Cuban children for giardiasis: a retrospective study in a paediatric hospital in Havana. Annals of tropical medicine and parasitology. 2011;105(1):47-56. 197. Ferreira CR, Magalhaes DR, Lippes J. Sonographic recognition of three cases of septate uteri diminishes failures of quinacrine sterilization. Contraception. 2006;73(4):433-436. 198. Garabedian V. Quinacrine sterilization (QS) in Syria: a preliminary report on 297 cases. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2003;83 Suppl 2:S133-135. 199. Kavousi S. Giardiasis in infancy and childhood: a prospective study of 160 cases with comparison of quinacrine (Atabrine) and metronidazole (Flagyl). The American journal of tropical medicine and hygiene. 1979;28(1):19-23.

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Appendix 2. Transcripts from focus groups/interviews INTERVIEW 1 END 03 Interviewer 1: And so there’s a couple other people. I don’t know if you remember SeJeong and Melissa - they were with me the last time that we talked, and then we have a new person, Stephanie and Kate, who are also in the room with me. I hope that that’s okay with you. END_03: Yep. No problem. Interviewer 1: We each kind of looked up different ones of these substances so we each kind of have our own supposed expert, I guess, on each one of them. END_03: Okay. Interviewer 1: I guess, kind of like a refresher from last time…so essentially what we’re looking at is we’re looking at why are some of these products used, and then, you know, how are they being used, particularly for you in endocrinology and then why would you maybe want the compounded version versus an FDA version if there is one available or over any other FDA approved product that might be available. END_03: Right. Interviewer 1: And do you mind if we record our conversation? END_03: No, that’s fine. Interviewer 1: Okay. Let me make sure that we’re getting this…okay. I think I have it going. So I know we sent you a pretty lengthy list, and so I know that you said that you use you use many of these in your particular practice, so I don’t know if you just kind of want to kind of just start with which ones do you use and then maybe we can start, you know, with our questions based off of that. END_03: Yeah, that’s fine. So, um, the list I have starts with Coenzyme Q10. Is that the one? Interviewer 1: Yes, that’s correct. END_03: Yeah. Yeah. So, I mean, again we use a lot of these. I mean, most of them are not necessarily compounded so I think, so CoQ10 I tell a lot of people to use, but they usually just buy it over the counter. Dexamethasone we usually just, also, although Dexamethasone I will say, I do have a few people that get it compounded. EDTA I don’t think we really use much. Estradiol I do think that we have at least a few folks that get that compounded, either the oral or the injectable. Lysine I’m not so sure we do a lot of. I think the progesterones, the medroxy and just regular progesterone, some people do prefer that compounded. The B12, I don’t think anyone’s really doing much of that. [Inaudible 02:16:03]. Triamcinolone we don’t really…I don’t think we use too much of. I don’t know what this, Quina-…Quinacrine…I’m not even sure what that’s for. I don’t know if we use that or not. Interviewer 1: Okay.

Appendix 3. 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 quinacrine. 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: Quinacrine Q1. What type(s) of product(s) do you use, prescribe, or recommend for quinacrine? 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 quinacrine? Please check all th... != Compounded drug product Skip To: Q2 If What type(s) of product(s) do you use, prescribe, or recommend for quinacrine? Please check all th... = Compounded drug product

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

Q2. Please list any conditions or diseases for which you use compounded quinacrine 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 quinacrine 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 quinacrine as a single agent active ingredient, or as one active ingredient... != Combination Display This Question: If Loop current: Do you use compounded quinacrine as a single agent active ingredient, or as one active ingredient... = Combination Q4. Please list all combination products in which you use compounded quinacrine.

______Q5. For which, if any, diseases or conditions do you consider compounded quinacrine standard therapy? ______Q6. Does your specialty describe the use of compounded quinacrine in medical practice guidelines or other resources? ______Q7. Over the past 5 years, has the frequency in which you have used compounded quinacrine 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 quinacrine instead of any FDA-approved drug product? ______Q9. Do you stock non-patient-specific compounded quinacrine in your practice location? o Yes o No Skip To: End of Block If Do you stock non-patient-specific compounded [substance] in your practice location? = No Display This Question: If Do you stock non-patient-specific compounded [substance] in your practice location? = Yes Q10. In what practice location(s) do you stock non-patient-specific compounded quinacrine? 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 quinacrine? 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 quinacrine? 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 [substance]? Please check all that apply. = Convenience Skip To: End of Block If Why do you keep a stock of non-patient-specific compounded [substance]? Please check all that apply. = Emergencies Skip To: End of Block If Why do you keep a stock of non-patient-specific compounded [substance]? Please check all that apply. = Other (please describe) Q13. For which, if any, diseases or conditions do you consider quinacrine standard therapy? ______Q14. Does your specialty describe the use of quinacrine in medical practice guidelines or other resources? ______End of Block: Quinacrine

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

Appendix 4. Raw survey data See attached PDF for raw survey data.

Q144. 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,, wewe areare interestedinterested inin thethe currentcurrent andand historichistoric useuse ofof thesethese substancessubstances inin clinicalclinical practice.practice.

There are twelve (12) substancessubstances containedcontained inin thisthis surveysurvey.. As a medical expert, we appreciate your input regarding the use of these substances 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,, andand aa personperson isis notnot requiredrequired toto respondrespond toto aa collectioncollection ofof informationinformation unless it displays a currently valid OMB control number..

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

Q1. Which of the following substances do you use in your practice? Please check all that apply.

Amphotericin B

Boric acid

Cantharidin

Ciclopirox olamine

Clioquinol

Deoxy-d-glucose

Diiodohydroxyquinoline

Diphenylcyclopropenone (DPCP)

Podophyllum

Podophyllum resin

Quinacrine

Squaric acid dibutyl ester (SADBE)

None of the above

Q2. What type(s) of product(s) do you use, prescribe, or recommend for amphotericin B? Please check all that apply.

This question was not displayed to the respondent.

Q3. Please list any conditions or diseases for which you use compounded amphotericin B 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).

This question was not displayed to the respondent.

Q4. Do you use compounded amphotericin B as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q5. Please list all combination products in which you use compounded amphotericin B.

This question was not displayed to the respondent.

Q6. For which, if any, diseases or conditions do you consider compounded amphotericin B standard therapy?

This question was not displayed to the respondent.

Q7. Does your specialty describe the use of compounded amphotericin B in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q8. Over the past 5 years, has the frequency in which you have used compounded amphotericin B changed?

This question was not displayed to the respondent.

Q9. Why do you use compounded amphotericin B instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q10. Do you stock non-patient-specific compounded amphotericin B in your practice location?

This question was not displayed to the respondent.

Q11. In what practice location(s) do you stock non-patient-specific compounded amphotericin B? Please check all that apply.

This question was not displayed to the respondent.

Q12. How do you obtain your stock of non-patient-specific compounded amphotericin B? Please check all that apply.

This question was not displayed to the respondent.

Q13. Why do you keep a stock of non-patient-specific compounded amphotericin B? Please check all that apply.

This question was not displayed to the respondent.

Q14. For which, if any, diseases or conditions do you consider amphotericin B standard therapy?

This question was not displayed to the respondent.

Q15. Does your specialty describe the use of amphotericin B in medical practice guidelines or other resources? This question was not displayed to the respondent.

Q388. What type(s) of product(s) do you use, prescribe, or recommend for boric acid? Please check all that apply.

This question was not displayed to the respondent.

Q389. Please list any conditions or diseases for which you use compounded boric 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).

This question was not displayed to the respondent.

Q390. Do you use compounded boric acid as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q391. Please list all combination products in which you use compounded boric acid.

This question was not displayed to the respondent.

Q392. For which, if any, diseases or conditions do you consider compounded boric acid standard therapy?

This question was not displayed to the respondent.

Q393. Does your specialty describe the use of compounded boric acid in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q394. Over the past 5 years, has the frequency in which you have used compounded boric acid changed?

This question was not displayed to the respondent.

Q395. Why do you use compounded boric acid instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q396. Do you stock non-patient-specific compounded boric acid in your practice location?

This question was not displayed to the respondent.

Q397. In what practice location(s) do you stock non-patient-specific compounded boric acid? Please check all that apply.

This question was not displayed to the respondent.

Q398. How do you obtain your stock of non-patient-specific compounded boric acid? Please check all that apply.

This question was not displayed to the respondent. Q399. Why do you keep a stock of non-patient-specific compounded boric acid? Please check all that apply.

This question was not displayed to the respondent.

Q400. For which, if any, diseases or conditions do you consider boric acid standard therapy?

This question was not displayed to the respondent.

Q401. Does your specialty describe the use of boric acid in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q402. What type(s) of product(s) do you use, prescribe, or recommend for cantharidin? 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

Q403. PleasePlease listlist anyany conditionsconditions oror diseasesdiseases forfor whichwhich youyou useuse compoundedcompounded cantharidin inin youryour practice.practice. PleasePlease includeinclude thethe strength(s), dosing frequency(ies), dosage form(s), route(s) of administration, duration of therapy,, andand patientpatient populationpopulation (ex.(ex. age,age, gender,, comorbidities,comorbidities, allergies,allergies, etc).etc).

Strength(s) (please include Dosing Route(s) of Duration of units) frequency(ies) Dosage form(s) administration therapy Patient population Condition 1 (please describe)

Molluscum contagiosum

0.7% q2wks liquid topical Until resolved Pediatric

Condition 2 (please describe)

Verruca plana

0.7% q2wks liquid topical Until resolved Pediatric / Adult

Condition 3 (please describe)

Condition 4 (please describe)

Condition 5 (please describe)

Condition 6 (please describe)

Condition 7 (please describe)

Condition 8 (please describe)

Q404. Do you use compounded cantharidin as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

Single

Combination

Q405. In which combination(s) do you use compounded cantharidin? Please check all that apply.

This question was not displayed to the respondent.

Q406. ForFor which,which, ifif anyany,, diseasesdiseases oror conditionsconditions dodo youyou considerconsider compoundedcompounded cantharidin standardstandard therapy?therapy?

Molluscum contagiosum

Q407. DoesDoes youryour specialtyspecialty describedescribe thethe useuse ofof compoundedcompounded cantharidin inin medicalmedical practicepractice guidelinesguidelines oror other resources?

Yes

Q408. Over the past 5 years, has the frequency in which you have used compounded cantharidin changed?

Yes - I use it MORE oftenoften nownow (briefly(briefly describedescribe why)why) More pediatric patients

Yes - I use it LESS oftenoften nownow (briefly(briefly describedescribe why)why) No - use has remained consistent

Q409. WhyWhy dodo youyou useuse compoundedcompounded cantharidin insteadinstead ofof anyany FDA-approvedFDA-approved drugdrug product?product?

Painless. High degree of efficacy. Reduced risk of scarring. Applied in office / controlled setting.

Q410. Do you stock non-patient-specific compounded cantharidin in your practice location?

Yes

Q411. In what practice location(s) do you stock non-patient-specific compounded cantharidin? Please check all that apply.

Physician officefice

Outpatient clinic

Emergency room

Operating room

InpatientInpatient wardward

Other (please describe)

Q412. How do you obtain your stock of non-patient-specific compounded cantharidin? Please check all that apply.

Purchase from a compounding pharmacy

Purchase from an outsourcing facility

Compound the product yourself

Other (please describe)

Q413. Why do you keep a stock of non-patient-specific compounded cantharidin? Please check all that apply.

Convenience

Emergencies

Other (please describe)

Q414. For which, if any, diseases or conditions do you consider cantharidin standard therapy?

This question was not displayed to the respondent.

Q415. Does your specialty describe the use of cantharidin in medical practice guidelines or other resources?

This question was not displayed to the respondent. Q416. What type(s) of product(s) do you use, prescribe, or recommend for ciclopirox olamine? 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

Q417. Please list any conditions or diseases for which you use compounded ciclopirox olamine 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).

This question was not displayed to the respondent.

Q418. Do you use compounded ciclopirox olamine as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q419. In which combination(s) do you use compounded ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent.

Q420. For which, if any, diseases or conditions do you consider compounded ciclopirox olamine standard therapy?

This question was not displayed to the respondent.

Q421. Does your specialty describe the use of compounded ciclopirox olamine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q422. Over the past 5 years, has the frequency in which you have used compounded ciclopirox olamine changed?

This question was not displayed to the respondent.

Q423. Why do you use compounded ciclopirox olamine instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q424. Do you stock non-patient-specific compounded ciclopirox olamine in your practice location?

This question was not displayed to the respondent.

Q425. In what practice location(s) do you stock non-patient-specific compounded ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent. Q426. How do you obtain your stock of non-patient-specific compounded ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent.

Q427. Why do you keep a stock of non-patient-specific compounded ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent.

Q428. ForFor which, if any,, diseasesdiseases oror conditionsconditions dodo youyou considerconsider ciclopirox olamine standardstandard therapy?therapy?

Onychomycosis, tinea pedis

Q429. DoesDoes your specialty describe the use of ciclopirox olamine inin medicalmedical practicepractice guidelines or other resources?

Yes

Q430. What type(s) of product(s) do you use, prescribe, or recommend for clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q431. Please list any conditions or diseases for which you use compounded clioquinol 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).

This question was not displayed to the respondent.

Q432. Do you use compounded clioquinol as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q433. In which combination(s) do you use compounded clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q434. For which, if any, diseases or conditions do you consider compounded clioquinol standard therapy?

This question was not displayed to the respondent.

Q435. Does your specialty describe the use of compounded clioquinol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q436. Over the past 5 years, has the frequency in which you have used compounded clioquinol changed?

This question was not displayed to the respondent. Q437. Why do you use compounded clioquinol instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q438. Do you stock non-patient-specific compounded clioquinol in your practice location?

This question was not displayed to the respondent.

Q439. In what practice location(s) do you stock non-patient-specific compounded clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q440. How do you obtain your stock of non-patient-specific compounded clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q441. Why do you keep a stock of non-patient-specific compounded clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q442. For which, if any, diseases or conditions do you consider clioquinol standard therapy?

This question was not displayed to the respondent.

Q443. Does your specialty describe the use of clioquinol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q444. What type(s) of product(s) do you use, prescribe, or recommend for deoxy-d-glucose? Please check all that apply.

This question was not displayed to the respondent.

Q445. Please list any conditions or diseases for which you use compounded deoxy-d-glucose 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).

This question was not displayed to the respondent.

Q446. Do you use compounded deoxy-d-glucose as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q447. In which combination(s) do you use compounded deoxy-d-glucose? Please check all that apply.

This question was not displayed to the respondent.

Q448. For which, if any, diseases or conditions do you consider compounded deoxy-d-glucose standard therapy? This question was not displayed to the respondent.

Q449. Does your specialty describe the use of compounded deoxy-d-glucose in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q450. Over the past 5 years, has the frequency in which you have used compounded deoxy-d- glucose changed?

This question was not displayed to the respondent.

Q451. Why do you use compounded deoxy-d-glucose instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q452. Do you stock non-patient-specific compounded deoxy-d-glucose in your practice location?

This question was not displayed to the respondent.

Q453. In what practice location(s) do you stock non-patient-specific compounded deoxy-d-glucose? Please check all that apply.

This question was not displayed to the respondent.

Q454. How do you obtain your stock of non-patient-specific compounded deoxy-d-glucose? Please check all that apply.

This question was not displayed to the respondent.

Q455. Why do you keep a stock of non-patient-specific compounded deoxy-d-glucose? Please check all that apply.

This question was not displayed to the respondent.

Q456. For which, if any, diseases or conditions do you consider deoxy-d-glucose standard therapy?

This question was not displayed to the respondent.

Q457. Does your specialty describe the use of deoxy-d-glucose in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q458. What type(s) of product(s) do you use, prescribe, or recommend for diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent.

Q459. Please list any conditions or diseases for which you use compounded diiodohydroxyquinoline 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).

This question was not displayed to the respondent. Q460. Do you use compounded diiodohydroxyquinoline as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q461. In which combination(s) do you use compounded diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent.

Q462. For which, if any, diseases or conditions do you consider compounded diiodohydroxyquinoline standard therapy?

This question was not displayed to the respondent.

Q463. Does your specialty describe the use of compounded diiodohydroxyquinoline in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q464. Over the past 5 years, has the frequency in which you have used compounded diiodohydroxyquinoline changed?

This question was not displayed to the respondent.

Q465. Why do you use compounded diiodohydroxyquinoline instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q466. Do you stock non-patient-specific compounded diiodohydroxyquinoline in your practice location?

This question was not displayed to the respondent.

Q467. In what practice location(s) do you stock non-patient-specific compounded diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent.

Q468. How do you obtain your stock of non-patient-specific compounded diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent.

Q469. Why do you keep a stock of non-patient-specific compounded diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent.

Q470. For which, if any, diseases or conditions do you consider diiodohydroxyquinoline standard therapy?

This question was not displayed to the respondent. Q471. Does your specialty describe the use of diiodohydroxyquinoline in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q472. What type(s) of product(s) do you use, prescribe, or recommend for diphenylcyclopropenone (DPCP)? Please check all that apply.

This question was not displayed to the respondent.

Q473. Please list any conditions or diseases for which you use compounded diphenylcyclopropenone (DPCP) 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).

This question was not displayed to the respondent.

Q474. Do you use compounded diphenylcyclopropenone (DPCP) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q475. Please list all combination products in which you use compounded diphenylcyclopropenone (DPCP).

This question was not displayed to the respondent.

Q476. For which, if any, diseases or conditions do you consider compounded diphenylcyclopropenone (DPCP) standard therapy?

This question was not displayed to the respondent.

Q477. Does your specialty describe the use of compounded diphenylcyclopropenone (DPCP) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q478. Over the past 5 years, has the frequency in which you have used compounded diphenylcyclopropenone (DPCP) changed?

This question was not displayed to the respondent.

Q479. Why do you use compounded diphenylcyclopropenone (DPCP) instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q480. Do you stock non-patient-specific compounded diphenylcyclopropenone (DPCP) in your practice location?

This question was not displayed to the respondent.

Q481. In what practice location(s) do you stock non-patient-specific compounded diphenylcyclopropenone (DPCP)? Please check all that apply.

This question was not displayed to the respondent. Q482. How do you obtain your stock of non-patient-specific compounded diphenylcyclopropenone (DPCP)? Please check all that apply.

This question was not displayed to the respondent.

Q483. Why do you keep a stock of non-patient-specific compounded diphenylcyclopropenone (DPCP)? Please check all that apply.

This question was not displayed to the respondent.

Q484. For which, if any, diseases or conditions do you consider diphenylcyclopropenone (DPCP) standard therapy?

This question was not displayed to the respondent.

Q485. Does your specialty describe the use of diphenylcyclopropenone (DPCP) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q486. What type(s) of product(s) do you use, prescribe, or recommend for podophyllum? Please check all that apply.

This question was not displayed to the respondent.

Q487. Please list any conditions or diseases for which you use compounded podophyllum 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).

This question was not displayed to the respondent.

Q488. Do you use compounded podophyllum as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q489. In which combination(s) do you use compounded podophyllum? Please check all that apply.

This question was not displayed to the respondent.

Q490. For which, if any, diseases or conditions do you consider compounded podophyllum standard therapy?

This question was not displayed to the respondent.

Q491. Does your specialty describe the use of compounded podophyllum in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q492. Over the past 5 years, has the frequency in which you have used compounded podophyllum changed?

This question was not displayed to the respondent. Q493. Why do you use compounded podophyllum instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q494. Do you stock non-patient-specific compounded podophyllum in your practice location?

This question was not displayed to the respondent.

Q495. In what practice location(s) do you stock non-patient-specific compounded podophyllum? Please check all that apply.

This question was not displayed to the respondent.

Q496. How do you obtain your stock of non-patient-specific compounded podophyllum? Please check all that apply.

This question was not displayed to the respondent.

Q497. Why do you keep a stock of non-patient-specific compounded podophyllum? Please check all that apply.

This question was not displayed to the respondent.

Q498. For which, if any, diseases or conditions do you consider podophyllum standard therapy?

This question was not displayed to the respondent.

Q499. Does your specialty describe the use of podophyllum in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q500. What type(s) of product(s) do you use, prescribe, or recommend for podophyllum resin? 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

Q501. Please list any conditions or diseases for which you use compounded podophyllum resin 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).

This question was not displayed to the respondent.

Q502. Do you use compounded podophyllum resin as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent. Q503. In which combination(s) do you use compounded podophyllum resin? Please check all that apply.

This question was not displayed to the respondent.

Q504. For which, if any, diseases or conditions do you consider compounded podophyllum resin standard therapy?

This question was not displayed to the respondent.

Q505. Does your specialty describe the use of compounded podophyllum resin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q506. Over the past 5 years, has the frequency in which you have used compounded podophyllum resin changed?

This question was not displayed to the respondent.

Q507. Why do you use compounded podophyllum resin instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q508. Do you stock non-patient-specific compounded podophyllum resin in your practice location?

This question was not displayed to the respondent.

Q509. In what practice location(s) do you stock non-patient-specific compounded podophyllum resin? Please check all that apply.

This question was not displayed to the respondent.

Q510. How do you obtain your stock of non-patient-specific compounded podophyllum resin? Please check all that apply.

This question was not displayed to the respondent.

Q511. Why do you keep a stock of non-patient-specific compounded podophyllum resin? Please check all that apply.

This question was not displayed to the respondent.

Q512. ForFor which, if any,, diseasesdiseases oror conditionsconditions dodo youyou considerconsider podophyllum resin standardstandard therapy?therapy?

Condyloma acuminata

Q513. DoesDoes your specialty describe the use of podophyllum resin inin medicalmedical practicepractice guidelines or other resources?

Yes Q529. What type(s) of product(s) do you use, prescribe, or recommend for quinacrine? 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

Q530. PleasePlease listlist anyany conditionsconditions oror diseasesdiseases forfor whichwhich youyou useuse compoundedcompounded quinacrine inin youryour practice.practice. PleasePlease includeinclude thethe strength(s), dosing frequency(ies), dosage form(s), route(s) of administration, duration of therapy,, andand patientpatient populationpopulation (ex.(ex. age,age, gender,, comorbidities,comorbidities, allergies,allergies, etc).etc).

Strength(s) (please include Dosing Route(s) of Duration of units) frequency(ies) Dosage form(s) administration therapy Patient population Condition 1 (please describe)

Lupus vulgaris

100mg qd tablet po indef Adult

Condition 2 (please describe)

Condition 3 (please describe)

Condition 4 (please describe)

Condition 5 (please describe)

Condition 6 (please describe)

Condition 7 (please describe)

Condition 8 (please describe)

Q531. Do you use compounded quinacrine as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

Single

Combination

Q532. Please list all combination products in which you use compounded quinacrine.

This question was not displayed to the respondent.

Q533. ForFor which,which, ifif anyany,, diseasesdiseases oror conditionsconditions dodo youyou considerconsider compoundedcompounded quinacrine standard therapy?

None (adjunct to hydroxychloroquine in recalcitrant cutaneous lupus)

Q534. DoesDoes youryour specialtyspecialty describedescribe thethe useuse ofof compoundedcompounded quinacrine inin medicalmedical practicepractice guidelinesguidelines oror other resources?

Yes

Q535. Over the past 5 years, has the frequency in which you have used compounded quinacrine changed?

Yes - I use it MORE oftenoften nownow (briefly(briefly describedescribe why)why)

Yes - I use it LESS oftenoften nownow (briefly(briefly describedescribe why)why) Shortage / unavailability

No - use has remained consistent

Q536. WhyWhy dodo youyou useuse compoundedcompounded quinacrine insteadinstead ofof anyany FDA-approvedFDA-approved drugdrug product?product?

Only available via compounding.

Q537. Do you stock non-patient-specific compounded quinacrine in your practice location?

Yes

No Q538. In what practice location(s) do you stock non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q539. How do you obtain your stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q540. Why do you keep a stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q541. For which, if any, diseases or conditions do you consider quinacrine standard therapy?

This question was not displayed to the respondent.

Q542. Does your specialty describe the use of quinacrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q543. What type(s) of product(s) do you use, prescribe, or recommend for squaric acid dibutyl ester (SADBE)? 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

Q544. PleasePlease listlist anyany conditionsconditions oror diseasesdiseases forfor whichwhich youyou useuse compoundedcompounded squaric acid dibutyl ester (SADBE) inin youryour practice.practice. Please include the strength(s), dosing frequency(ies), dosage form(s), route(s) of administration, duration of therapy,, andand patientpatient population (ex. age, gender,, comorbidities,comorbidities, allergies,allergies, etc).etc).

Strength(s) (please include Dosing Route(s) of Duration of units) frequency(ies) Dosage form(s) administration therapy Patient population Condition 1 (please describe)

Alopecia areata

2%, 0.0001% qwk acetone based topical Regrowth of hair All solution

Condition 2 (please describe)

Verruca plana / vulgaris

2%, 0.2% tiw acetone based topical clearance All solution Condition 3 (please describe)

Condition 4 (please describe)

Condition 5 (please describe)

Condition 6 (please describe)

Condition 7 (please describe)

Condition 8 (please describe)

Q545. Do you use compounded squaric acid dibutyl ester (SADBE) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

Single

Combination

Q546. Please list all combination products in which you use compounded squaric acid dibutyl ester (SADBE).

This question was not displayed to the respondent.

Q547. ForFor which,which, ifif anyany,, diseasesdiseases oror conditionsconditions dodo youyou considerconsider compoundedcompounded squaric acid dibutyl ester (SADBE) standard therapy? Alopecia areata

Q548. DoesDoes youryour specialtyspecialty describedescribe thethe useuse ofof compoundedcompounded squaric acid dibutyl ester (SADBE) inin medicalmedical practice guidelines or other resources?

Yes

Q549. Over the past 5 years, has the frequency in which you have used compounded squaric acid dibutyl ester (SADBE) changed?

Yes - I use it MORE oftenoften nownow (briefly(briefly describedescribe why)why)

Yes - I use it LESS oftenoften nownow (briefly(briefly describedescribe why)why)

No - use has remained consistent

Q550. WhyWhy dodo youyou useuse compoundedcompounded squaric acid dibutyl ester (SADBE) insteadinstead ofof anyany FDA-approvedFDA-approved drug product?

Only available compounded

Q551. Do you stock non-patient-specific compounded squaric acid dibutyl ester (SADBE) in your practice location?

Yes

Q552. In what practice location(s) do you stock non-patient-specific compounded squaric acid dibutyl ester (SADBE)? Please check all that apply.

This question was not displayed to the respondent.

Q553. How do you obtain your stock of non-patient-specific compounded squaric acid dibutyl ester (SADBE)? Please check all that apply.

This question was not displayed to the respondent.

Q554. Why do you keep a stock of non-patient-specific compounded squaric acid dibutyl ester (SADBE)? Please check all that apply.

This question was not displayed to the respondent.

Q555. For which, if any, diseases or conditions do you consider squaric acid dibutyl ester (SADBE) standard therapy?

This question was not displayed to the respondent.

Q556. Does your specialty describe the use of squaric acid dibutyl ester (SADBE) in medical practice guidelines or other resources?

This question was not displayed to the respondent. Q16. 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)

Q17. 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,, DiabetesDiabetes andand MetabolismMetabolism

Family Medicine

Gastroenterology

Hematology

InfectiousInfectious DiseaseDisease

InternalInternal MedicineMedicine

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) Q144. 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,, wewe areare interestedinterested inin thethe currentcurrent andand historichistoric useuse ofof thesethese substancessubstances inin clinicalclinical practice.practice.

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

Q1. Which of the following substances do you use in your practice? Please check all that apply.

Amphotericin B

Boric acid

Cantharidin

Ciclopirox olamine

Clioquinol

Deoxy-d-glucose

Diiodohydroxyquinoline

Diphenylcyclopropenone (DPCP)

Podophyllum

Podophyllum resin

Quinacrine

Squaric acid dibutyl ester (SADBE)

None of the above

Q2. What type(s) of product(s) do you use, prescribe, or recommend for amphotericin B? Please check all that apply.

This question was not displayed to the respondent.

Q4. Do you use compounded amphotericin B as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q5. Please list all combination products in which you use compounded amphotericin B.

This question was not displayed to the respondent.

Q6. For which, if any, diseases or conditions do you consider compounded amphotericin B standard therapy?

This question was not displayed to the respondent.

Q7. Does your specialty describe the use of compounded amphotericin B in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q8. Over the past 5 years, has the frequency in which you have used compounded amphotericin B changed?

This question was not displayed to the respondent.

Q9. Why do you use compounded amphotericin B instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q10. Do you stock non-patient-specific compounded amphotericin B in your practice location?

This question was not displayed to the respondent.

Q11. In what practice location(s) do you stock non-patient-specific compounded amphotericin B? Please check all that apply.

This question was not displayed to the respondent.

Q12. How do you obtain your stock of non-patient-specific compounded amphotericin B? Please check all that apply.

This question was not displayed to the respondent.

Q13. Why do you keep a stock of non-patient-specific compounded amphotericin B? Please check all that apply.

This question was not displayed to the respondent.

Q14. For which, if any, diseases or conditions do you consider amphotericin B standard therapy?

This question was not displayed to the respondent.

Q15. Does your specialty describe the use of amphotericin B in medical practice guidelines or other resources? This question was not displayed to the respondent.

Q388. What type(s) of product(s) do you use, prescribe, or recommend for boric acid? Please check all that apply.

This question was not displayed to the respondent.

Q390. Do you use compounded boric acid as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q391. Please list all combination products in which you use compounded boric acid.

This question was not displayed to the respondent.

Q392. For which, if any, diseases or conditions do you consider compounded boric acid standard therapy?

This question was not displayed to the respondent.

Q393. Does your specialty describe the use of compounded boric acid in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q394. Over the past 5 years, has the frequency in which you have used compounded boric acid changed?

This question was not displayed to the respondent.

Q395. Why do you use compounded boric acid instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q396. Do you stock non-patient-specific compounded boric acid in your practice location?

This question was not displayed to the respondent.

Q397. In what practice location(s) do you stock non-patient-specific compounded boric acid? Please check all that apply.

This question was not displayed to the respondent.

Q398. How do you obtain your stock of non-patient-specific compounded boric acid? Please check all that apply.

This question was not displayed to the respondent. Q399. Why do you keep a stock of non-patient-specific compounded boric acid? Please check all that apply.

This question was not displayed to the respondent.

Q400. For which, if any, diseases or conditions do you consider boric acid standard therapy?

This question was not displayed to the respondent.

Q401. Does your specialty describe the use of boric acid in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q402. What type(s) of product(s) do you use, prescribe, or recommend for cantharidin? Please check all that apply.

This question was not displayed to the respondent.

Q403. Please list any conditions or diseases for which you use compounded cantharidin 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).

This question was not displayed to the respondent.

Q404. Do you use compounded cantharidin as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q405. In which combination(s) do you use compounded cantharidin? Please check all that apply.

This question was not displayed to the respondent.

Q406. For which, if any, diseases or conditions do you consider compounded cantharidin standard therapy?

This question was not displayed to the respondent.

Q407. Does your specialty describe the use of compounded cantharidin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q408. Over the past 5 years, has the frequency in which you have used compounded cantharidin changed?

This question was not displayed to the respondent.

Q409. Why do you use compounded cantharidin instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q410. Do you stock non-patient-specific compounded cantharidin in your practice location?

This question was not displayed to the respondent. Q411. In what practice location(s) do you stock non-patient-specific compounded cantharidin? Please check all that apply.

This question was not displayed to the respondent.

Q412. How do you obtain your stock of non-patient-specific compounded cantharidin? Please check all that apply.

This question was not displayed to the respondent.

Q413. Why do you keep a stock of non-patient-specific compounded cantharidin? Please check all that apply.

This question was not displayed to the respondent.

Q414. For which, if any, diseases or conditions do you consider cantharidin standard therapy?

This question was not displayed to the respondent.

Q415. Does your specialty describe the use of cantharidin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q416. What type(s) of product(s) do you use, prescribe, or recommend for ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent.

Q418. Do you use compounded ciclopirox olamine as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q419. In which combination(s) do you use compounded ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent.

Q420. For which, if any, diseases or conditions do you consider compounded ciclopirox olamine standard therapy?

This question was not displayed to the respondent.

Q421. Does your specialty describe the use of compounded ciclopirox olamine in medical practice guidelines or other resources?

This question was not displayed to the respondent. Q422. Over the past 5 years, has the frequency in which you have used compounded ciclopirox olamine changed?

This question was not displayed to the respondent.

Q423. Why do you use compounded ciclopirox olamine instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q424. Do you stock non-patient-specific compounded ciclopirox olamine in your practice location?

This question was not displayed to the respondent.

Q425. In what practice location(s) do you stock non-patient-specific compounded ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent.

Q426. How do you obtain your stock of non-patient-specific compounded ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent.

Q427. Why do you keep a stock of non-patient-specific compounded ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent.

Q428. For which, if any, diseases or conditions do you consider ciclopirox olamine standard therapy?

This question was not displayed to the respondent.

Q429. Does your specialty describe the use of ciclopirox olamine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q430. What type(s) of product(s) do you use, prescribe, or recommend for clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q432. Do you use compounded clioquinol as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent. Q433. In which combination(s) do you use compounded clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q434. For which, if any, diseases or conditions do you consider compounded clioquinol standard therapy?

This question was not displayed to the respondent.

Q435. Does your specialty describe the use of compounded clioquinol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q436. Over the past 5 years, has the frequency in which you have used compounded clioquinol changed?

This question was not displayed to the respondent.

Q437. Why do you use compounded clioquinol instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q438. Do you stock non-patient-specific compounded clioquinol in your practice location?

This question was not displayed to the respondent.

Q439. In what practice location(s) do you stock non-patient-specific compounded clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q440. How do you obtain your stock of non-patient-specific compounded clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q441. Why do you keep a stock of non-patient-specific compounded clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q442. For which, if any, diseases or conditions do you consider clioquinol standard therapy?

This question was not displayed to the respondent.

Q443. Does your specialty describe the use of clioquinol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q444. What type(s) of product(s) do you use, prescribe, or recommend for deoxy-d-glucose? 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

Q445. PleasePlease listlist anyany conditionsconditions oror diseasesdiseases forfor whichwhich youyou useuse compoundedcompounded deoxy-d-glucose inin youryour practice.practice. PleasePlease includeinclude thethe strength(s), dosing frequency(ies), dosage form(s), route(s) of administration, duration of therapy,, andand patientpatient populationpopulation (ex.(ex. age,age, gender,, comorbidities,comorbidities, allergies,allergies, etc).etc).

Strength(s) (please include Dosing Route(s) of Duration of units) frequency(ies) Dosage form(s) administration therapy Patient population Condition 1 (please describe)

Condition 2 (please describe)

Condition 3 (please describe)

Condition 4 (please describe)

Condition 5 (please describe)

Q446. Do you use compounded deoxy-d-glucose as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

Single

Combination

Q447. In which combination(s) do you use compounded deoxy-d-glucose? Please check all that apply.

Deoxy-d-glucose 0.2% / Acyclovir 3% / Lidocaine 1% Deoxy-d-glucose 0.2% / Cimetidine 10% / Ibuprofen 2% / Lidocaine 5% / Salicylic acid 15%

Other (please describe)

Q448. ForFor which,which, ifif anyany,, diseasesdiseases oror conditionsconditions dodo youyou considerconsider compoundedcompounded deoxy-d-glucose standardstandard therapy?therapy?

Q449. DoesDoes youryour specialtyspecialty describedescribe thethe useuse ofof compoundedcompounded deoxy-d-glucose inin medicalmedical practicepractice guidelinesguidelines or other resources?

Q450. Over the past 5 years, has the frequency in which you have used compounded deoxy-d- glucose changed?

Yes - I use it MORE oftenoften nownow (briefly(briefly describedescribe why)why)

Yes - I use it LESS oftenoften nownow (briefly(briefly describedescribe why)why)

No - use has remained consistent

Q451. WhyWhy dodo youyou useuse compoundedcompounded deoxy-d-glucose insteadinstead ofof anyany FDA-approvedFDA-approved drugdrug product?product?

Q452. Do you stock non-patient-specific compounded deoxy-d-glucose in your practice location?

Yes

Q453. In what practice location(s) do you stock non-patient-specific compounded deoxy-d-glucose? Please check all that apply.

Physician officefice

Outpatient clinic

Emergency room

Operating room

InpatientInpatient wardward

Other (please describe)

Q454. How do you obtain your stock of non-patient-specific compounded deoxy-d-glucose? Please check all that apply.

Purchase from a compounding pharmacy

Purchase from an outsourcing facility Compound the product yourself

Other (please describe)

Q455. Why do you keep a stock of non-patient-specific compounded deoxy-d-glucose? Please check all that apply.

Convenience

Emergencies

Other (please describe)

Q456. For which, if any, diseases or conditions do you consider deoxy-d-glucose standard therapy?

This question was not displayed to the respondent.

Q457. Does your specialty describe the use of deoxy-d-glucose in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q458. What type(s) of product(s) do you use, prescribe, or recommend for diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent.

Q460. Do you use compounded diiodohydroxyquinoline as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q461. In which combination(s) do you use compounded diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent.

Q462. For which, if any, diseases or conditions do you consider compounded diiodohydroxyquinoline standard therapy?

This question was not displayed to the respondent.

Q463. Does your specialty describe the use of compounded diiodohydroxyquinoline in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q464. Over the past 5 years, has the frequency in which you have used compounded diiodohydroxyquinoline changed? This question was not displayed to the respondent.

Q465. Why do you use compounded diiodohydroxyquinoline instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q466. Do you stock non-patient-specific compounded diiodohydroxyquinoline in your practice location?

This question was not displayed to the respondent.

Q467. In what practice location(s) do you stock non-patient-specific compounded diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent.

Q468. How do you obtain your stock of non-patient-specific compounded diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent.

Q469. Why do you keep a stock of non-patient-specific compounded diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent.

Q470. For which, if any, diseases or conditions do you consider diiodohydroxyquinoline standard therapy?

This question was not displayed to the respondent.

Q471. Does your specialty describe the use of diiodohydroxyquinoline in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q472. What type(s) of product(s) do you use, prescribe, or recommend for diphenylcyclopropenone (DPCP)? Please check all that apply.

This question was not displayed to the respondent.

Q474. Do you use compounded diphenylcyclopropenone (DPCP) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q475. Please list all combination products in which you use compounded diphenylcyclopropenone (DPCP). This question was not displayed to the respondent.

Q476. For which, if any, diseases or conditions do you consider compounded diphenylcyclopropenone (DPCP) standard therapy?

This question was not displayed to the respondent.

Q477. Does your specialty describe the use of compounded diphenylcyclopropenone (DPCP) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q478. Over the past 5 years, has the frequency in which you have used compounded diphenylcyclopropenone (DPCP) changed?

This question was not displayed to the respondent.

Q479. Why do you use compounded diphenylcyclopropenone (DPCP) instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q480. Do you stock non-patient-specific compounded diphenylcyclopropenone (DPCP) in your practice location?

This question was not displayed to the respondent.

Q481. In what practice location(s) do you stock non-patient-specific compounded diphenylcyclopropenone (DPCP)? Please check all that apply.

This question was not displayed to the respondent.

Q482. How do you obtain your stock of non-patient-specific compounded diphenylcyclopropenone (DPCP)? Please check all that apply.

This question was not displayed to the respondent.

Q483. Why do you keep a stock of non-patient-specific compounded diphenylcyclopropenone (DPCP)? Please check all that apply.

This question was not displayed to the respondent.

Q484. For which, if any, diseases or conditions do you consider diphenylcyclopropenone (DPCP) standard therapy?

This question was not displayed to the respondent.

Q485. Does your specialty describe the use of diphenylcyclopropenone (DPCP) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q486. What type(s) of product(s) do you use, prescribe, or recommend for podophyllum? Please check all that apply. This question was not displayed to the respondent.

This question was not displayed to the respondent.

Q488. Do you use compounded podophyllum as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q489. In which combination(s) do you use compounded podophyllum? Please check all that apply.

This question was not displayed to the respondent.

Q490. For which, if any, diseases or conditions do you consider compounded podophyllum standard therapy?

This question was not displayed to the respondent.

Q491. Does your specialty describe the use of compounded podophyllum in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q492. Over the past 5 years, has the frequency in which you have used compounded podophyllum changed?

This question was not displayed to the respondent.

Q493. Why do you use compounded podophyllum instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q494. Do you stock non-patient-specific compounded podophyllum in your practice location?

This question was not displayed to the respondent.

Q495. In what practice location(s) do you stock non-patient-specific compounded podophyllum? Please check all that apply.

This question was not displayed to the respondent.

Q496. How do you obtain your stock of non-patient-specific compounded podophyllum? Please check all that apply.

This question was not displayed to the respondent.

Q497. Why do you keep a stock of non-patient-specific compounded podophyllum? Please check all that apply. This question was not displayed to the respondent.

Q498. For which, if any, diseases or conditions do you consider podophyllum standard therapy?

This question was not displayed to the respondent.

Q499. Does your specialty describe the use of podophyllum in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q500. What type(s) of product(s) do you use, prescribe, or recommend for podophyllum resin? Please check all that apply.

This question was not displayed to the respondent.

Q502. Do you use compounded podophyllum resin as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q503. In which combination(s) do you use compounded podophyllum resin? Please check all that apply.

This question was not displayed to the respondent.

Q504. For which, if any, diseases or conditions do you consider compounded podophyllum resin standard therapy?

This question was not displayed to the respondent.

Q505. Does your specialty describe the use of compounded podophyllum resin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q506. Over the past 5 years, has the frequency in which you have used compounded podophyllum resin changed?

This question was not displayed to the respondent.

Q507. Why do you use compounded podophyllum resin instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q508. Do you stock non-patient-specific compounded podophyllum resin in your practice location?

This question was not displayed to the respondent. Q509. In what practice location(s) do you stock non-patient-specific compounded podophyllum resin? Please check all that apply.

This question was not displayed to the respondent.

Q510. How do you obtain your stock of non-patient-specific compounded podophyllum resin? Please check all that apply.

This question was not displayed to the respondent.

Q511. Why do you keep a stock of non-patient-specific compounded podophyllum resin? Please check all that apply.

This question was not displayed to the respondent.

Q512. For which, if any, diseases or conditions do you consider podophyllum resin standard therapy?

This question was not displayed to the respondent.

Q513. Does your specialty describe the use of podophyllum resin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q529. What type(s) of product(s) do you use, prescribe, or recommend for quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q530. Please list any conditions or diseases for which you use compounded quinacrine 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).

This question was not displayed to the respondent.

Q531. Do you use compounded quinacrine as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q532. Please list all combination products in which you use compounded quinacrine.

This question was not displayed to the respondent.

Q533. For which, if any, diseases or conditions do you consider compounded quinacrine standard therapy?

This question was not displayed to the respondent.

Q534. Does your specialty describe the use of compounded quinacrine in medical practice guidelines or other resources?

This question was not displayed to the respondent. Q535. Over the past 5 years, has the frequency in which you have used compounded quinacrine changed?

This question was not displayed to the respondent.

Q536. Why do you use compounded quinacrine instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q537. Do you stock non-patient-specific compounded quinacrine in your practice location?

This question was not displayed to the respondent.

Q538. In what practice location(s) do you stock non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q539. How do you obtain your stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q540. Why do you keep a stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q541. For which, if any, diseases or conditions do you consider quinacrine standard therapy?

This question was not displayed to the respondent.

Q542. Does your specialty describe the use of quinacrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q543. What type(s) of product(s) do you use, prescribe, or recommend for squaric acid dibutyl ester (SADBE)? Please check all that apply.

This question was not displayed to the respondent.

Q544. Please list any conditions or diseases for which you use compounded squaric acid dibutyl ester (SADBE) 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).

This question was not displayed to the respondent.

Q545. Do you use compounded squaric acid dibutyl ester (SADBE) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q546. Please list all combination products in which you use compounded squaric acid dibutyl ester (SADBE). This question was not displayed to the respondent.

Q547. For which, if any, diseases or conditions do you consider compounded squaric acid dibutyl ester (SADBE) standard therapy?

This question was not displayed to the respondent.

Q548. Does your specialty describe the use of compounded squaric acid dibutyl ester (SADBE) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q549. Over the past 5 years, has the frequency in which you have used compounded squaric acid dibutyl ester (SADBE) changed?

This question was not displayed to the respondent.

Q550. Why do you use compounded squaric acid dibutyl ester (SADBE) instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q551. Do you stock non-patient-specific compounded squaric acid dibutyl ester (SADBE) in your practice location?

This question was not displayed to the respondent.

Q552. In what practice location(s) do you stock non-patient-specific compounded squaric acid dibutyl ester (SADBE)? Please check all that apply.

This question was not displayed to the respondent.

Q553. How do you obtain your stock of non-patient-specific compounded squaric acid dibutyl ester (SADBE)? Please check all that apply.

This question was not displayed to the respondent.

Q554. Why do you keep a stock of non-patient-specific compounded squaric acid dibutyl ester (SADBE)? Please check all that apply.

This question was not displayed to the respondent.

Q555. For which, if any, diseases or conditions do you consider squaric acid dibutyl ester (SADBE) standard therapy?

This question was not displayed to the respondent.

Q556. Does your specialty describe the use of squaric acid dibutyl ester (SADBE) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q16. What is your terminal clinical degree? Please check all that apply. This question was not displayed to the respondent.

Q17. Which of the following Board certification(s) do you hold? Please check all that apply.

This question was not displayed to the respondent. Q144. 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,, wewe areare interestedinterested inin thethe currentcurrent andand historichistoric useuse ofof thesethese substancessubstances inin clinicalclinical practice.practice.

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

Q1. Which of the following substances do you use in your practice? Please check all that apply.

Amphotericin B

Boric acid

Cantharidin

Ciclopirox olamine

Clioquinol

Deoxy-d-glucose

Diiodohydroxyquinoline

Diphenylcyclopropenone (DPCP)

Podophyllum

Podophyllum resin

Quinacrine

Squaric acid dibutyl ester (SADBE)

None of the above

Q2. What type(s) of product(s) do you use, prescribe, or recommend for amphotericin B? Please check all that apply.

This question was not displayed to the respondent.

Q4. Do you use compounded amphotericin B as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q5. Please list all combination products in which you use compounded amphotericin B.

This question was not displayed to the respondent.

Q6. For which, if any, diseases or conditions do you consider compounded amphotericin B standard therapy?

This question was not displayed to the respondent.

Q7. Does your specialty describe the use of compounded amphotericin B in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q8. Over the past 5 years, has the frequency in which you have used compounded amphotericin B changed?

This question was not displayed to the respondent.

Q9. Why do you use compounded amphotericin B instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q10. Do you stock non-patient-specific compounded amphotericin B in your practice location?

This question was not displayed to the respondent.

Q11. In what practice location(s) do you stock non-patient-specific compounded amphotericin B? Please check all that apply.

This question was not displayed to the respondent.

Q12. How do you obtain your stock of non-patient-specific compounded amphotericin B? Please check all that apply.

This question was not displayed to the respondent.

Q13. Why do you keep a stock of non-patient-specific compounded amphotericin B? Please check all that apply.

This question was not displayed to the respondent.

Q14. For which, if any, diseases or conditions do you consider amphotericin B standard therapy?

This question was not displayed to the respondent.

Q15. Does your specialty describe the use of amphotericin B in medical practice guidelines or other resources? This question was not displayed to the respondent.

Q388. What type(s) of product(s) do you use, prescribe, or recommend for boric acid? Please check all that apply.

This question was not displayed to the respondent.

Q390. Do you use compounded boric acid as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q391. Please list all combination products in which you use compounded boric acid.

This question was not displayed to the respondent.

Q392. For which, if any, diseases or conditions do you consider compounded boric acid standard therapy?

This question was not displayed to the respondent.

Q393. Does your specialty describe the use of compounded boric acid in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q394. Over the past 5 years, has the frequency in which you have used compounded boric acid changed?

This question was not displayed to the respondent.

Q395. Why do you use compounded boric acid instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q396. Do you stock non-patient-specific compounded boric acid in your practice location?

This question was not displayed to the respondent.

Q397. In what practice location(s) do you stock non-patient-specific compounded boric acid? Please check all that apply.

This question was not displayed to the respondent.

Q398. How do you obtain your stock of non-patient-specific compounded boric acid? Please check all that apply.

This question was not displayed to the respondent. Q399. Why do you keep a stock of non-patient-specific compounded boric acid? Please check all that apply.

This question was not displayed to the respondent.

Q400. For which, if any, diseases or conditions do you consider boric acid standard therapy?

This question was not displayed to the respondent.

Q401. Does your specialty describe the use of boric acid in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q402. What type(s) of product(s) do you use, prescribe, or recommend for cantharidin? 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

Strength(s) (please include Dosing Route(s) of Duration of units) frequency(ies) Dosage form(s) administration therapy Patient population Condition 1 (please describe)

Molluscum

Colloid, solution Topical

Condition 2 (please describe)

Warts

Condition 3 (please describe)

Condition 4 (please describe)

Condition 5 (please describe)

Condition 6 (please describe)

Condition 7 (please describe)

Condition 8 (please describe)

Q404. Do you use compounded cantharidin as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

Single

Combination

Q405. In which combination(s) do you use compounded cantharidin? Please check all that apply.

Cantharidin 1% / Podophyllum resin 5% / Salicylic acid 30%

Other (please describe) Cantharidin/ salicylic acid

Q406. ForFor which,which, ifif anyany,, diseasesdiseases oror conditionsconditions dodo youyou considerconsider compoundedcompounded cantharidin standardstandard therapy?therapy?

Molluscum, warts

Q407. DoesDoes youryour specialtyspecialty describedescribe thethe useuse ofof compoundedcompounded cantharidin inin medicalmedical practicepractice guidelinesguidelines oror other resources?

Many journal articles, texts

Q408. Over the past 5 years, has the frequency in which you have used compounded cantharidin changed? Yes - I use it MORE oftenoften nownow (briefly(briefly describedescribe why)why)

Yes - I use it LESS oftenoften nownow (briefly(briefly describedescribe why)why) Compounding shortage

No - use has remained consistent

Q409. WhyWhy dodo youyou useuse compoundedcompounded cantharidin insteadinstead ofof anyany FDA-approvedFDA-approved drugdrug product?product?

No FDA approved treatment

Q410. Do you stock non-patient-specific compounded cantharidin in your practice location?

Yes

Q411. In what practice location(s) do you stock non-patient-specific compounded cantharidin? Please check all that apply.

Physician officefice

Outpatient clinic

Emergency room

Operating room

InpatientInpatient wardward

Other (please describe)

Q412. How do you obtain your stock of non-patient-specific compounded cantharidin? Please check all that apply.

Purchase from a compounding pharmacy

Purchase from an outsourcing facility

Compound the product yourself

Other (please describe)

Q413. Why do you keep a stock of non-patient-specific compounded cantharidin? Please check all that apply.

Convenience

Emergencies

Other (please describe)

Q414. For which, if any, diseases or conditions do you consider cantharidin standard therapy?

This question was not displayed to the respondent.

Q415. Does your specialty describe the use of cantharidin in medical practice guidelines or other resources?

This question was not displayed to the respondent. Q416. What type(s) of product(s) do you use, prescribe, or recommend for ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent.

Q418. Do you use compounded ciclopirox olamine as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q419. In which combination(s) do you use compounded ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent.

Q420. For which, if any, diseases or conditions do you consider compounded ciclopirox olamine standard therapy?

This question was not displayed to the respondent.

Q421. Does your specialty describe the use of compounded ciclopirox olamine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q422. Over the past 5 years, has the frequency in which you have used compounded ciclopirox olamine changed?

This question was not displayed to the respondent.

Q423. Why do you use compounded ciclopirox olamine instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q424. Do you stock non-patient-specific compounded ciclopirox olamine in your practice location?

This question was not displayed to the respondent.

Q425. In what practice location(s) do you stock non-patient-specific compounded ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent.

Q426. How do you obtain your stock of non-patient-specific compounded ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent. Q427. Why do you keep a stock of non-patient-specific compounded ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent.

Q428. For which, if any, diseases or conditions do you consider ciclopirox olamine standard therapy?

This question was not displayed to the respondent.

Q429. Does your specialty describe the use of ciclopirox olamine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q430. What type(s) of product(s) do you use, prescribe, or recommend for clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q432. Do you use compounded clioquinol as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q433. In which combination(s) do you use compounded clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q434. For which, if any, diseases or conditions do you consider compounded clioquinol standard therapy?

This question was not displayed to the respondent.

Q435. Does your specialty describe the use of compounded clioquinol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q436. Over the past 5 years, has the frequency in which you have used compounded clioquinol changed?

This question was not displayed to the respondent.

Q437. Why do you use compounded clioquinol instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q438. Do you stock non-patient-specific compounded clioquinol in your practice location? This question was not displayed to the respondent.

Q439. In what practice location(s) do you stock non-patient-specific compounded clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q440. How do you obtain your stock of non-patient-specific compounded clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q441. Why do you keep a stock of non-patient-specific compounded clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q442. For which, if any, diseases or conditions do you consider clioquinol standard therapy?

This question was not displayed to the respondent.

Q443. Does your specialty describe the use of clioquinol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q444. What type(s) of product(s) do you use, prescribe, or recommend for deoxy-d-glucose? Please check all that apply.

This question was not displayed to the respondent.

Q446. Do you use compounded deoxy-d-glucose as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q447. In which combination(s) do you use compounded deoxy-d-glucose? Please check all that apply.

This question was not displayed to the respondent.

Q448. For which, if any, diseases or conditions do you consider compounded deoxy-d-glucose standard therapy?

This question was not displayed to the respondent.

Q449. Does your specialty describe the use of compounded deoxy-d-glucose in medical practice guidelines or other resources?

This question was not displayed to the respondent. Q450. Over the past 5 years, has the frequency in which you have used compounded deoxy-d- glucose changed?

This question was not displayed to the respondent.

Q451. Why do you use compounded deoxy-d-glucose instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q452. Do you stock non-patient-specific compounded deoxy-d-glucose in your practice location?

This question was not displayed to the respondent.

Q453. In what practice location(s) do you stock non-patient-specific compounded deoxy-d-glucose? Please check all that apply.

This question was not displayed to the respondent.

Q454. How do you obtain your stock of non-patient-specific compounded deoxy-d-glucose? Please check all that apply.

This question was not displayed to the respondent.

Q455. Why do you keep a stock of non-patient-specific compounded deoxy-d-glucose? Please check all that apply.

This question was not displayed to the respondent.

Q456. For which, if any, diseases or conditions do you consider deoxy-d-glucose standard therapy?

This question was not displayed to the respondent.

Q457. Does your specialty describe the use of deoxy-d-glucose in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q458. What type(s) of product(s) do you use, prescribe, or recommend for diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent.

Q460. Do you use compounded diiodohydroxyquinoline as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent. Q461. In which combination(s) do you use compounded diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent.

Q462. For which, if any, diseases or conditions do you consider compounded diiodohydroxyquinoline standard therapy?

This question was not displayed to the respondent.

Q463. Does your specialty describe the use of compounded diiodohydroxyquinoline in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q464. Over the past 5 years, has the frequency in which you have used compounded diiodohydroxyquinoline changed?

This question was not displayed to the respondent.

Q465. Why do you use compounded diiodohydroxyquinoline instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q466. Do you stock non-patient-specific compounded diiodohydroxyquinoline in your practice location?

This question was not displayed to the respondent.

Q467. In what practice location(s) do you stock non-patient-specific compounded diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent.

Q468. How do you obtain your stock of non-patient-specific compounded diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent.

Q469. Why do you keep a stock of non-patient-specific compounded diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent.

Q470. For which, if any, diseases or conditions do you consider diiodohydroxyquinoline standard therapy?

This question was not displayed to the respondent.

Q471. Does your specialty describe the use of diiodohydroxyquinoline in medical practice guidelines or other resources?

This question was not displayed to the respondent. Q472. What type(s) of product(s) do you use, prescribe, or recommend for diphenylcyclopropenone (DPCP)? 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

This question was not displayed to the respondent.

Q474. Do you use compounded diphenylcyclopropenone (DPCP) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q475. Please list all combination products in which you use compounded diphenylcyclopropenone (DPCP).

This question was not displayed to the respondent.

Q476. For which, if any, diseases or conditions do you consider compounded diphenylcyclopropenone (DPCP) standard therapy?

This question was not displayed to the respondent.

Q477. Does your specialty describe the use of compounded diphenylcyclopropenone (DPCP) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q478. Over the past 5 years, has the frequency in which you have used compounded diphenylcyclopropenone (DPCP) changed?

This question was not displayed to the respondent.

Q479. Why do you use compounded diphenylcyclopropenone (DPCP) instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q480. Do you stock non-patient-specific compounded diphenylcyclopropenone (DPCP) in your practice location?

This question was not displayed to the respondent.

Q481. In what practice location(s) do you stock non-patient-specific compounded diphenylcyclopropenone (DPCP)? Please check all that apply.

This question was not displayed to the respondent. Q482. How do you obtain your stock of non-patient-specific compounded diphenylcyclopropenone (DPCP)? Please check all that apply.

This question was not displayed to the respondent.

Q483. Why do you keep a stock of non-patient-specific compounded diphenylcyclopropenone (DPCP)? Please check all that apply.

This question was not displayed to the respondent.

Q484. For which, if any, diseases or conditions do you consider diphenylcyclopropenone (DPCP) standard therapy?

This question was not displayed to the respondent.

Q485. Does your specialty describe the use of diphenylcyclopropenone (DPCP) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q486. What type(s) of product(s) do you use, prescribe, or recommend for podophyllum? Please check all that apply.

This question was not displayed to the respondent.

Q488. Do you use compounded podophyllum as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q489. In which combination(s) do you use compounded podophyllum? Please check all that apply.

This question was not displayed to the respondent.

Q490. For which, if any, diseases or conditions do you consider compounded podophyllum standard therapy?

This question was not displayed to the respondent.

Q491. Does your specialty describe the use of compounded podophyllum in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q492. Over the past 5 years, has the frequency in which you have used compounded podophyllum changed? This question was not displayed to the respondent.

Q493. Why do you use compounded podophyllum instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q494. Do you stock non-patient-specific compounded podophyllum in your practice location?

This question was not displayed to the respondent.

Q495. In what practice location(s) do you stock non-patient-specific compounded podophyllum? Please check all that apply.

This question was not displayed to the respondent.

Q496. How do you obtain your stock of non-patient-specific compounded podophyllum? Please check all that apply.

This question was not displayed to the respondent.

Q497. Why do you keep a stock of non-patient-specific compounded podophyllum? Please check all that apply.

This question was not displayed to the respondent.

Q498. For which, if any, diseases or conditions do you consider podophyllum standard therapy?

This question was not displayed to the respondent.

Q499. Does your specialty describe the use of podophyllum in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q500. What type(s) of product(s) do you use, prescribe, or recommend for podophyllum resin? Please check all that apply.

This question was not displayed to the respondent.

Q502. Do you use compounded podophyllum resin as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q503. In which combination(s) do you use compounded podophyllum resin? Please check all that apply.

This question was not displayed to the respondent. Q504. For which, if any, diseases or conditions do you consider compounded podophyllum resin standard therapy?

This question was not displayed to the respondent.

Q505. Does your specialty describe the use of compounded podophyllum resin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q506. Over the past 5 years, has the frequency in which you have used compounded podophyllum resin changed?

This question was not displayed to the respondent.

Q507. Why do you use compounded podophyllum resin instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q508. Do you stock non-patient-specific compounded podophyllum resin in your practice location?

This question was not displayed to the respondent.

Q509. In what practice location(s) do you stock non-patient-specific compounded podophyllum resin? Please check all that apply.

This question was not displayed to the respondent.

Q510. How do you obtain your stock of non-patient-specific compounded podophyllum resin? Please check all that apply.

This question was not displayed to the respondent.

Q511. Why do you keep a stock of non-patient-specific compounded podophyllum resin? Please check all that apply.

This question was not displayed to the respondent.

Q512. For which, if any, diseases or conditions do you consider podophyllum resin standard therapy?

This question was not displayed to the respondent.

Q513. Does your specialty describe the use of podophyllum resin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q529. What type(s) of product(s) do you use, prescribe, or recommend for quinacrine? Please check all that apply.

This question was not displayed to the respondent. Q530. Please list any conditions or diseases for which you use compounded quinacrine 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).

This question was not displayed to the respondent.

Q531. Do you use compounded quinacrine as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q532. Please list all combination products in which you use compounded quinacrine.

This question was not displayed to the respondent.

Q533. For which, if any, diseases or conditions do you consider compounded quinacrine standard therapy?

This question was not displayed to the respondent.

Q534. Does your specialty describe the use of compounded quinacrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q535. Over the past 5 years, has the frequency in which you have used compounded quinacrine changed?

This question was not displayed to the respondent.

Q536. Why do you use compounded quinacrine instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q537. Do you stock non-patient-specific compounded quinacrine in your practice location?

This question was not displayed to the respondent.

Q538. In what practice location(s) do you stock non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q539. How do you obtain your stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q540. Why do you keep a stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q541. For which, if any, diseases or conditions do you consider quinacrine standard therapy? This question was not displayed to the respondent.

Q542. Does your specialty describe the use of quinacrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q543. What type(s) of product(s) do you use, prescribe, or recommend for squaric acid dibutyl ester (SADBE)? Please check all that apply.

This question was not displayed to the respondent.

Q545. Do you use compounded squaric acid dibutyl ester (SADBE) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q546. Please list all combination products in which you use compounded squaric acid dibutyl ester (SADBE).

This question was not displayed to the respondent.

Q547. For which, if any, diseases or conditions do you consider compounded squaric acid dibutyl ester (SADBE) standard therapy?

This question was not displayed to the respondent.

Q548. Does your specialty describe the use of compounded squaric acid dibutyl ester (SADBE) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q549. Over the past 5 years, has the frequency in which you have used compounded squaric acid dibutyl ester (SADBE) changed?

This question was not displayed to the respondent.

Q550. Why do you use compounded squaric acid dibutyl ester (SADBE) instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q551. Do you stock non-patient-specific compounded squaric acid dibutyl ester (SADBE) in your practice location?

This question was not displayed to the respondent.

Q552. In what practice location(s) do you stock non-patient-specific compounded squaric acid dibutyl ester (SADBE)? Please check all that apply. This question was not displayed to the respondent.

Q553. How do you obtain your stock of non-patient-specific compounded squaric acid dibutyl ester (SADBE)? Please check all that apply.

This question was not displayed to the respondent.

Q554. Why do you keep a stock of non-patient-specific compounded squaric acid dibutyl ester (SADBE)? Please check all that apply.

This question was not displayed to the respondent.

Q555. For which, if any, diseases or conditions do you consider squaric acid dibutyl ester (SADBE) standard therapy?

This question was not displayed to the respondent.

Q556. Does your specialty describe the use of squaric acid dibutyl ester (SADBE) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q16. What is your terminal clinical degree? Please check all that apply.

This question was not displayed to the respondent.

Q17. Which of the following Board certification(s) do you hold? Please check all that apply.

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

Q1. Which of the following substances do you use in your practice? Please check all that apply.

Amphotericin B

Boric acid

Cantharidin

Ciclopirox olamine

Clioquinol

Deoxy-d-glucose

Diiodohydroxyquinoline

Diphenylcyclopropenone (DPCP)

Podophyllum

Podophyllum resin

Quinacrine

Squaric acid dibutyl ester (SADBE)

None of the above

Q2. What type(s) of product(s) do you use, prescribe, or recommend for amphotericin B? Please check all that apply. This question was not displayed to the respondent.

This question was not displayed to the respondent.

Q4. Do you use compounded amphotericin B as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q5. Please list all combination products in which you use compounded amphotericin B.

This question was not displayed to the respondent.

Q6. For which, if any, diseases or conditions do you consider compounded amphotericin B standard therapy?

This question was not displayed to the respondent.

Q7. Does your specialty describe the use of compounded amphotericin B in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q8. Over the past 5 years, has the frequency in which you have used compounded amphotericin B changed?

This question was not displayed to the respondent.

Q9. Why do you use compounded amphotericin B instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q10. Do you stock non-patient-specific compounded amphotericin B in your practice location?

This question was not displayed to the respondent.

Q11. In what practice location(s) do you stock non-patient-specific compounded amphotericin B? Please check all that apply.

This question was not displayed to the respondent. Q12. How do you obtain your stock of non-patient-specific compounded amphotericin B? Please check all that apply.

This question was not displayed to the respondent.

Q13. Why do you keep a stock of non-patient-specific compounded amphotericin B? Please check all that apply.

This question was not displayed to the respondent.

Q14. For which, if any, diseases or conditions do you consider amphotericin B standard therapy?

This question was not displayed to the respondent.

Q15. Does your specialty describe the use of amphotericin B in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q388. What type(s) of product(s) do you use, prescribe, or recommend for boric acid? Please check all that apply.

This question was not displayed to the respondent.

Q390. Do you use compounded boric acid as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q391. Please list all combination products in which you use compounded boric acid.

This question was not displayed to the respondent.

Q392. For which, if any, diseases or conditions do you consider compounded boric acid standard therapy?

This question was not displayed to the respondent. Q393. Does your specialty describe the use of compounded boric acid in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q394. Over the past 5 years, has the frequency in which you have used compounded boric acid changed?

This question was not displayed to the respondent.

Q395. Why do you use compounded boric acid instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q396. Do you stock non-patient-specific compounded boric acid in your practice location?

This question was not displayed to the respondent.

Q397. In what practice location(s) do you stock non-patient-specific compounded boric acid? Please check all that apply.

This question was not displayed to the respondent.

Q398. How do you obtain your stock of non-patient-specific compounded boric acid? Please check all that apply.

This question was not displayed to the respondent.

Q399. Why do you keep a stock of non-patient-specific compounded boric acid? Please check all that apply.

This question was not displayed to the respondent.

Q400. For which, if any, diseases or conditions do you consider boric acid standard therapy?

This question was not displayed to the respondent.

Q401. Does your specialty describe the use of boric acid in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q402. What type(s) of product(s) do you use, prescribe, or recommend for cantharidin? 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

This question was not displayed to the respondent.

Q404. Do you use compounded cantharidin as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q405. In which combination(s) do you use compounded cantharidin? Please check all that apply.

This question was not displayed to the respondent.

Q406. For which, if any, diseases or conditions do you consider compounded cantharidin standard therapy?

This question was not displayed to the respondent.

Q407. Does your specialty describe the use of compounded cantharidin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q408. Over the past 5 years, has the frequency in which you have used compounded cantharidin changed?

This question was not displayed to the respondent.

Q409. Why do you use compounded cantharidin instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q410. Do you stock non-patient-specific compounded cantharidin in your practice location?

This question was not displayed to the respondent.

Q411. In what practice location(s) do you stock non-patient-specific compounded cantharidin? Please check all that apply. This question was not displayed to the respondent.

Q412. How do you obtain your stock of non-patient-specific compounded cantharidin? Please check all that apply.

This question was not displayed to the respondent.

Q413. Why do you keep a stock of non-patient-specific compounded cantharidin? Please check all that apply.

This question was not displayed to the respondent.

Q414. For which, if any, diseases or conditions do you consider cantharidin standard therapy?

This question was not displayed to the respondent.

Q415. Does your specialty describe the use of cantharidin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q416. What type(s) of product(s) do you use, prescribe, or recommend for ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent.

Q418. Do you use compounded ciclopirox olamine as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q419. In which combination(s) do you use compounded ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent.

Q420. For which, if any, diseases or conditions do you consider compounded ciclopirox olamine standard therapy? This question was not displayed to the respondent.

Q421. Does your specialty describe the use of compounded ciclopirox olamine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q422. Over the past 5 years, has the frequency in which you have used compounded ciclopirox olamine changed?

This question was not displayed to the respondent.

Q423. Why do you use compounded ciclopirox olamine instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q424. Do you stock non-patient-specific compounded ciclopirox olamine in your practice location?

This question was not displayed to the respondent.

Q425. In what practice location(s) do you stock non-patient-specific compounded ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent.

Q426. How do you obtain your stock of non-patient-specific compounded ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent.

Q427. Why do you keep a stock of non-patient-specific compounded ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent.

Q428. For which, if any, diseases or conditions do you consider ciclopirox olamine standard therapy?

This question was not displayed to the respondent.

Q429. Does your specialty describe the use of ciclopirox olamine in medical practice guidelines or other resources?

This question was not displayed to the respondent. Q430. What type(s) of product(s) do you use, prescribe, or recommend for clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q432. Do you use compounded clioquinol as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q433. In which combination(s) do you use compounded clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q434. For which, if any, diseases or conditions do you consider compounded clioquinol standard therapy?

This question was not displayed to the respondent.

Q435. Does your specialty describe the use of compounded clioquinol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q436. Over the past 5 years, has the frequency in which you have used compounded clioquinol changed?

This question was not displayed to the respondent.

Q437. Why do you use compounded clioquinol instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q438. Do you stock non-patient-specific compounded clioquinol in your practice location?

This question was not displayed to the respondent.

Q439. In what practice location(s) do you stock non-patient-specific compounded clioquinol? Please check all that apply. This question was not displayed to the respondent.

Q440. How do you obtain your stock of non-patient-specific compounded clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q441. Why do you keep a stock of non-patient-specific compounded clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q442. For which, if any, diseases or conditions do you consider clioquinol standard therapy?

This question was not displayed to the respondent.

Q443. Does your specialty describe the use of clioquinol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q444. What type(s) of product(s) do you use, prescribe, or recommend for deoxy-d-glucose? Please check all that apply.

This question was not displayed to the respondent.

Q446. Do you use compounded deoxy-d-glucose as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q447. In which combination(s) do you use compounded deoxy-d-glucose? Please check all that apply.

This question was not displayed to the respondent.

Q448. For which, if any, diseases or conditions do you consider compounded deoxy-d-glucose standard therapy?

This question was not displayed to the respondent. Q449. Does your specialty describe the use of compounded deoxy-d-glucose in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q450. Over the past 5 years, has the frequency in which you have used compounded deoxy-d- glucose changed?

This question was not displayed to the respondent.

Q451. Why do you use compounded deoxy-d-glucose instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q452. Do you stock non-patient-specific compounded deoxy-d-glucose in your practice location?

This question was not displayed to the respondent.

Q453. In what practice location(s) do you stock non-patient-specific compounded deoxy-d-glucose? Please check all that apply.

This question was not displayed to the respondent.

Q454. How do you obtain your stock of non-patient-specific compounded deoxy-d-glucose? Please check all that apply.

This question was not displayed to the respondent.

Q455. Why do you keep a stock of non-patient-specific compounded deoxy-d-glucose? Please check all that apply.

This question was not displayed to the respondent.

Q456. For which, if any, diseases or conditions do you consider deoxy-d-glucose standard therapy?

This question was not displayed to the respondent.

Q457. Does your specialty describe the use of deoxy-d-glucose in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q458. What type(s) of product(s) do you use, prescribe, or recommend for diiodohydroxyquinoline? Please check all that apply. This question was not displayed to the respondent.

This question was not displayed to the respondent.

Q460. Do you use compounded diiodohydroxyquinoline as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q461. In which combination(s) do you use compounded diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent.

Q462. For which, if any, diseases or conditions do you consider compounded diiodohydroxyquinoline standard therapy?

This question was not displayed to the respondent.

Q463. Does your specialty describe the use of compounded diiodohydroxyquinoline in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q464. Over the past 5 years, has the frequency in which you have used compounded diiodohydroxyquinoline changed?

This question was not displayed to the respondent.

Q465. Why do you use compounded diiodohydroxyquinoline instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q466. Do you stock non-patient-specific compounded diiodohydroxyquinoline in your practice location?

This question was not displayed to the respondent.

Q467. In what practice location(s) do you stock non-patient-specific compounded diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent. Q468. How do you obtain your stock of non-patient-specific compounded diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent.

Q469. Why do you keep a stock of non-patient-specific compounded diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent.

Q470. For which, if any, diseases or conditions do you consider diiodohydroxyquinoline standard therapy?

This question was not displayed to the respondent.

Q471. Does your specialty describe the use of diiodohydroxyquinoline in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q472. What type(s) of product(s) do you use, prescribe, or recommend for diphenylcyclopropenone (DPCP)? Please check all that apply.

This question was not displayed to the respondent.

Q474. Do you use compounded diphenylcyclopropenone (DPCP) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q475. Please list all combination products in which you use compounded diphenylcyclopropenone (DPCP).

This question was not displayed to the respondent.

Q476. For which, if any, diseases or conditions do you consider compounded diphenylcyclopropenone (DPCP) standard therapy?

This question was not displayed to the respondent. Q477. Does your specialty describe the use of compounded diphenylcyclopropenone (DPCP) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q478. Over the past 5 years, has the frequency in which you have used compounded diphenylcyclopropenone (DPCP) changed?

This question was not displayed to the respondent.

Q479. Why do you use compounded diphenylcyclopropenone (DPCP) instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q480. Do you stock non-patient-specific compounded diphenylcyclopropenone (DPCP) in your practice location?

This question was not displayed to the respondent.

Q481. In what practice location(s) do you stock non-patient-specific compounded diphenylcyclopropenone (DPCP)? Please check all that apply.

This question was not displayed to the respondent.

Q482. How do you obtain your stock of non-patient-specific compounded diphenylcyclopropenone (DPCP)? Please check all that apply.

This question was not displayed to the respondent.

Q483. Why do you keep a stock of non-patient-specific compounded diphenylcyclopropenone (DPCP)? Please check all that apply.

This question was not displayed to the respondent.

Q484. For which, if any, diseases or conditions do you consider diphenylcyclopropenone (DPCP) standard therapy?

This question was not displayed to the respondent.

Q485. Does your specialty describe the use of diphenylcyclopropenone (DPCP) in medical practice guidelines or other resources?

This question was not displayed to the respondent. Q486. What type(s) of product(s) do you use, prescribe, or recommend for podophyllum? Please check all that apply.

This question was not displayed to the respondent.

Q488. Do you use compounded podophyllum as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q489. In which combination(s) do you use compounded podophyllum? Please check all that apply.

This question was not displayed to the respondent.

Q490. For which, if any, diseases or conditions do you consider compounded podophyllum standard therapy?

This question was not displayed to the respondent.

Q491. Does your specialty describe the use of compounded podophyllum in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q492. Over the past 5 years, has the frequency in which you have used compounded podophyllum changed?

This question was not displayed to the respondent.

Q493. Why do you use compounded podophyllum instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q494. Do you stock non-patient-specific compounded podophyllum in your practice location?

This question was not displayed to the respondent. Q495. In what practice location(s) do you stock non-patient-specific compounded podophyllum? Please check all that apply.

This question was not displayed to the respondent.

Q496. How do you obtain your stock of non-patient-specific compounded podophyllum? Please check all that apply.

This question was not displayed to the respondent.

Q497. Why do you keep a stock of non-patient-specific compounded podophyllum? Please check all that apply.

This question was not displayed to the respondent.

Q498. For which, if any, diseases or conditions do you consider podophyllum standard therapy?

This question was not displayed to the respondent.

Q499. Does your specialty describe the use of podophyllum in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q500. What type(s) of product(s) do you use, prescribe, or recommend for podophyllum resin? Please check all that apply.

This question was not displayed to the respondent.

Q502. Do you use compounded podophyllum resin as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q503. In which combination(s) do you use compounded podophyllum resin? Please check all that apply.

This question was not displayed to the respondent. Q504. For which, if any, diseases or conditions do you consider compounded podophyllum resin standard therapy?

This question was not displayed to the respondent.

Q505. Does your specialty describe the use of compounded podophyllum resin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q506. Over the past 5 years, has the frequency in which you have used compounded podophyllum resin changed?

This question was not displayed to the respondent.

Q507. Why do you use compounded podophyllum resin instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q508. Do you stock non-patient-specific compounded podophyllum resin in your practice location?

This question was not displayed to the respondent.

Q509. In what practice location(s) do you stock non-patient-specific compounded podophyllum resin? Please check all that apply.

This question was not displayed to the respondent.

Q510. How do you obtain your stock of non-patient-specific compounded podophyllum resin? Please check all that apply.

This question was not displayed to the respondent.

Q511. Why do you keep a stock of non-patient-specific compounded podophyllum resin? Please check all that apply.

This question was not displayed to the respondent.

Q512. For which, if any, diseases or conditions do you consider podophyllum resin standard therapy?

This question was not displayed to the respondent.

Q513. Does your specialty describe the use of podophyllum resin in medical practice guidelines or other resources? This question was not displayed to the respondent.

Q529. What type(s) of product(s) do you use, prescribe, or recommend for quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q531. Do you use compounded quinacrine as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q532. Please list all combination products in which you use compounded quinacrine.

This question was not displayed to the respondent.

Q533. For which, if any, diseases or conditions do you consider compounded quinacrine standard therapy?

This question was not displayed to the respondent.

Q534. Does your specialty describe the use of compounded quinacrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q535. Over the past 5 years, has the frequency in which you have used compounded quinacrine changed?

This question was not displayed to the respondent.

Q536. Why do you use compounded quinacrine instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q537. Do you stock non-patient-specific compounded quinacrine in your practice location?

This question was not displayed to the respondent. Q538. In what practice location(s) do you stock non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q539. How do you obtain your stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q540. Why do you keep a stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q541. For which, if any, diseases or conditions do you consider quinacrine standard therapy?

This question was not displayed to the respondent.

Q542. Does your specialty describe the use of quinacrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q543. What type(s) of product(s) do you use, prescribe, or recommend for squaric acid dibutyl ester (SADBE)? Please check all that apply.

This question was not displayed to the respondent.

Q545. Do you use compounded squaric acid dibutyl ester (SADBE) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q546. Please list all combination products in which you use compounded squaric acid dibutyl ester (SADBE).

This question was not displayed to the respondent. Q547. For which, if any, diseases or conditions do you consider compounded squaric acid dibutyl ester (SADBE) standard therapy?

This question was not displayed to the respondent.

Q548. Does your specialty describe the use of compounded squaric acid dibutyl ester (SADBE) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q549. Over the past 5 years, has the frequency in which you have used compounded squaric acid dibutyl ester (SADBE) changed?

This question was not displayed to the respondent.

Q550. Why do you use compounded squaric acid dibutyl ester (SADBE) instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q551. Do you stock non-patient-specific compounded squaric acid dibutyl ester (SADBE) in your practice location?

This question was not displayed to the respondent.

Q552. In what practice location(s) do you stock non-patient-specific compounded squaric acid dibutyl ester (SADBE)? Please check all that apply.

This question was not displayed to the respondent.

Q553. How do you obtain your stock of non-patient-specific compounded squaric acid dibutyl ester (SADBE)? Please check all that apply.

This question was not displayed to the respondent.

Q554. Why do you keep a stock of non-patient-specific compounded squaric acid dibutyl ester (SADBE)? Please check all that apply.

This question was not displayed to the respondent.

Q555. For which, if any, diseases or conditions do you consider squaric acid dibutyl ester (SADBE) standard therapy?

This question was not displayed to the respondent. Q556. Does your specialty describe the use of squaric acid dibutyl ester (SADBE) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q16. What is your terminal clinical degree? Please check all that apply.

This question was not displayed to the respondent.

Q17. Which of the following Board certification(s) do you hold? Please check all that apply.

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

Q1. Which of the following substances do you use in your practice? Please check all that apply.

Amphotericin B

Boric acid

Cantharidin

Ciclopirox olamine

Clioquinol

Deoxy-d-glucose

Diiodohydroxyquinoline

Diphenylcyclopropenone (DPCP)

Podophyllum

Podophyllum resin

Quinacrine

Squaric acid dibutyl ester (SADBE)

None of the above

Q2. What type(s) of product(s) do you use, prescribe, or recommend for amphotericin B? Please check all that apply.

This question was not displayed to the respondent.

Q4. Do you use compounded amphotericin B as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q5. Please list all combination products in which you use compounded amphotericin B.

This question was not displayed to the respondent.

Q6. For which, if any, diseases or conditions do you consider compounded amphotericin B standard therapy?

This question was not displayed to the respondent.

Q7. Does your specialty describe the use of compounded amphotericin B in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q8. Over the past 5 years, has the frequency in which you have used compounded amphotericin B changed?

This question was not displayed to the respondent.

Q9. Why do you use compounded amphotericin B instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q10. Do you stock non-patient-specific compounded amphotericin B in your practice location?

This question was not displayed to the respondent.

Q11. In what practice location(s) do you stock non-patient-specific compounded amphotericin B? Please check all that apply.

This question was not displayed to the respondent.

Q12. How do you obtain your stock of non-patient-specific compounded amphotericin B? Please check all that apply.

This question was not displayed to the respondent.

Q13. Why do you keep a stock of non-patient-specific compounded amphotericin B? Please check all that apply.

This question was not displayed to the respondent.

Q14. For which, if any, diseases or conditions do you consider amphotericin B standard therapy?

This question was not displayed to the respondent.

Q15. Does your specialty describe the use of amphotericin B in medical practice guidelines or other resources? This question was not displayed to the respondent.

Q388. What type(s) of product(s) do you use, prescribe, or recommend for boric acid? Please check all that apply.

This question was not displayed to the respondent.

Q390. Do you use compounded boric acid as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q391. Please list all combination products in which you use compounded boric acid.

This question was not displayed to the respondent.

Q392. For which, if any, diseases or conditions do you consider compounded boric acid standard therapy?

This question was not displayed to the respondent.

Q393. Does your specialty describe the use of compounded boric acid in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q394. Over the past 5 years, has the frequency in which you have used compounded boric acid changed?

This question was not displayed to the respondent.

Q395. Why do you use compounded boric acid instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q396. Do you stock non-patient-specific compounded boric acid in your practice location?

This question was not displayed to the respondent.

Q397. In what practice location(s) do you stock non-patient-specific compounded boric acid? Please check all that apply.

This question was not displayed to the respondent.

Q398. How do you obtain your stock of non-patient-specific compounded boric acid? Please check all that apply.

This question was not displayed to the respondent. Q399. Why do you keep a stock of non-patient-specific compounded boric acid? Please check all that apply.

This question was not displayed to the respondent.

Q400. For which, if any, diseases or conditions do you consider boric acid standard therapy?

This question was not displayed to the respondent.

Q401. Does your specialty describe the use of boric acid in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q402. What type(s) of product(s) do you use, prescribe, or recommend for cantharidin? Please check all that apply.

This question was not displayed to the respondent.

Q404. Do you use compounded cantharidin as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q405. In which combination(s) do you use compounded cantharidin? Please check all that apply.

This question was not displayed to the respondent.

Q406. For which, if any, diseases or conditions do you consider compounded cantharidin standard therapy?

This question was not displayed to the respondent.

Q407. Does your specialty describe the use of compounded cantharidin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q408. Over the past 5 years, has the frequency in which you have used compounded cantharidin changed?

This question was not displayed to the respondent.

Q409. Why do you use compounded cantharidin instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q410. Do you stock non-patient-specific compounded cantharidin in your practice location?

This question was not displayed to the respondent. Q411. In what practice location(s) do you stock non-patient-specific compounded cantharidin? Please check all that apply.

This question was not displayed to the respondent.

Q412. How do you obtain your stock of non-patient-specific compounded cantharidin? Please check all that apply.

This question was not displayed to the respondent.

Q413. Why do you keep a stock of non-patient-specific compounded cantharidin? Please check all that apply.

This question was not displayed to the respondent.

Q414. For which, if any, diseases or conditions do you consider cantharidin standard therapy?

This question was not displayed to the respondent.

Q415. Does your specialty describe the use of cantharidin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q416. What type(s) of product(s) do you use, prescribe, or recommend for ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent.

Q418. Do you use compounded ciclopirox olamine as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q419. In which combination(s) do you use compounded ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent.

Q420. For which, if any, diseases or conditions do you consider compounded ciclopirox olamine standard therapy?

This question was not displayed to the respondent.

Q421. Does your specialty describe the use of compounded ciclopirox olamine in medical practice guidelines or other resources?

This question was not displayed to the respondent. Q422. Over the past 5 years, has the frequency in which you have used compounded ciclopirox olamine changed?

This question was not displayed to the respondent.

Q423. Why do you use compounded ciclopirox olamine instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q424. Do you stock non-patient-specific compounded ciclopirox olamine in your practice location?

This question was not displayed to the respondent.

Q425. In what practice location(s) do you stock non-patient-specific compounded ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent.

Q426. How do you obtain your stock of non-patient-specific compounded ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent.

Q427. Why do you keep a stock of non-patient-specific compounded ciclopirox olamine? Please check all that apply.

This question was not displayed to the respondent.

Q428. For which, if any, diseases or conditions do you consider ciclopirox olamine standard therapy?

This question was not displayed to the respondent.

Q429. Does your specialty describe the use of ciclopirox olamine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q430. What type(s) of product(s) do you use, prescribe, or recommend for clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q432. Do you use compounded clioquinol as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent. Q433. In which combination(s) do you use compounded clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q434. For which, if any, diseases or conditions do you consider compounded clioquinol standard therapy?

This question was not displayed to the respondent.

Q435. Does your specialty describe the use of compounded clioquinol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q436. Over the past 5 years, has the frequency in which you have used compounded clioquinol changed?

This question was not displayed to the respondent.

Q437. Why do you use compounded clioquinol instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q438. Do you stock non-patient-specific compounded clioquinol in your practice location?

This question was not displayed to the respondent.

Q439. In what practice location(s) do you stock non-patient-specific compounded clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q440. How do you obtain your stock of non-patient-specific compounded clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q441. Why do you keep a stock of non-patient-specific compounded clioquinol? Please check all that apply.

This question was not displayed to the respondent.

Q442. For which, if any, diseases or conditions do you consider clioquinol standard therapy?

This question was not displayed to the respondent.

Q443. Does your specialty describe the use of clioquinol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q444. What type(s) of product(s) do you use, prescribe, or recommend for deoxy-d-glucose? Please check all that apply.

This question was not displayed to the respondent. Q445. Please list any conditions or diseases for which you use compounded deoxy-d-glucose 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).

This question was not displayed to the respondent.

Q446. Do you use compounded deoxy-d-glucose as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q447. In which combination(s) do you use compounded deoxy-d-glucose? Please check all that apply.

This question was not displayed to the respondent.

Q448. For which, if any, diseases or conditions do you consider compounded deoxy-d-glucose standard therapy?

This question was not displayed to the respondent.

Q449. Does your specialty describe the use of compounded deoxy-d-glucose in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q450. Over the past 5 years, has the frequency in which you have used compounded deoxy-d- glucose changed?

This question was not displayed to the respondent.

Q451. Why do you use compounded deoxy-d-glucose instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q452. Do you stock non-patient-specific compounded deoxy-d-glucose in your practice location?

This question was not displayed to the respondent.

Q453. In what practice location(s) do you stock non-patient-specific compounded deoxy-d-glucose? Please check all that apply.

This question was not displayed to the respondent.

Q454. How do you obtain your stock of non-patient-specific compounded deoxy-d-glucose? Please check all that apply.

This question was not displayed to the respondent.

Q455. Why do you keep a stock of non-patient-specific compounded deoxy-d-glucose? Please check all that apply.

This question was not displayed to the respondent. Q456. For which, if any, diseases or conditions do you consider deoxy-d-glucose standard therapy?

This question was not displayed to the respondent.

Q457. Does your specialty describe the use of deoxy-d-glucose in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q458. What type(s) of product(s) do you use, prescribe, or recommend for diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent.

Q460. Do you use compounded diiodohydroxyquinoline as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q461. In which combination(s) do you use compounded diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent.

Q462. For which, if any, diseases or conditions do you consider compounded diiodohydroxyquinoline standard therapy?

This question was not displayed to the respondent.

Q463. Does your specialty describe the use of compounded diiodohydroxyquinoline in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q464. Over the past 5 years, has the frequency in which you have used compounded diiodohydroxyquinoline changed?

This question was not displayed to the respondent.

Q465. Why do you use compounded diiodohydroxyquinoline instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q466. Do you stock non-patient-specific compounded diiodohydroxyquinoline in your practice location?

This question was not displayed to the respondent. Q467. In what practice location(s) do you stock non-patient-specific compounded diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent.

Q468. How do you obtain your stock of non-patient-specific compounded diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent.

Q469. Why do you keep a stock of non-patient-specific compounded diiodohydroxyquinoline? Please check all that apply.

This question was not displayed to the respondent.

Q470. For which, if any, diseases or conditions do you consider diiodohydroxyquinoline standard therapy?

This question was not displayed to the respondent.

Q471. Does your specialty describe the use of diiodohydroxyquinoline in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q472. What type(s) of product(s) do you use, prescribe, or recommend for diphenylcyclopropenone (DPCP)? Please check all that apply.

This question was not displayed to the respondent.

Q474. Do you use compounded diphenylcyclopropenone (DPCP) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q475. Please list all combination products in which you use compounded diphenylcyclopropenone (DPCP).

This question was not displayed to the respondent.

Q476. For which, if any, diseases or conditions do you consider compounded diphenylcyclopropenone (DPCP) standard therapy?

This question was not displayed to the respondent.

Q477. Does your specialty describe the use of compounded diphenylcyclopropenone (DPCP) in medical practice guidelines or other resources?

This question was not displayed to the respondent. Q478. Over the past 5 years, has the frequency in which you have used compounded diphenylcyclopropenone (DPCP) changed?

This question was not displayed to the respondent.

Q479. Why do you use compounded diphenylcyclopropenone (DPCP) instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q480. Do you stock non-patient-specific compounded diphenylcyclopropenone (DPCP) in your practice location?

This question was not displayed to the respondent.

Q481. In what practice location(s) do you stock non-patient-specific compounded diphenylcyclopropenone (DPCP)? Please check all that apply.

This question was not displayed to the respondent.

Q482. How do you obtain your stock of non-patient-specific compounded diphenylcyclopropenone (DPCP)? Please check all that apply.

This question was not displayed to the respondent.

Q483. Why do you keep a stock of non-patient-specific compounded diphenylcyclopropenone (DPCP)? Please check all that apply.

This question was not displayed to the respondent.

Q484. For which, if any, diseases or conditions do you consider diphenylcyclopropenone (DPCP) standard therapy?

This question was not displayed to the respondent.

Q485. Does your specialty describe the use of diphenylcyclopropenone (DPCP) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q486. What type(s) of product(s) do you use, prescribe, or recommend for podophyllum? Please check all that apply.

This question was not displayed to the respondent.

Q488. Do you use compounded podophyllum as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply. This question was not displayed to the respondent.

Q489. In which combination(s) do you use compounded podophyllum? Please check all that apply.

This question was not displayed to the respondent.

Q490. For which, if any, diseases or conditions do you consider compounded podophyllum standard therapy?

This question was not displayed to the respondent.

Q491. Does your specialty describe the use of compounded podophyllum in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q492. Over the past 5 years, has the frequency in which you have used compounded podophyllum changed?

This question was not displayed to the respondent.

Q493. Why do you use compounded podophyllum instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q494. Do you stock non-patient-specific compounded podophyllum in your practice location?

This question was not displayed to the respondent.

Q495. In what practice location(s) do you stock non-patient-specific compounded podophyllum? Please check all that apply.

This question was not displayed to the respondent.

Q496. How do you obtain your stock of non-patient-specific compounded podophyllum? Please check all that apply.

This question was not displayed to the respondent.

Q497. Why do you keep a stock of non-patient-specific compounded podophyllum? Please check all that apply.

This question was not displayed to the respondent.

Q498. For which, if any, diseases or conditions do you consider podophyllum standard therapy?

This question was not displayed to the respondent.

Q499. Does your specialty describe the use of podophyllum in medical practice guidelines or other resources?

This question was not displayed to the respondent. Q500. What type(s) of product(s) do you use, prescribe, or recommend for podophyllum resin? Please check all that apply.

This question was not displayed to the respondent.

Q502. Do you use compounded podophyllum resin as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q503. In which combination(s) do you use compounded podophyllum resin? Please check all that apply.

This question was not displayed to the respondent.

Q504. For which, if any, diseases or conditions do you consider compounded podophyllum resin standard therapy?

This question was not displayed to the respondent.

Q505. Does your specialty describe the use of compounded podophyllum resin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q506. Over the past 5 years, has the frequency in which you have used compounded podophyllum resin changed?

This question was not displayed to the respondent.

Q507. Why do you use compounded podophyllum resin instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q508. Do you stock non-patient-specific compounded podophyllum resin in your practice location?

This question was not displayed to the respondent.

Q509. In what practice location(s) do you stock non-patient-specific compounded podophyllum resin? Please check all that apply.

This question was not displayed to the respondent.

Q510. How do you obtain your stock of non-patient-specific compounded podophyllum resin? Please check all that apply.

This question was not displayed to the respondent. Q511. Why do you keep a stock of non-patient-specific compounded podophyllum resin? Please check all that apply.

This question was not displayed to the respondent.

Q512. For which, if any, diseases or conditions do you consider podophyllum resin standard therapy?

This question was not displayed to the respondent.

Q513. Does your specialty describe the use of podophyllum resin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q529. What type(s) of product(s) do you use, prescribe, or recommend for quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q531. Do you use compounded quinacrine as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q532. Please list all combination products in which you use compounded quinacrine.

This question was not displayed to the respondent.

Q533. For which, if any, diseases or conditions do you consider compounded quinacrine standard therapy?

This question was not displayed to the respondent.

Q534. Does your specialty describe the use of compounded quinacrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q535. Over the past 5 years, has the frequency in which you have used compounded quinacrine changed?

This question was not displayed to the respondent.

Q536. Why do you use compounded quinacrine instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q537. Do you stock non-patient-specific compounded quinacrine in your practice location? This question was not displayed to the respondent.

Q538. In what practice location(s) do you stock non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q539. How do you obtain your stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q540. Why do you keep a stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q541. For which, if any, diseases or conditions do you consider quinacrine standard therapy?

This question was not displayed to the respondent.

Q542. Does your specialty describe the use of quinacrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q543. What type(s) of product(s) do you use, prescribe, or recommend for squaric acid dibutyl ester (SADBE)? 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

Strength(s) (please include Dosing Route(s) of Duration of units) frequency(ies) Dosage form(s) administration therapy Patient population Condition 1 (please describe)

Alopecia areata

1% daily solution topical as long as adult/ male and beneficial female

Condition 2 (please describe)

Condition 3 (please describe)

Condition 4 (please describe)

Condition 5 (please describe)

Condition 6 (please describe)

Condition 7 (please describe)

Condition 8 (please describe)

Q545. Do you use compounded squaric acid dibutyl ester (SADBE) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

Single

Combination

Q546. Please list all combination products in which you use compounded squaric acid dibutyl ester (SADBE).

This question was not displayed to the respondent.

Q548. DoesDoes youryour specialtyspecialty describedescribe thethe useuse ofof compoundedcompounded squaric acid dibutyl ester (SADBE) inin medicalmedical practice guidelines or other resources?

Yes

Q549. Over the past 5 years, has the frequency in which you have used compounded squaric acid dibutyl ester (SADBE) changed?

Yes - I use it MORE oftenoften nownow (briefly(briefly describedescribe why)why) lack of other effective treatment for severe alopecia aerate

Yes - I use it LESS oftenoften nownow (briefly(briefly describedescribe why)why)

No - use has remained consistent

Q550. WhyWhy dodo youyou useuse compoundedcompounded squaric acid dibutyl ester (SADBE) insteadinstead ofof anyany FDA-approvedFDA-approved drug product?

No approve FDA product available

Q551. Do you stock non-patient-specific compounded squaric acid dibutyl ester (SADBE) in your practice location?

Yes

Q552. In what practice location(s) do you stock non-patient-specific compounded squaric acid dibutyl ester (SADBE)? Please check all that apply.

This question was not displayed to the respondent.

Q553. How do you obtain your stock of non-patient-specific compounded squaric acid dibutyl ester (SADBE)? Please check all that apply.

This question was not displayed to the respondent.

Q554. Why do you keep a stock of non-patient-specific compounded squaric acid dibutyl ester (SADBE)? Please check all that apply.

This question was not displayed to the respondent.

Q555. For which, if any, diseases or conditions do you consider squaric acid dibutyl ester (SADBE) standard therapy?

This question was not displayed to the respondent.

Q556. Does your specialty describe the use of squaric acid dibutyl ester (SADBE) in medical practice guidelines or other resources? This question was not displayed to the respondent.

Q16. 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)

Q17. 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,, DiabetesDiabetes andand MetabolismMetabolism

Family Medicine

Gastroenterology

Hematology

InfectiousInfectious DiseaseDisease

InternalInternal MedicineMedicine

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

There are ten (10) substancessubstances containedcontained inin thisthis surveysurvey.. As a medical expert, we appreciate your input regarding the use of these substances 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

Q1. Which of the following substances do you use in your practice? Please check all that apply.

Alpha lipoic acid (ALA)

Dexamethasone acetate

InositolInositol

Methylcobalamin

Methylsulfonylmethane (MSM)

Phenylephrine

Pitcher plant

Pregnenolone

Quinacrine

Zinc sulfate

None of the above

Q2. What type(s) of product(s) do you use, prescribe, or recommend for alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent. Q3. Please list any conditions or diseases for which you use compounded alpha lipoic acid (ALA) 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).

This question was not displayed to the respondent.

Q4. Do you use compounded alpha lipoic acid (ALA) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q5. Please list all combination products in which you use compounded alpha lipoic acid (ALA).

This question was not displayed to the respondent.

Q6. For which, if any, diseases or conditions do you consider compounded alpha lipoic acid (ALA) standard therapy?

This question was not displayed to the respondent.

Q7. Does your specialty describe the use of compounded alpha lipoic acid (ALA) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q8. Over the past 5 years, has the frequency in which you have used compounded alpha lipoic acid (ALA) changed?

This question was not displayed to the respondent.

Q9. Why do you use compounded alpha lipoic acid (ALA) instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q10. Do you stock non-patient-specific compounded alpha lipoic acid (ALA) in your practice location?

This question was not displayed to the respondent.

Q11. In what practice location(s) do you stock non-patient-specific compounded alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent. Q12. How do you obtain your stock of non-patient-specific compounded alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent.

Q13. Why do you keep a stock of non-patient-specific compounded alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent.

Q14. For which, if any, diseases or conditions do you consider alpha lipoic acid (ALA) standard therapy?

This question was not displayed to the respondent.

Q15. Does your specialty describe the use of alpha lipoic acid (ALA) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q515. What type(s) of product(s) do you use, prescribe, or recommend for dexamethasone acetate? 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

Q516. Please list any conditions or diseases for which you use compounded dexamethasone acetate 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).

This question was not displayed to the respondent.

Q517. Do you use compounded dexamethasone acetate as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q518. Please list all combination products in which you use compounded dexamethasone acetate. This question was not displayed to the respondent.

Q519. For which, if any, diseases or conditions do you consider compounded dexamethasone acetate standard therapy?

This question was not displayed to the respondent.

Q520. Does your specialty describe the use of compounded dexamethasone acetate in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q521. Over the past 5 years, has the frequency in which you have used compounded dexamethasone acetate changed?

This question was not displayed to the respondent.

Q522. Why do you use compounded dexamethasone acetate instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q523. Do you stock non-patient-specific compounded dexamethasone acetate in your practice location?

This question was not displayed to the respondent.

Q524. In what practice location(s) do you stock non-patient-specific compounded dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q525. How do you obtain your stock of non-patient-specific compounded dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q526. Why do you keep a stock of non-patient-specific compounded dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q527. ForFor which, if any,, diseasesdiseases oror conditionsconditions dodo youyou considerconsider dexamethasone acetate standardstandard therapy?therapy?

Radicular pain Q528. DoesDoes your specialty describe the use of dexamethasone acetate inin medicalmedical practicepractice guidelines or other resources?

Guidelines

Q543. What type(s) of product(s) do you use, prescribe, or recommend for inositol? Please check all that apply.

This question was not displayed to the respondent.

Q544. Please list any conditions or diseases for which you use compounded inositol 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).

This question was not displayed to the respondent.

Q545. Do you use compounded inositol as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q546. In which combination(s) do you use compounded inositol? Please check all that apply.

This question was not displayed to the respondent.

Q547. For which, if any, diseases or conditions do you consider compounded inositol standard therapy?

This question was not displayed to the respondent.

Q548. Does your specialty describe the use of compounded inositol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q549. Over the past 5 years, has the frequency in which you have used compounded inositol changed?

This question was not displayed to the respondent.

Q550. Why do you use compounded inositol instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q551. Do you stock non-patient-specific compounded inositol in your practice location? This question was not displayed to the respondent.

Q552. In what practice location(s) do you stock non-patient-specific compounded inositol? Please check all that apply.

This question was not displayed to the respondent.

Q553. How do you obtain your stock of non-patient-specific compounded inositol? Please check all that apply.

This question was not displayed to the respondent.

Q554. Why do you keep a stock of non-patient-specific compounded inositol? Please check all that apply.

This question was not displayed to the respondent.

Q555. For which, if any, diseases or conditions do you consider inositol standard therapy?

This question was not displayed to the respondent.

Q556. Does your specialty describe the use of inositol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q388. What type(s) of product(s) do you use, prescribe, or recommend for methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q389. Please list any conditions or diseases for which you use compounded methylcobalamin in your practice. Please include the strength(s), dosing frequency(ies), dosage form(s), route(s) of administration, duration of therapy, and patient population (ex. age, gender, comorbidities, allergies, etc).

This question was not displayed to the respondent.

Q390. Do you use compounded methylcobalamin as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q391. In which combination(s) do you use compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent. Q392. For which, if any, diseases or conditions do you consider compounded methylcobalamin standard therapy?

This question was not displayed to the respondent.

Q393. Does your specialty describe the use of compounded methylcobalamin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q394. Over the past 5 years, has the frequency in which you have used compounded methylcobalamin changed?

This question was not displayed to the respondent.

Q395. Why do you use compounded methylcobalamin instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q396. Do you stock non-patient-specific compounded methylcobalamin in your practice location?

This question was not displayed to the respondent.

Q397. In what practice location(s) do you stock non-patient-specific compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q398. How do you obtain your stock of non-patient-specific compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q399. Why do you keep a stock of non-patient-specific compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q400. For which, if any, diseases or conditions do you consider methylcobalamin standard therapy?

This question was not displayed to the respondent. Q401. Does your specialty describe the use of methylcobalamin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q557. What type(s) of product(s) do you use, prescribe, or recommend for methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q558. Please list any conditions or diseases for which you use compounded methylsulfonylmethane (MSM) 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).

This question was not displayed to the respondent.

Q559. Do you use compounded methylsulfonylmethane (MSM) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q560. Please list all combination products in which you use compounded methylsulfonylmethane (MSM).

This question was not displayed to the respondent.

Q561. For which, if any, diseases or conditions do you consider compounded methylsulfonylmethane (MSM) standard therapy?

This question was not displayed to the respondent.

Q562. Does your specialty describe the use of compounded methylsulfonylmethane (MSM) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q563. Over the past 5 years, has the frequency in which you have used compounded methylsulfonylmethane (MSM) changed?

This question was not displayed to the respondent.

Q564. Why do you use compounded methylsulfonylmethane (MSM) instead of any FDA-approved drug product?

This question was not displayed to the respondent. Q565. Do you stock non-patient-specific compounded methylsulfonylmethane (MSM) in your practice location?

This question was not displayed to the respondent.

Q566. In what practice location(s) do you stock non-patient-specific compounded methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q567. How do you obtain your stock of non-patient-specific compounded methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q568. Why do you keep a stock of non-patient-specific compounded methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q569. For which, if any, diseases or conditions do you consider methylsulfonylmethane (MSM) standard therapy?

This question was not displayed to the respondent.

Q570. Does your specialty describe the use of methylsulfonylmethane (MSM) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q529. What type(s) of product(s) do you use, prescribe, or recommend for phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q530. Please list any conditions or diseases for which you use compounded phenylephrine 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).

This question was not displayed to the respondent.

Q531. Do you use compounded phenylephrine as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply. This question was not displayed to the respondent.

Q532. In which combination(s) do you use compounded phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q533. For which, if any, diseases or conditions do you consider compounded phenylephrine standard therapy?

This question was not displayed to the respondent.

Q534. Does your specialty describe the use of compounded phenylephrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q535. Over the past 5 years, has the frequency in which you have used compounded phenylephrine changed?

This question was not displayed to the respondent.

Q536. Why do you use compounded phenylephrine instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q537. Do you stock non-patient-specific compounded phenylephrine in your practice location?

This question was not displayed to the respondent.

Q538. In what practice location(s) do you stock non-patient-specific compounded phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q539. How do you obtain your stock of non-patient-specific compounded phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q540. Why do you keep a stock of non-patient-specific compounded phenylephrine? Please check all that apply.

This question was not displayed to the respondent. Q541. For which, if any, diseases or conditions do you consider phenylephrine standard therapy?

This question was not displayed to the respondent.

Q542. Does your specialty describe the use of phenylephrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q402. What type(s) of product(s) do you use, prescribe, or recommend for pitcher plant? Please check all that apply.

This question was not displayed to the respondent.

Q403. Please list any conditions or diseases for which you use compounded pitcher plant 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).

This question was not displayed to the respondent.

Q404. Do you use compounded pitcher plant as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q405. Please list all combination products in which you use compounded pitcher plant.

This question was not displayed to the respondent.

Q406. For which, if any, diseases or conditions do you consider compounded pitcher plant standard therapy?

This question was not displayed to the respondent.

Q407. Does your specialty describe the use of compounded pitcher plant in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q408. Over the past 5 years, has the frequency in which you have used compounded pitcher plant changed?

This question was not displayed to the respondent. Q409. Why do you use compounded pitcher plant instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q410. Do you stock non-patient-specific compounded pitcher plant in your practice location?

This question was not displayed to the respondent.

Q411. In what practice location(s) do you stock non-patient-specific compounded pitcher plant? Please check all that apply.

This question was not displayed to the respondent.

Q412. How do you obtain your stock of non-patient-specific compounded pitcher plant? Please check all that apply.

This question was not displayed to the respondent.

Q413. Why do you keep a stock of non-patient-specific compounded pitcher plant? Please check all that apply.

This question was not displayed to the respondent.

Q414. For which, if any, diseases or conditions do you consider pitcher plant standard therapy?

This question was not displayed to the respondent.

Q415. Does your specialty describe the use of pitcher plant in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q416. What type(s) of product(s) do you use, prescribe, or recommend for pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q417. Please list any conditions or diseases for which you use compounded pregnenolone 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).

This question was not displayed to the respondent.

Q418. Do you use compounded pregnenolone as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q419. Please list all combination products in which you use compounded pregnenolone.

This question was not displayed to the respondent.

Q420. For which, if any, diseases or conditions do you consider compounded pregnenolone standard therapy?

This question was not displayed to the respondent.

Q421. Does your specialty describe the use of compounded pregnenolone in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q422. Over the past 5 years, has the frequency in which you have used compounded pregnenolone changed?

This question was not displayed to the respondent.

Q423. Why do you use compounded pregnenolone instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q424. Do you stock non-patient-specific compounded pregnenolone in your practice location?

This question was not displayed to the respondent.

Q425. In what practice location(s) do you stock non-patient-specific compounded pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q426. How do you obtain your stock of non-patient-specific compounded pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q427. Why do you keep a stock of non-patient-specific compounded pregnenolone? Please check all that apply. This question was not displayed to the respondent.

Q428. For which, if any, diseases or conditions do you consider pregnenolone standard therapy?

This question was not displayed to the respondent.

Q429. Does your specialty describe the use of pregnenolone in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q444. What type(s) of product(s) do you use, prescribe, or recommend for quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q445. Please list any conditions or diseases for which you use compounded quinacrine 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).

This question was not displayed to the respondent.

Q446. Do you use compounded quinacrine as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q447. Please list all combination products in which you use compounded quinacrine.

This question was not displayed to the respondent.

Q448. For which, if any, diseases or conditions do you consider compounded quinacrine standard therapy?

This question was not displayed to the respondent.

Q449. Does your specialty describe the use of compounded quinacrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q450. Over the past 5 years, has the frequency in which you have used compounded quinacrine changed?

This question was not displayed to the respondent. Q451. Why do you use compounded quinacrine instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q452. Do you stock non-patient-specific compounded quinacrine in your practice location?

This question was not displayed to the respondent.

Q453. In what practice location(s) do you stock non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q454. How do you obtain your stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q455. Why do you keep a stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q456. For which, if any, diseases or conditions do you consider quinacrine standard therapy?

This question was not displayed to the respondent.

Q457. Does your specialty describe the use of quinacrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q458. What type(s) of product(s) do you use, prescribe, or recommend for zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

Q459. Please list any conditions or diseases for which you use compounded zinc sulfate 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).

This question was not displayed to the respondent.

Q460. Do you use compounded zinc sulfate as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply. This question was not displayed to the respondent.

Q461. Please list all combination products in which you use compounded zinc sulfate.

This question was not displayed to the respondent.

Q462. For which, if any, diseases or conditions do you consider compounded zinc sulfate standard therapy?

This question was not displayed to the respondent.

Q463. Does your specialty describe the use of compounded zinc sulfate in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q464. Over the past 5 years, has the frequency in which you have used compounded zinc sulfate changed?

This question was not displayed to the respondent.

Q465. Why do you use compounded zinc sulfate instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q466. Do you stock non-patient-specific compounded zinc sulfate in your practice location?

This question was not displayed to the respondent.

Q467. In what practice location(s) do you stock non-patient-specific compounded zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

Q468. How do you obtain your stock of non-patient-specific compounded zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

Q469. Why do you keep a stock of non-patient-specific compounded zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

Q470. For which, if any, diseases or conditions do you consider zinc sulfate standard therapy? This question was not displayed to the respondent.

Q471. Does your specialty describe the use of zinc sulfate in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q16. 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)

Q17. 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,, DiabetesDiabetes andand MetabolismMetabolism

Family Medicine

Gastroenterology

Hematology

InfectiousInfectious DiseaseDisease

InternalInternal MedicineMedicine

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

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

Q1. Which of the following substances do you use in your practice? Please check all that apply.

Alpha lipoic acid (ALA)

Dexamethasone acetate

InositolInositol

Methylcobalamin

Methylsulfonylmethane (MSM)

Phenylephrine

Pitcher plant

Pregnenolone

Quinacrine

Zinc sulfate

None of the above

Q2. What type(s) of product(s) do you use, prescribe, or recommend for alpha lipoic acid (ALA)? 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

Q3. Please list any conditions or diseases for which you use compounded alpha lipoic acid (ALA) 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).

This question was not displayed to the respondent.

Q4. Do you use compounded alpha lipoic acid (ALA) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q5. Please list all combination products in which you use compounded alpha lipoic acid (ALA).

This question was not displayed to the respondent.

Q6. For which, if any, diseases or conditions do you consider compounded alpha lipoic acid (ALA) standard therapy?

This question was not displayed to the respondent.

Q7. Does your specialty describe the use of compounded alpha lipoic acid (ALA) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q8. Over the past 5 years, has the frequency in which you have used compounded alpha lipoic acid (ALA) changed?

This question was not displayed to the respondent.

Q9. Why do you use compounded alpha lipoic acid (ALA) instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q10. Do you stock non-patient-specific compounded alpha lipoic acid (ALA) in your practice location?

This question was not displayed to the respondent. Q11. In what practice location(s) do you stock non-patient-specific compounded alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent.

Q12. How do you obtain your stock of non-patient-specific compounded alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent.

Q13. Why do you keep a stock of non-patient-specific compounded alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent.

Q14. ForFor which, if any,, diseasesdiseases oror conditionsconditions dodo youyou considerconsider alphalpha lipoiclipoic acidacid (ALA)(ALA) standard therapy?

diabetic neuropathy

Q15. DoesDoes your specialty describe the use of alphalpha lipoiclipoic acidacid (ALA)(ALA) inin medicalmedical practicepractice guidelines or other resources?

not sure

Q515. What type(s) of product(s) do you use, prescribe, or recommend for dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q517. Do you use compounded dexamethasone acetate as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q518. Please list all combination products in which you use compounded dexamethasone acetate. This question was not displayed to the respondent.

Q519. For which, if any, diseases or conditions do you consider compounded dexamethasone acetate standard therapy?

This question was not displayed to the respondent.

Q520. Does your specialty describe the use of compounded dexamethasone acetate in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q521. Over the past 5 years, has the frequency in which you have used compounded dexamethasone acetate changed?

This question was not displayed to the respondent.

Q522. Why do you use compounded dexamethasone acetate instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q523. Do you stock non-patient-specific compounded dexamethasone acetate in your practice location?

This question was not displayed to the respondent.

Q524. In what practice location(s) do you stock non-patient-specific compounded dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q525. How do you obtain your stock of non-patient-specific compounded dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q526. Why do you keep a stock of non-patient-specific compounded dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q527. For which, if any, diseases or conditions do you consider dexamethasone acetate standard therapy?

This question was not displayed to the respondent. Q528. Does your specialty describe the use of dexamethasone acetate in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q543. What type(s) of product(s) do you use, prescribe, or recommend for inositol? Please check all that apply.

This question was not displayed to the respondent.

Q545. Do you use compounded inositol as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q546. In which combination(s) do you use compounded inositol? Please check all that apply.

This question was not displayed to the respondent.

Q547. For which, if any, diseases or conditions do you consider compounded inositol standard therapy?

This question was not displayed to the respondent.

Q548. Does your specialty describe the use of compounded inositol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q549. Over the past 5 years, has the frequency in which you have used compounded inositol changed?

This question was not displayed to the respondent.

Q550. Why do you use compounded inositol instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q551. Do you stock non-patient-specific compounded inositol in your practice location? This question was not displayed to the respondent.

Q552. In what practice location(s) do you stock non-patient-specific compounded inositol? Please check all that apply.

This question was not displayed to the respondent.

Q553. How do you obtain your stock of non-patient-specific compounded inositol? Please check all that apply.

This question was not displayed to the respondent.

Q554. Why do you keep a stock of non-patient-specific compounded inositol? Please check all that apply.

This question was not displayed to the respondent.

Q555. For which, if any, diseases or conditions do you consider inositol standard therapy?

This question was not displayed to the respondent.

Q556. Does your specialty describe the use of inositol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q388. What type(s) of product(s) do you use, prescribe, or recommend for methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q390. Do you use compounded methylcobalamin as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q391. In which combination(s) do you use compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent. Q392. For which, if any, diseases or conditions do you consider compounded methylcobalamin standard therapy?

This question was not displayed to the respondent.

Q393. Does your specialty describe the use of compounded methylcobalamin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q394. Over the past 5 years, has the frequency in which you have used compounded methylcobalamin changed?

This question was not displayed to the respondent.

Q395. Why do you use compounded methylcobalamin instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q396. Do you stock non-patient-specific compounded methylcobalamin in your practice location?

This question was not displayed to the respondent.

Q397. In what practice location(s) do you stock non-patient-specific compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q398. How do you obtain your stock of non-patient-specific compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q399. Why do you keep a stock of non-patient-specific compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q400. For which, if any, diseases or conditions do you consider methylcobalamin standard therapy?

This question was not displayed to the respondent.

Q401. Does your specialty describe the use of methylcobalamin in medical practice guidelines or other resources? This question was not displayed to the respondent.

Q557. What type(s) of product(s) do you use, prescribe, or recommend for methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q559. Do you use compounded methylsulfonylmethane (MSM) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q560. Please list all combination products in which you use compounded methylsulfonylmethane (MSM).

This question was not displayed to the respondent.

Q561. For which, if any, diseases or conditions do you consider compounded methylsulfonylmethane (MSM) standard therapy?

This question was not displayed to the respondent.

Q562. Does your specialty describe the use of compounded methylsulfonylmethane (MSM) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q563. Over the past 5 years, has the frequency in which you have used compounded methylsulfonylmethane (MSM) changed?

This question was not displayed to the respondent.

Q564. Why do you use compounded methylsulfonylmethane (MSM) instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q565. Do you stock non-patient-specific compounded methylsulfonylmethane (MSM) in your practice location? This question was not displayed to the respondent.

Q566. In what practice location(s) do you stock non-patient-specific compounded methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q567. How do you obtain your stock of non-patient-specific compounded methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q568. Why do you keep a stock of non-patient-specific compounded methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q569. For which, if any, diseases or conditions do you consider methylsulfonylmethane (MSM) standard therapy?

This question was not displayed to the respondent.

Q570. Does your specialty describe the use of methylsulfonylmethane (MSM) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q529. What type(s) of product(s) do you use, prescribe, or recommend for phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q531. Do you use compounded phenylephrine as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q532. In which combination(s) do you use compounded phenylephrine? Please check all that apply. This question was not displayed to the respondent.

Q533. For which, if any, diseases or conditions do you consider compounded phenylephrine standard therapy?

This question was not displayed to the respondent.

Q534. Does your specialty describe the use of compounded phenylephrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q535. Over the past 5 years, has the frequency in which you have used compounded phenylephrine changed?

This question was not displayed to the respondent.

Q536. Why do you use compounded phenylephrine instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q537. Do you stock non-patient-specific compounded phenylephrine in your practice location?

This question was not displayed to the respondent.

Q538. In what practice location(s) do you stock non-patient-specific compounded phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q539. How do you obtain your stock of non-patient-specific compounded phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q540. Why do you keep a stock of non-patient-specific compounded phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q541. For which, if any, diseases or conditions do you consider phenylephrine standard therapy?

This question was not displayed to the respondent. Q542. Does your specialty describe the use of phenylephrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q402. What type(s) of product(s) do you use, prescribe, or recommend for pitcher plant? Please check all that apply.

This question was not displayed to the respondent.

Q404. Do you use compounded pitcher plant as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q405. Please list all combination products in which you use compounded pitcher plant.

This question was not displayed to the respondent.

Q406. For which, if any, diseases or conditions do you consider compounded pitcher plant standard therapy?

This question was not displayed to the respondent.

Q407. Does your specialty describe the use of compounded pitcher plant in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q408. Over the past 5 years, has the frequency in which you have used compounded pitcher plant changed?

This question was not displayed to the respondent.

Q409. Why do you use compounded pitcher plant instead of any FDA-approved drug product?

This question was not displayed to the respondent. Q410. Do you stock non-patient-specific compounded pitcher plant in your practice location?

This question was not displayed to the respondent.

Q411. In what practice location(s) do you stock non-patient-specific compounded pitcher plant? Please check all that apply.

This question was not displayed to the respondent.

Q412. How do you obtain your stock of non-patient-specific compounded pitcher plant? Please check all that apply.

This question was not displayed to the respondent.

Q413. Why do you keep a stock of non-patient-specific compounded pitcher plant? Please check all that apply.

This question was not displayed to the respondent.

Q414. For which, if any, diseases or conditions do you consider pitcher plant standard therapy?

This question was not displayed to the respondent.

Q415. Does your specialty describe the use of pitcher plant in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q416. What type(s) of product(s) do you use, prescribe, or recommend for pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q418. Do you use compounded pregnenolone as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent. Q419. Please list all combination products in which you use compounded pregnenolone.

This question was not displayed to the respondent.

Q420. For which, if any, diseases or conditions do you consider compounded pregnenolone standard therapy?

This question was not displayed to the respondent.

Q421. Does your specialty describe the use of compounded pregnenolone in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q422. Over the past 5 years, has the frequency in which you have used compounded pregnenolone changed?

This question was not displayed to the respondent.

Q423. Why do you use compounded pregnenolone instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q424. Do you stock non-patient-specific compounded pregnenolone in your practice location?

This question was not displayed to the respondent.

Q425. In what practice location(s) do you stock non-patient-specific compounded pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q426. How do you obtain your stock of non-patient-specific compounded pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q427. Why do you keep a stock of non-patient-specific compounded pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q428. For which, if any, diseases or conditions do you consider pregnenolone standard therapy? This question was not displayed to the respondent.

Q429. Does your specialty describe the use of pregnenolone in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q444. What type(s) of product(s) do you use, prescribe, or recommend for quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q446. Do you use compounded quinacrine as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q447. Please list all combination products in which you use compounded quinacrine.

This question was not displayed to the respondent.

Q448. For which, if any, diseases or conditions do you consider compounded quinacrine standard therapy?

This question was not displayed to the respondent.

Q449. Does your specialty describe the use of compounded quinacrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q450. Over the past 5 years, has the frequency in which you have used compounded quinacrine changed?

This question was not displayed to the respondent.

Q451. Why do you use compounded quinacrine instead of any FDA-approved drug product?

This question was not displayed to the respondent. Q452. Do you stock non-patient-specific compounded quinacrine in your practice location?

This question was not displayed to the respondent.

Q453. In what practice location(s) do you stock non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q454. How do you obtain your stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q455. Why do you keep a stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q456. For which, if any, diseases or conditions do you consider quinacrine standard therapy?

This question was not displayed to the respondent.

Q457. Does your specialty describe the use of quinacrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q458. What type(s) of product(s) do you use, prescribe, or recommend for zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

Q460. Do you use compounded zinc sulfate as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q461. Please list all combination products in which you use compounded zinc sulfate. This question was not displayed to the respondent.

Q462. For which, if any, diseases or conditions do you consider compounded zinc sulfate standard therapy?

This question was not displayed to the respondent.

Q463. Does your specialty describe the use of compounded zinc sulfate in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q464. Over the past 5 years, has the frequency in which you have used compounded zinc sulfate changed?

This question was not displayed to the respondent.

Q465. Why do you use compounded zinc sulfate instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q466. Do you stock non-patient-specific compounded zinc sulfate in your practice location?

This question was not displayed to the respondent.

Q467. In what practice location(s) do you stock non-patient-specific compounded zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

Q468. How do you obtain your stock of non-patient-specific compounded zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

Q469. Why do you keep a stock of non-patient-specific compounded zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

Q470. For which, if any, diseases or conditions do you consider zinc sulfate standard therapy?

This question was not displayed to the respondent.

Q471. Does your specialty describe the use of zinc sulfate in medical practice guidelines or other resources? This question was not displayed to the respondent.

Q16. 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)

Q17. 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,, DiabetesDiabetes andand MetabolismMetabolism

Family Medicine

Gastroenterology

Hematology

InfectiousInfectious DiseaseDisease

InternalInternal MedicineMedicine

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

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

Q1. Which of the following substances do you use in your practice? Please check all that apply.

Alpha lipoic acid (ALA)

Dexamethasone acetate

InositolInositol

Methylcobalamin

Methylsulfonylmethane (MSM)

Phenylephrine

Pitcher plant

Pregnenolone

Quinacrine

Zinc sulfate

None of the above

Q2. What type(s) of product(s) do you use, prescribe, or recommend for alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent.

Q4. Do you use compounded alpha lipoic acid (ALA) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q5. Please list all combination products in which you use compounded alpha lipoic acid (ALA).

This question was not displayed to the respondent.

Q6. For which, if any, diseases or conditions do you consider compounded alpha lipoic acid (ALA) standard therapy?

This question was not displayed to the respondent.

Q7. Does your specialty describe the use of compounded alpha lipoic acid (ALA) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q8. Over the past 5 years, has the frequency in which you have used compounded alpha lipoic acid (ALA) changed?

This question was not displayed to the respondent.

Q9. Why do you use compounded alpha lipoic acid (ALA) instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q10. Do you stock non-patient-specific compounded alpha lipoic acid (ALA) in your practice location?

This question was not displayed to the respondent.

Q11. In what practice location(s) do you stock non-patient-specific compounded alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent. Q12. How do you obtain your stock of non-patient-specific compounded alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent.

Q13. Why do you keep a stock of non-patient-specific compounded alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent.

Q14. For which, if any, diseases or conditions do you consider alpha lipoic acid (ALA) standard therapy?

This question was not displayed to the respondent.

Q15. Does your specialty describe the use of alpha lipoic acid (ALA) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q515. What type(s) of product(s) do you use, prescribe, or recommend for dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q517. Do you use compounded dexamethasone acetate as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q518. Please list all combination products in which you use compounded dexamethasone acetate.

This question was not displayed to the respondent.

Q519. For which, if any, diseases or conditions do you consider compounded dexamethasone acetate standard therapy?

This question was not displayed to the respondent. Q520. Does your specialty describe the use of compounded dexamethasone acetate in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q521. Over the past 5 years, has the frequency in which you have used compounded dexamethasone acetate changed?

This question was not displayed to the respondent.

Q522. Why do you use compounded dexamethasone acetate instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q523. Do you stock non-patient-specific compounded dexamethasone acetate in your practice location?

This question was not displayed to the respondent.

Q524. In what practice location(s) do you stock non-patient-specific compounded dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q525. How do you obtain your stock of non-patient-specific compounded dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q526. Why do you keep a stock of non-patient-specific compounded dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q527. For which, if any, diseases or conditions do you consider dexamethasone acetate standard therapy?

This question was not displayed to the respondent.

Q528. Does your specialty describe the use of dexamethasone acetate in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q543. What type(s) of product(s) do you use, prescribe, or recommend for inositol? Please check all that apply. This question was not displayed to the respondent.

This question was not displayed to the respondent.

Q545. Do you use compounded inositol as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q546. In which combination(s) do you use compounded inositol? Please check all that apply.

This question was not displayed to the respondent.

Q547. For which, if any, diseases or conditions do you consider compounded inositol standard therapy?

This question was not displayed to the respondent.

Q548. Does your specialty describe the use of compounded inositol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q549. Over the past 5 years, has the frequency in which you have used compounded inositol changed?

This question was not displayed to the respondent.

Q550. Why do you use compounded inositol instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q551. Do you stock non-patient-specific compounded inositol in your practice location?

This question was not displayed to the respondent.

Q552. In what practice location(s) do you stock non-patient-specific compounded inositol? Please check all that apply.

This question was not displayed to the respondent. Q553. How do you obtain your stock of non-patient-specific compounded inositol? Please check all that apply.

This question was not displayed to the respondent.

Q554. Why do you keep a stock of non-patient-specific compounded inositol? Please check all that apply.

This question was not displayed to the respondent.

Q555. For which, if any, diseases or conditions do you consider inositol standard therapy?

This question was not displayed to the respondent.

Q556. Does your specialty describe the use of inositol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q388. What type(s) of product(s) do you use, prescribe, or recommend for methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q390. Do you use compounded methylcobalamin as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q391. In which combination(s) do you use compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q392. For which, if any, diseases or conditions do you consider compounded methylcobalamin standard therapy?

This question was not displayed to the respondent. Q393. Does your specialty describe the use of compounded methylcobalamin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q394. Over the past 5 years, has the frequency in which you have used compounded methylcobalamin changed?

This question was not displayed to the respondent.

Q395. Why do you use compounded methylcobalamin instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q396. Do you stock non-patient-specific compounded methylcobalamin in your practice location?

This question was not displayed to the respondent.

Q397. In what practice location(s) do you stock non-patient-specific compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q398. How do you obtain your stock of non-patient-specific compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q399. Why do you keep a stock of non-patient-specific compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q400. For which, if any, diseases or conditions do you consider methylcobalamin standard therapy?

This question was not displayed to the respondent.

Q401. Does your specialty describe the use of methylcobalamin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q557. What type(s) of product(s) do you use, prescribe, or recommend for methylsulfonylmethane (MSM)? Please check all that apply. This question was not displayed to the respondent.

This question was not displayed to the respondent.

Q559. Do you use compounded methylsulfonylmethane (MSM) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q560. Please list all combination products in which you use compounded methylsulfonylmethane (MSM).

This question was not displayed to the respondent.

Q561. For which, if any, diseases or conditions do you consider compounded methylsulfonylmethane (MSM) standard therapy?

This question was not displayed to the respondent.

Q562. Does your specialty describe the use of compounded methylsulfonylmethane (MSM) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q563. Over the past 5 years, has the frequency in which you have used compounded methylsulfonylmethane (MSM) changed?

This question was not displayed to the respondent.

Q564. Why do you use compounded methylsulfonylmethane (MSM) instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q565. Do you stock non-patient-specific compounded methylsulfonylmethane (MSM) in your practice location?

This question was not displayed to the respondent.

Q566. In what practice location(s) do you stock non-patient-specific compounded methylsulfonylmethane (MSM)? Please check all that apply. This question was not displayed to the respondent.

Q567. How do you obtain your stock of non-patient-specific compounded methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q568. Why do you keep a stock of non-patient-specific compounded methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q569. For which, if any, diseases or conditions do you consider methylsulfonylmethane (MSM) standard therapy?

This question was not displayed to the respondent.

Q570. Does your specialty describe the use of methylsulfonylmethane (MSM) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q529. What type(s) of product(s) do you use, prescribe, or recommend for phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q531. Do you use compounded phenylephrine as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q532. In which combination(s) do you use compounded phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q533. For which, if any, diseases or conditions do you consider compounded phenylephrine standard therapy? This question was not displayed to the respondent.

Q534. Does your specialty describe the use of compounded phenylephrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q535. Over the past 5 years, has the frequency in which you have used compounded phenylephrine changed?

This question was not displayed to the respondent.

Q536. Why do you use compounded phenylephrine instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q537. Do you stock non-patient-specific compounded phenylephrine in your practice location?

This question was not displayed to the respondent.

Q538. In what practice location(s) do you stock non-patient-specific compounded phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q539. How do you obtain your stock of non-patient-specific compounded phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q540. Why do you keep a stock of non-patient-specific compounded phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q541. For which, if any, diseases or conditions do you consider phenylephrine standard therapy?

This question was not displayed to the respondent.

Q542. Does your specialty describe the use of phenylephrine in medical practice guidelines or other resources?

This question was not displayed to the respondent. Q402. What type(s) of product(s) do you use, prescribe, or recommend for pitcher plant? Please check all that apply.

This question was not displayed to the respondent.

Q404. Do you use compounded pitcher plant as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q405. Please list all combination products in which you use compounded pitcher plant.

This question was not displayed to the respondent.

Q406. For which, if any, diseases or conditions do you consider compounded pitcher plant standard therapy?

This question was not displayed to the respondent.

Q407. Does your specialty describe the use of compounded pitcher plant in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q408. Over the past 5 years, has the frequency in which you have used compounded pitcher plant changed?

This question was not displayed to the respondent.

Q409. Why do you use compounded pitcher plant instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q410. Do you stock non-patient-specific compounded pitcher plant in your practice location?

This question was not displayed to the respondent. Q411. In what practice location(s) do you stock non-patient-specific compounded pitcher plant? Please check all that apply.

This question was not displayed to the respondent.

Q412. How do you obtain your stock of non-patient-specific compounded pitcher plant? Please check all that apply.

This question was not displayed to the respondent.

Q413. Why do you keep a stock of non-patient-specific compounded pitcher plant? Please check all that apply.

This question was not displayed to the respondent.

Q414. For which, if any, diseases or conditions do you consider pitcher plant standard therapy?

This question was not displayed to the respondent.

Q415. Does your specialty describe the use of pitcher plant in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q416. What type(s) of product(s) do you use, prescribe, or recommend for pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q418. Do you use compounded pregnenolone as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q419. Please list all combination products in which you use compounded pregnenolone.

This question was not displayed to the respondent. Q420. For which, if any, diseases or conditions do you consider compounded pregnenolone standard therapy?

This question was not displayed to the respondent.

Q421. Does your specialty describe the use of compounded pregnenolone in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q422. Over the past 5 years, has the frequency in which you have used compounded pregnenolone changed?

This question was not displayed to the respondent.

Q423. Why do you use compounded pregnenolone instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q424. Do you stock non-patient-specific compounded pregnenolone in your practice location?

This question was not displayed to the respondent.

Q425. In what practice location(s) do you stock non-patient-specific compounded pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q426. How do you obtain your stock of non-patient-specific compounded pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q427. Why do you keep a stock of non-patient-specific compounded pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q428. For which, if any, diseases or conditions do you consider pregnenolone standard therapy?

This question was not displayed to the respondent.

Q429. Does your specialty describe the use of pregnenolone in medical practice guidelines or other resources? This question was not displayed to the respondent.

Q444. What type(s) of product(s) do you use, prescribe, or recommend for quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q446. Do you use compounded quinacrine as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q447. Please list all combination products in which you use compounded quinacrine.

This question was not displayed to the respondent.

Q448. For which, if any, diseases or conditions do you consider compounded quinacrine standard therapy?

This question was not displayed to the respondent.

Q449. Does your specialty describe the use of compounded quinacrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q450. Over the past 5 years, has the frequency in which you have used compounded quinacrine changed?

This question was not displayed to the respondent.

Q451. Why do you use compounded quinacrine instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q452. Do you stock non-patient-specific compounded quinacrine in your practice location?

This question was not displayed to the respondent. Q453. In what practice location(s) do you stock non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q454. How do you obtain your stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q455. Why do you keep a stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q456. For which, if any, diseases or conditions do you consider quinacrine standard therapy?

This question was not displayed to the respondent.

Q457. Does your specialty describe the use of quinacrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q458. What type(s) of product(s) do you use, prescribe, or recommend for zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

Q460. Do you use compounded zinc sulfate as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q461. Please list all combination products in which you use compounded zinc sulfate.

This question was not displayed to the respondent.

Q462. For which, if any, diseases or conditions do you consider compounded zinc sulfate standard therapy? This question was not displayed to the respondent.

Q463. Does your specialty describe the use of compounded zinc sulfate in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q464. Over the past 5 years, has the frequency in which you have used compounded zinc sulfate changed?

This question was not displayed to the respondent.

Q465. Why do you use compounded zinc sulfate instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q466. Do you stock non-patient-specific compounded zinc sulfate in your practice location?

This question was not displayed to the respondent.

Q467. In what practice location(s) do you stock non-patient-specific compounded zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

Q468. How do you obtain your stock of non-patient-specific compounded zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

Q469. Why do you keep a stock of non-patient-specific compounded zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

Q470. For which, if any, diseases or conditions do you consider zinc sulfate standard therapy?

This question was not displayed to the respondent.

Q471. Does your specialty describe the use of zinc sulfate in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q16. 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)

Q17. 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,, DiabetesDiabetes andand MetabolismMetabolism

Family Medicine

Gastroenterology

Hematology

InfectiousInfectious DiseaseDisease

InternalInternal MedicineMedicine

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

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

Q1. Which of the following substances do you use in your practice? Please check all that apply.

Alpha lipoic acid (ALA)

Dexamethasone acetate

InositolInositol

Methylcobalamin

Methylsulfonylmethane (MSM)

Phenylephrine

Pitcher plant

Pregnenolone

Quinacrine

Zinc sulfate

None of the above

Q2. What type(s) of product(s) do you use, prescribe, or recommend for alpha lipoic acid (ALA)? 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

Q3. PleasePlease listlist anyany conditionsconditions oror diseasesdiseases forfor whichwhich youyou useuse compoundedcompounded alphalpha lipoiclipoic acidacid (ALA)(ALA) inin youryour practice.practice. PleasePlease includeinclude thethe strength(s),strength(s), dosingdosing frequency(ies),frequency(ies), dosagedosage form(s),form(s), route(s)route(s) ofof administration,administration, durationduration ofof therapytherapy,, andand patientpatient populationpopulation (ex.(ex. age,age, gender,, comorbidities,comorbidities, allergies,allergies, etc).etc). Strength(s) (please include Dosing Route(s) of Duration of units) frequency(ies) Dosage form(s) administration therapy Patient population Condition 1 (please describe)

Condition 2 (please describe)

Condition 3 (please describe)

Condition 4 (please describe)

Condition 5 (please describe)

Q4. Do you use compounded alpha lipoic acid (ALA) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

Single

Combination

Q5. Please list all combination products in which you use compounded alpha lipoic acid (ALA).

This question was not displayed to the respondent.

Q6. ForFor which,which, ifif anyany,, diseasesdiseases oror conditionsconditions dodo youyou considerconsider compoundedcompounded alphalpha lipoiclipoic acidacid (ALA)(ALA) standardstandard therapy?therapy?

Q7. DoesDoes youryour specialtyspecialty describedescribe thethe useuse ofof compoundedcompounded alphalpha lipoiclipoic acidacid (ALA)(ALA) inin medicalmedical practicepractice guidelines or other resources? Q8. Over the past 5 years, has the frequency in which you have used compounded alpha lipoic acid (ALA) changed?

Yes - I use it MORE oftenoften nownow (briefly(briefly describedescribe why)why)

Yes - I use it LESS oftenoften nownow (briefly(briefly describedescribe why)why)

No - use has remained consistent

Q9. WhyWhy dodo youyou useuse compoundedcompounded alphalpha lipoiclipoic acidacid (ALA)(ALA) insteadinstead ofof anyany FDA-approvedFDA-approved drugdrug product?product?

Q10. Do you stock non-patient-specific compounded alpha lipoic acid (ALA) in your practice location?

Yes

Q11. In what practice location(s) do you stock non-patient-specific compounded alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent.

Q12. How do you obtain your stock of non-patient-specific compounded alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent.

Q13. Why do you keep a stock of non-patient-specific compounded alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent.

Q14. For which, if any, diseases or conditions do you consider alpha lipoic acid (ALA) standard therapy?

This question was not displayed to the respondent.

Q15. Does your specialty describe the use of alpha lipoic acid (ALA) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q515. What type(s) of product(s) do you use, prescribe, or recommend for dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q517. Do you use compounded dexamethasone acetate as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q518. Please list all combination products in which you use compounded dexamethasone acetate.

This question was not displayed to the respondent.

Q519. For which, if any, diseases or conditions do you consider compounded dexamethasone acetate standard therapy?

This question was not displayed to the respondent.

Q520. Does your specialty describe the use of compounded dexamethasone acetate in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q521. Over the past 5 years, has the frequency in which you have used compounded dexamethasone acetate changed?

This question was not displayed to the respondent.

Q522. Why do you use compounded dexamethasone acetate instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q523. Do you stock non-patient-specific compounded dexamethasone acetate in your practice location?

This question was not displayed to the respondent.

Q524. In what practice location(s) do you stock non-patient-specific compounded dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q525. How do you obtain your stock of non-patient-specific compounded dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q526. Why do you keep a stock of non-patient-specific compounded dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q527. For which, if any, diseases or conditions do you consider dexamethasone acetate standard therapy? This question was not displayed to the respondent.

Q528. Does your specialty describe the use of dexamethasone acetate in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q543. What type(s) of product(s) do you use, prescribe, or recommend for inositol? Please check all that apply.

This question was not displayed to the respondent.

Q545. Do you use compounded inositol as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q546. In which combination(s) do you use compounded inositol? Please check all that apply.

This question was not displayed to the respondent.

Q547. For which, if any, diseases or conditions do you consider compounded inositol standard therapy?

This question was not displayed to the respondent.

Q548. Does your specialty describe the use of compounded inositol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q549. Over the past 5 years, has the frequency in which you have used compounded inositol changed?

This question was not displayed to the respondent.

Q550. Why do you use compounded inositol instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q551. Do you stock non-patient-specific compounded inositol in your practice location?

This question was not displayed to the respondent.

Q552. In what practice location(s) do you stock non-patient-specific compounded inositol? Please check all that apply.

This question was not displayed to the respondent. Q553. How do you obtain your stock of non-patient-specific compounded inositol? Please check all that apply.

This question was not displayed to the respondent.

Q554. Why do you keep a stock of non-patient-specific compounded inositol? Please check all that apply.

This question was not displayed to the respondent.

Q555. For which, if any, diseases or conditions do you consider inositol standard therapy?

This question was not displayed to the respondent.

Q556. Does your specialty describe the use of inositol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q388. What type(s) of product(s) do you use, prescribe, or recommend for methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q390. Do you use compounded methylcobalamin as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q391. In which combination(s) do you use compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q392. For which, if any, diseases or conditions do you consider compounded methylcobalamin standard therapy?

This question was not displayed to the respondent.

Q393. Does your specialty describe the use of compounded methylcobalamin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q394. Over the past 5 years, has the frequency in which you have used compounded methylcobalamin changed?

This question was not displayed to the respondent.

Q395. Why do you use compounded methylcobalamin instead of any FDA-approved drug product? This question was not displayed to the respondent.

Q396. Do you stock non-patient-specific compounded methylcobalamin in your practice location?

This question was not displayed to the respondent.

Q397. In what practice location(s) do you stock non-patient-specific compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q398. How do you obtain your stock of non-patient-specific compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q399. Why do you keep a stock of non-patient-specific compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q400. For which, if any, diseases or conditions do you consider methylcobalamin standard therapy?

This question was not displayed to the respondent.

Q401. Does your specialty describe the use of methylcobalamin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q557. What type(s) of product(s) do you use, prescribe, or recommend for methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q559. Do you use compounded methylsulfonylmethane (MSM) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q560. Please list all combination products in which you use compounded methylsulfonylmethane (MSM).

This question was not displayed to the respondent.

Q561. For which, if any, diseases or conditions do you consider compounded methylsulfonylmethane (MSM) standard therapy? This question was not displayed to the respondent.

Q562. Does your specialty describe the use of compounded methylsulfonylmethane (MSM) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q563. Over the past 5 years, has the frequency in which you have used compounded methylsulfonylmethane (MSM) changed?

This question was not displayed to the respondent.

Q564. Why do you use compounded methylsulfonylmethane (MSM) instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q565. Do you stock non-patient-specific compounded methylsulfonylmethane (MSM) in your practice location?

This question was not displayed to the respondent.

Q566. In what practice location(s) do you stock non-patient-specific compounded methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q567. How do you obtain your stock of non-patient-specific compounded methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q568. Why do you keep a stock of non-patient-specific compounded methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q569. For which, if any, diseases or conditions do you consider methylsulfonylmethane (MSM) standard therapy?

This question was not displayed to the respondent.

Q570. Does your specialty describe the use of methylsulfonylmethane (MSM) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q529. What type(s) of product(s) do you use, prescribe, or recommend for phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q531. Do you use compounded phenylephrine as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q532. In which combination(s) do you use compounded phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q533. For which, if any, diseases or conditions do you consider compounded phenylephrine standard therapy?

This question was not displayed to the respondent.

Q534. Does your specialty describe the use of compounded phenylephrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q535. Over the past 5 years, has the frequency in which you have used compounded phenylephrine changed?

This question was not displayed to the respondent.

Q536. Why do you use compounded phenylephrine instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q537. Do you stock non-patient-specific compounded phenylephrine in your practice location?

This question was not displayed to the respondent.

Q538. In what practice location(s) do you stock non-patient-specific compounded phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q539. How do you obtain your stock of non-patient-specific compounded phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q540. Why do you keep a stock of non-patient-specific compounded phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q541. For which, if any, diseases or conditions do you consider phenylephrine standard therapy?

This question was not displayed to the respondent. Q542. Does your specialty describe the use of phenylephrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q402. What type(s) of product(s) do you use, prescribe, or recommend for pitcher plant? Please check all that apply.

This question was not displayed to the respondent.

Q404. Do you use compounded pitcher plant as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q405. Please list all combination products in which you use compounded pitcher plant.

This question was not displayed to the respondent.

Q406. For which, if any, diseases or conditions do you consider compounded pitcher plant standard therapy?

This question was not displayed to the respondent.

Q407. Does your specialty describe the use of compounded pitcher plant in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q408. Over the past 5 years, has the frequency in which you have used compounded pitcher plant changed?

This question was not displayed to the respondent.

Q409. Why do you use compounded pitcher plant instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q410. Do you stock non-patient-specific compounded pitcher plant in your practice location?

This question was not displayed to the respondent.

Q411. In what practice location(s) do you stock non-patient-specific compounded pitcher plant? Please check all that apply.

This question was not displayed to the respondent. Q412. How do you obtain your stock of non-patient-specific compounded pitcher plant? Please check all that apply.

This question was not displayed to the respondent.

Q413. Why do you keep a stock of non-patient-specific compounded pitcher plant? Please check all that apply.

This question was not displayed to the respondent.

Q414. For which, if any, diseases or conditions do you consider pitcher plant standard therapy?

This question was not displayed to the respondent.

Q415. Does your specialty describe the use of pitcher plant in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q416. What type(s) of product(s) do you use, prescribe, or recommend for pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q418. Do you use compounded pregnenolone as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q419. Please list all combination products in which you use compounded pregnenolone.

This question was not displayed to the respondent.

Q420. For which, if any, diseases or conditions do you consider compounded pregnenolone standard therapy?

This question was not displayed to the respondent.

Q421. Does your specialty describe the use of compounded pregnenolone in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q422. Over the past 5 years, has the frequency in which you have used compounded pregnenolone changed?

This question was not displayed to the respondent. Q423. Why do you use compounded pregnenolone instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q424. Do you stock non-patient-specific compounded pregnenolone in your practice location?

This question was not displayed to the respondent.

Q425. In what practice location(s) do you stock non-patient-specific compounded pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q426. How do you obtain your stock of non-patient-specific compounded pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q427. Why do you keep a stock of non-patient-specific compounded pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q428. For which, if any, diseases or conditions do you consider pregnenolone standard therapy?

This question was not displayed to the respondent.

Q429. Does your specialty describe the use of pregnenolone in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q444. What type(s) of product(s) do you use, prescribe, or recommend for quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q446. Do you use compounded quinacrine as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q447. Please list all combination products in which you use compounded quinacrine.

This question was not displayed to the respondent. Q448. For which, if any, diseases or conditions do you consider compounded quinacrine standard therapy?

This question was not displayed to the respondent.

Q449. Does your specialty describe the use of compounded quinacrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q450. Over the past 5 years, has the frequency in which you have used compounded quinacrine changed?

This question was not displayed to the respondent.

Q451. Why do you use compounded quinacrine instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q452. Do you stock non-patient-specific compounded quinacrine in your practice location?

This question was not displayed to the respondent.

Q453. In what practice location(s) do you stock non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q454. How do you obtain your stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q455. Why do you keep a stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q456. For which, if any, diseases or conditions do you consider quinacrine standard therapy?

This question was not displayed to the respondent.

Q457. Does your specialty describe the use of quinacrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q458. What type(s) of product(s) do you use, prescribe, or recommend for zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

This question was not displayed to the respondent. Q460. Do you use compounded zinc sulfate as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q461. Please list all combination products in which you use compounded zinc sulfate.

This question was not displayed to the respondent.

Q462. For which, if any, diseases or conditions do you consider compounded zinc sulfate standard therapy?

This question was not displayed to the respondent.

Q463. Does your specialty describe the use of compounded zinc sulfate in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q464. Over the past 5 years, has the frequency in which you have used compounded zinc sulfate changed?

This question was not displayed to the respondent.

Q465. Why do you use compounded zinc sulfate instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q466. Do you stock non-patient-specific compounded zinc sulfate in your practice location?

This question was not displayed to the respondent.

Q467. In what practice location(s) do you stock non-patient-specific compounded zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

Q468. How do you obtain your stock of non-patient-specific compounded zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

Q469. Why do you keep a stock of non-patient-specific compounded zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

Q470. For which, if any, diseases or conditions do you consider zinc sulfate standard therapy?

This question was not displayed to the respondent.

Q471. Does your specialty describe the use of zinc sulfate in medical practice guidelines or other resources?

This question was not displayed to the respondent. Q16. What is your terminal clinical degree? Please check all that apply.

This question was not displayed to the respondent.

Q17. Which of the following Board certification(s) do you hold? Please check all that apply.

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

Q1. Which of the following substances do you use in your practice? Please check all that apply.

Alpha lipoic acid (ALA)

Dexamethasone acetate

InositolInositol

Methylcobalamin

Methylsulfonylmethane (MSM)

Phenylephrine

Pitcher plant

Pregnenolone

Quinacrine

Zinc sulfate

None of the above

Q2. What type(s) of product(s) do you use, prescribe, or recommend for alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent.

Q4. Do you use compounded alpha lipoic acid (ALA) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q5. Please list all combination products in which you use compounded alpha lipoic acid (ALA).

This question was not displayed to the respondent.

Q6. For which, if any, diseases or conditions do you consider compounded alpha lipoic acid (ALA) standard therapy?

This question was not displayed to the respondent.

Q7. Does your specialty describe the use of compounded alpha lipoic acid (ALA) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q8. Over the past 5 years, has the frequency in which you have used compounded alpha lipoic acid (ALA) changed?

This question was not displayed to the respondent.

Q9. Why do you use compounded alpha lipoic acid (ALA) instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q10. Do you stock non-patient-specific compounded alpha lipoic acid (ALA) in your practice location?

This question was not displayed to the respondent.

Q11. In what practice location(s) do you stock non-patient-specific compounded alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent. Q12. How do you obtain your stock of non-patient-specific compounded alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent.

Q13. Why do you keep a stock of non-patient-specific compounded alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent.

Q14. For which, if any, diseases or conditions do you consider alpha lipoic acid (ALA) standard therapy?

This question was not displayed to the respondent.

Q15. Does your specialty describe the use of alpha lipoic acid (ALA) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q515. What type(s) of product(s) do you use, prescribe, or recommend for dexamethasone acetate? 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

This question was not displayed to the respondent.

Q517. Do you use compounded dexamethasone acetate as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q518. Please list all combination products in which you use compounded dexamethasone acetate. This question was not displayed to the respondent.

Q519. For which, if any, diseases or conditions do you consider compounded dexamethasone acetate standard therapy?

This question was not displayed to the respondent.

Q520. Does your specialty describe the use of compounded dexamethasone acetate in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q521. Over the past 5 years, has the frequency in which you have used compounded dexamethasone acetate changed?

This question was not displayed to the respondent.

Q522. Why do you use compounded dexamethasone acetate instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q523. Do you stock non-patient-specific compounded dexamethasone acetate in your practice location?

This question was not displayed to the respondent.

Q524. In what practice location(s) do you stock non-patient-specific compounded dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q525. How do you obtain your stock of non-patient-specific compounded dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q526. Why do you keep a stock of non-patient-specific compounded dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q527. ForFor which, if any,, diseasesdiseases oror conditionsconditions dodo youyou considerconsider dexamethasone acetate standardstandard therapy?therapy? Q528. DoesDoes your specialty describe the use of dexamethasone acetate inin medicalmedical practicepractice guidelines or other resources?

Q543. What type(s) of product(s) do you use, prescribe, or recommend for inositol? Please check all that apply.

This question was not displayed to the respondent.

Q545. Do you use compounded inositol as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q546. In which combination(s) do you use compounded inositol? Please check all that apply.

This question was not displayed to the respondent.

Q547. For which, if any, diseases or conditions do you consider compounded inositol standard therapy?

This question was not displayed to the respondent.

Q548. Does your specialty describe the use of compounded inositol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q549. Over the past 5 years, has the frequency in which you have used compounded inositol changed?

This question was not displayed to the respondent.

Q550. Why do you use compounded inositol instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q551. Do you stock non-patient-specific compounded inositol in your practice location? This question was not displayed to the respondent.

Q552. In what practice location(s) do you stock non-patient-specific compounded inositol? Please check all that apply.

This question was not displayed to the respondent.

Q553. How do you obtain your stock of non-patient-specific compounded inositol? Please check all that apply.

This question was not displayed to the respondent.

Q554. Why do you keep a stock of non-patient-specific compounded inositol? Please check all that apply.

This question was not displayed to the respondent.

Q555. For which, if any, diseases or conditions do you consider inositol standard therapy?

This question was not displayed to the respondent.

Q556. Does your specialty describe the use of inositol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q388. What type(s) of product(s) do you use, prescribe, or recommend for methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q390. Do you use compounded methylcobalamin as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q391. In which combination(s) do you use compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent. Q392. For which, if any, diseases or conditions do you consider compounded methylcobalamin standard therapy?

This question was not displayed to the respondent.

Q393. Does your specialty describe the use of compounded methylcobalamin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q394. Over the past 5 years, has the frequency in which you have used compounded methylcobalamin changed?

This question was not displayed to the respondent.

Q395. Why do you use compounded methylcobalamin instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q396. Do you stock non-patient-specific compounded methylcobalamin in your practice location?

This question was not displayed to the respondent.

Q397. In what practice location(s) do you stock non-patient-specific compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q398. How do you obtain your stock of non-patient-specific compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q399. Why do you keep a stock of non-patient-specific compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q400. For which, if any, diseases or conditions do you consider methylcobalamin standard therapy?

This question was not displayed to the respondent. Q401. Does your specialty describe the use of methylcobalamin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q557. What type(s) of product(s) do you use, prescribe, or recommend for methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q559. Do you use compounded methylsulfonylmethane (MSM) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q560. Please list all combination products in which you use compounded methylsulfonylmethane (MSM).

This question was not displayed to the respondent.

Q561. For which, if any, diseases or conditions do you consider compounded methylsulfonylmethane (MSM) standard therapy?

This question was not displayed to the respondent.

Q562. Does your specialty describe the use of compounded methylsulfonylmethane (MSM) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q563. Over the past 5 years, has the frequency in which you have used compounded methylsulfonylmethane (MSM) changed?

This question was not displayed to the respondent.

Q564. Why do you use compounded methylsulfonylmethane (MSM) instead of any FDA-approved drug product?

This question was not displayed to the respondent. Q565. Do you stock non-patient-specific compounded methylsulfonylmethane (MSM) in your practice location?

This question was not displayed to the respondent.

Q566. In what practice location(s) do you stock non-patient-specific compounded methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q567. How do you obtain your stock of non-patient-specific compounded methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q568. Why do you keep a stock of non-patient-specific compounded methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q569. For which, if any, diseases or conditions do you consider methylsulfonylmethane (MSM) standard therapy?

This question was not displayed to the respondent.

Q570. Does your specialty describe the use of methylsulfonylmethane (MSM) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q529. What type(s) of product(s) do you use, prescribe, or recommend for phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q532. In which combination(s) do you use compounded phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q533. For which, if any, diseases or conditions do you consider compounded phenylephrine standard therapy?

This question was not displayed to the respondent.

Q534. Does your specialty describe the use of compounded phenylephrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q535. Over the past 5 years, has the frequency in which you have used compounded phenylephrine changed?

This question was not displayed to the respondent.

Q536. Why do you use compounded phenylephrine instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q537. Do you stock non-patient-specific compounded phenylephrine in your practice location?

This question was not displayed to the respondent.

Q538. In what practice location(s) do you stock non-patient-specific compounded phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q539. How do you obtain your stock of non-patient-specific compounded phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q540. Why do you keep a stock of non-patient-specific compounded phenylephrine? Please check all that apply.

This question was not displayed to the respondent. Q541. For which, if any, diseases or conditions do you consider phenylephrine standard therapy?

This question was not displayed to the respondent.

Q542. Does your specialty describe the use of phenylephrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q402. What type(s) of product(s) do you use, prescribe, or recommend for pitcher plant? Please check all that apply.

This question was not displayed to the respondent.

Q404. Do you use compounded pitcher plant as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q405. Please list all combination products in which you use compounded pitcher plant.

This question was not displayed to the respondent.

Q406. For which, if any, diseases or conditions do you consider compounded pitcher plant standard therapy?

This question was not displayed to the respondent.

Q407. Does your specialty describe the use of compounded pitcher plant in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q408. Over the past 5 years, has the frequency in which you have used compounded pitcher plant changed?

This question was not displayed to the respondent. Q409. Why do you use compounded pitcher plant instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q410. Do you stock non-patient-specific compounded pitcher plant in your practice location?

This question was not displayed to the respondent.

Q411. In what practice location(s) do you stock non-patient-specific compounded pitcher plant? Please check all that apply.

This question was not displayed to the respondent.

Q412. How do you obtain your stock of non-patient-specific compounded pitcher plant? Please check all that apply.

This question was not displayed to the respondent.

Q413. Why do you keep a stock of non-patient-specific compounded pitcher plant? Please check all that apply.

This question was not displayed to the respondent.

Q414. For which, if any, diseases or conditions do you consider pitcher plant standard therapy?

This question was not displayed to the respondent.

Q415. Does your specialty describe the use of pitcher plant in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q416. What type(s) of product(s) do you use, prescribe, or recommend for pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q418. Do you use compounded pregnenolone as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q419. Please list all combination products in which you use compounded pregnenolone.

This question was not displayed to the respondent.

Q420. For which, if any, diseases or conditions do you consider compounded pregnenolone standard therapy?

This question was not displayed to the respondent.

Q421. Does your specialty describe the use of compounded pregnenolone in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q422. Over the past 5 years, has the frequency in which you have used compounded pregnenolone changed?

This question was not displayed to the respondent.

Q423. Why do you use compounded pregnenolone instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q424. Do you stock non-patient-specific compounded pregnenolone in your practice location?

This question was not displayed to the respondent.

Q425. In what practice location(s) do you stock non-patient-specific compounded pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q426. How do you obtain your stock of non-patient-specific compounded pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q427. Why do you keep a stock of non-patient-specific compounded pregnenolone? Please check all that apply. This question was not displayed to the respondent.

Q428. For which, if any, diseases or conditions do you consider pregnenolone standard therapy?

This question was not displayed to the respondent.

Q429. Does your specialty describe the use of pregnenolone in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q444. What type(s) of product(s) do you use, prescribe, or recommend for quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q446. Do you use compounded quinacrine as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q447. Please list all combination products in which you use compounded quinacrine.

This question was not displayed to the respondent.

Q448. For which, if any, diseases or conditions do you consider compounded quinacrine standard therapy?

This question was not displayed to the respondent.

Q449. Does your specialty describe the use of compounded quinacrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q450. Over the past 5 years, has the frequency in which you have used compounded quinacrine changed?

This question was not displayed to the respondent. Q451. Why do you use compounded quinacrine instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q452. Do you stock non-patient-specific compounded quinacrine in your practice location?

This question was not displayed to the respondent.

Q453. In what practice location(s) do you stock non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q454. How do you obtain your stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q455. Why do you keep a stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q456. For which, if any, diseases or conditions do you consider quinacrine standard therapy?

This question was not displayed to the respondent.

Q457. Does your specialty describe the use of quinacrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q458. What type(s) of product(s) do you use, prescribe, or recommend for zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

Q461. Please list all combination products in which you use compounded zinc sulfate.

This question was not displayed to the respondent.

Q462. For which, if any, diseases or conditions do you consider compounded zinc sulfate standard therapy?

This question was not displayed to the respondent.

Q463. Does your specialty describe the use of compounded zinc sulfate in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q464. Over the past 5 years, has the frequency in which you have used compounded zinc sulfate changed?

This question was not displayed to the respondent.

Q465. Why do you use compounded zinc sulfate instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q466. Do you stock non-patient-specific compounded zinc sulfate in your practice location?

This question was not displayed to the respondent.

Q467. In what practice location(s) do you stock non-patient-specific compounded zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

Q468. How do you obtain your stock of non-patient-specific compounded zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

Q469. Why do you keep a stock of non-patient-specific compounded zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

Q470. For which, if any, diseases or conditions do you consider zinc sulfate standard therapy? This question was not displayed to the respondent.

Q471. Does your specialty describe the use of zinc sulfate in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q16. What is your terminal clinical degree? Please check all that apply.

This question was not displayed to the respondent.

Q17. Which of the following Board certification(s) do you hold? Please check all that apply.

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

Q1. Which of the following substances do you use in your practice? Please check all that apply.

Alpha lipoic acid (ALA)

Dexamethasone acetate

InositolInositol

Methylcobalamin

Methylsulfonylmethane (MSM)

Phenylephrine

Pitcher plant

Pregnenolone

Quinacrine

Zinc sulfate

None of the above

Q2. What type(s) of product(s) do you use, prescribe, or recommend for alpha lipoic acid (ALA)? 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

This question was not displayed to the respondent.

Q4. Do you use compounded alpha lipoic acid (ALA) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q5. Please list all combination products in which you use compounded alpha lipoic acid (ALA).

This question was not displayed to the respondent.

Q6. For which, if any, diseases or conditions do you consider compounded alpha lipoic acid (ALA) standard therapy?

This question was not displayed to the respondent.

Q7. Does your specialty describe the use of compounded alpha lipoic acid (ALA) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q8. Over the past 5 years, has the frequency in which you have used compounded alpha lipoic acid (ALA) changed?

This question was not displayed to the respondent.

Q9. Why do you use compounded alpha lipoic acid (ALA) instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q10. Do you stock non-patient-specific compounded alpha lipoic acid (ALA) in your practice location?

This question was not displayed to the respondent. Q11. In what practice location(s) do you stock non-patient-specific compounded alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent.

Q12. How do you obtain your stock of non-patient-specific compounded alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent.

Q13. Why do you keep a stock of non-patient-specific compounded alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent.

Q14. ForFor which, if any,, diseasesdiseases oror conditionsconditions dodo youyou considerconsider alphalpha lipoiclipoic acidacid (ALA)(ALA) standard therapy?

None

Q15. DoesDoes your specialty describe the use of alphalpha lipoiclipoic acidacid (ALA)(ALA) inin medicalmedical practicepractice guidelines or other resources?

Q515. What type(s) of product(s) do you use, prescribe, or recommend for dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q517. Do you use compounded dexamethasone acetate as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q518. Please list all combination products in which you use compounded dexamethasone acetate. This question was not displayed to the respondent.

Q519. For which, if any, diseases or conditions do you consider compounded dexamethasone acetate standard therapy?

This question was not displayed to the respondent.

Q520. Does your specialty describe the use of compounded dexamethasone acetate in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q521. Over the past 5 years, has the frequency in which you have used compounded dexamethasone acetate changed?

This question was not displayed to the respondent.

Q522. Why do you use compounded dexamethasone acetate instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q523. Do you stock non-patient-specific compounded dexamethasone acetate in your practice location?

This question was not displayed to the respondent.

Q524. In what practice location(s) do you stock non-patient-specific compounded dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q525. How do you obtain your stock of non-patient-specific compounded dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q526. Why do you keep a stock of non-patient-specific compounded dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q527. For which, if any, diseases or conditions do you consider dexamethasone acetate standard therapy?

This question was not displayed to the respondent. Q528. Does your specialty describe the use of dexamethasone acetate in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q543. What type(s) of product(s) do you use, prescribe, or recommend for inositol? Please check all that apply.

This question was not displayed to the respondent.

Q545. Do you use compounded inositol as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q546. In which combination(s) do you use compounded inositol? Please check all that apply.

This question was not displayed to the respondent.

Q547. For which, if any, diseases or conditions do you consider compounded inositol standard therapy?

This question was not displayed to the respondent.

Q548. Does your specialty describe the use of compounded inositol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q549. Over the past 5 years, has the frequency in which you have used compounded inositol changed?

This question was not displayed to the respondent.

Q550. Why do you use compounded inositol instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q551. Do you stock non-patient-specific compounded inositol in your practice location? This question was not displayed to the respondent.

Q552. In what practice location(s) do you stock non-patient-specific compounded inositol? Please check all that apply.

This question was not displayed to the respondent.

Q553. How do you obtain your stock of non-patient-specific compounded inositol? Please check all that apply.

This question was not displayed to the respondent.

Q554. Why do you keep a stock of non-patient-specific compounded inositol? Please check all that apply.

This question was not displayed to the respondent.

Q555. For which, if any, diseases or conditions do you consider inositol standard therapy?

This question was not displayed to the respondent.

Q556. Does your specialty describe the use of inositol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q388. What type(s) of product(s) do you use, prescribe, or recommend for methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q390. Do you use compounded methylcobalamin as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q391. In which combination(s) do you use compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent. Q392. For which, if any, diseases or conditions do you consider compounded methylcobalamin standard therapy?

This question was not displayed to the respondent.

Q393. Does your specialty describe the use of compounded methylcobalamin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q394. Over the past 5 years, has the frequency in which you have used compounded methylcobalamin changed?

This question was not displayed to the respondent.

Q395. Why do you use compounded methylcobalamin instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q396. Do you stock non-patient-specific compounded methylcobalamin in your practice location?

This question was not displayed to the respondent.

Q397. In what practice location(s) do you stock non-patient-specific compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q398. How do you obtain your stock of non-patient-specific compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q399. Why do you keep a stock of non-patient-specific compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q400. For which, if any, diseases or conditions do you consider methylcobalamin standard therapy?

This question was not displayed to the respondent.

Q401. Does your specialty describe the use of methylcobalamin in medical practice guidelines or other resources? This question was not displayed to the respondent.

Q557. What type(s) of product(s) do you use, prescribe, or recommend for methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q559. Do you use compounded methylsulfonylmethane (MSM) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q560. Please list all combination products in which you use compounded methylsulfonylmethane (MSM).

This question was not displayed to the respondent.

Q561. For which, if any, diseases or conditions do you consider compounded methylsulfonylmethane (MSM) standard therapy?

This question was not displayed to the respondent.

Q562. Does your specialty describe the use of compounded methylsulfonylmethane (MSM) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q563. Over the past 5 years, has the frequency in which you have used compounded methylsulfonylmethane (MSM) changed?

This question was not displayed to the respondent.

Q564. Why do you use compounded methylsulfonylmethane (MSM) instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q565. Do you stock non-patient-specific compounded methylsulfonylmethane (MSM) in your practice location? This question was not displayed to the respondent.

Q566. In what practice location(s) do you stock non-patient-specific compounded methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q567. How do you obtain your stock of non-patient-specific compounded methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q568. Why do you keep a stock of non-patient-specific compounded methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q569. For which, if any, diseases or conditions do you consider methylsulfonylmethane (MSM) standard therapy?

This question was not displayed to the respondent.

Q570. Does your specialty describe the use of methylsulfonylmethane (MSM) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q529. What type(s) of product(s) do you use, prescribe, or recommend for phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q531. Do you use compounded phenylephrine as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q532. In which combination(s) do you use compounded phenylephrine? Please check all that apply. This question was not displayed to the respondent.

Q533. For which, if any, diseases or conditions do you consider compounded phenylephrine standard therapy?

This question was not displayed to the respondent.

Q534. Does your specialty describe the use of compounded phenylephrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q535. Over the past 5 years, has the frequency in which you have used compounded phenylephrine changed?

This question was not displayed to the respondent.

Q536. Why do you use compounded phenylephrine instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q537. Do you stock non-patient-specific compounded phenylephrine in your practice location?

This question was not displayed to the respondent.

Q538. In what practice location(s) do you stock non-patient-specific compounded phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q539. How do you obtain your stock of non-patient-specific compounded phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q540. Why do you keep a stock of non-patient-specific compounded phenylephrine? Please check all that apply.

This question was not displayed to the respondent.

Q541. For which, if any, diseases or conditions do you consider phenylephrine standard therapy?

This question was not displayed to the respondent. Q542. Does your specialty describe the use of phenylephrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q402. What type(s) of product(s) do you use, prescribe, or recommend for pitcher plant? Please check all that apply.

This question was not displayed to the respondent.

Q404. Do you use compounded pitcher plant as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q405. Please list all combination products in which you use compounded pitcher plant.

This question was not displayed to the respondent.

Q406. For which, if any, diseases or conditions do you consider compounded pitcher plant standard therapy?

This question was not displayed to the respondent.

Q407. Does your specialty describe the use of compounded pitcher plant in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q408. Over the past 5 years, has the frequency in which you have used compounded pitcher plant changed?

This question was not displayed to the respondent.

Q409. Why do you use compounded pitcher plant instead of any FDA-approved drug product?

This question was not displayed to the respondent. Q410. Do you stock non-patient-specific compounded pitcher plant in your practice location?

This question was not displayed to the respondent.

Q411. In what practice location(s) do you stock non-patient-specific compounded pitcher plant? Please check all that apply.

This question was not displayed to the respondent.

Q412. How do you obtain your stock of non-patient-specific compounded pitcher plant? Please check all that apply.

This question was not displayed to the respondent.

Q413. Why do you keep a stock of non-patient-specific compounded pitcher plant? Please check all that apply.

This question was not displayed to the respondent.

Q414. For which, if any, diseases or conditions do you consider pitcher plant standard therapy?

This question was not displayed to the respondent.

Q415. Does your specialty describe the use of pitcher plant in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q416. What type(s) of product(s) do you use, prescribe, or recommend for pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q418. Do you use compounded pregnenolone as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent. Q419. Please list all combination products in which you use compounded pregnenolone.

This question was not displayed to the respondent.

Q420. For which, if any, diseases or conditions do you consider compounded pregnenolone standard therapy?

This question was not displayed to the respondent.

Q421. Does your specialty describe the use of compounded pregnenolone in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q422. Over the past 5 years, has the frequency in which you have used compounded pregnenolone changed?

This question was not displayed to the respondent.

Q423. Why do you use compounded pregnenolone instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q424. Do you stock non-patient-specific compounded pregnenolone in your practice location?

This question was not displayed to the respondent.

Q425. In what practice location(s) do you stock non-patient-specific compounded pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q426. How do you obtain your stock of non-patient-specific compounded pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q427. Why do you keep a stock of non-patient-specific compounded pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q428. For which, if any, diseases or conditions do you consider pregnenolone standard therapy? This question was not displayed to the respondent.

Q429. Does your specialty describe the use of pregnenolone in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q444. What type(s) of product(s) do you use, prescribe, or recommend for quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q446. Do you use compounded quinacrine as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q447. Please list all combination products in which you use compounded quinacrine.

This question was not displayed to the respondent.

Q448. For which, if any, diseases or conditions do you consider compounded quinacrine standard therapy?

This question was not displayed to the respondent.

Q449. Does your specialty describe the use of compounded quinacrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q450. Over the past 5 years, has the frequency in which you have used compounded quinacrine changed?

This question was not displayed to the respondent.

Q451. Why do you use compounded quinacrine instead of any FDA-approved drug product?

This question was not displayed to the respondent. Q452. Do you stock non-patient-specific compounded quinacrine in your practice location?

This question was not displayed to the respondent.

Q453. In what practice location(s) do you stock non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q454. How do you obtain your stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q455. Why do you keep a stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q456. For which, if any, diseases or conditions do you consider quinacrine standard therapy?

This question was not displayed to the respondent.

Q457. Does your specialty describe the use of quinacrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q458. What type(s) of product(s) do you use, prescribe, or recommend for zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

Q460. Do you use compounded zinc sulfate as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q461. Please list all combination products in which you use compounded zinc sulfate. This question was not displayed to the respondent.

Q462. For which, if any, diseases or conditions do you consider compounded zinc sulfate standard therapy?

This question was not displayed to the respondent.

Q463. Does your specialty describe the use of compounded zinc sulfate in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q464. Over the past 5 years, has the frequency in which you have used compounded zinc sulfate changed?

This question was not displayed to the respondent.

Q465. Why do you use compounded zinc sulfate instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q466. Do you stock non-patient-specific compounded zinc sulfate in your practice location?

This question was not displayed to the respondent.

Q467. In what practice location(s) do you stock non-patient-specific compounded zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

Q468. How do you obtain your stock of non-patient-specific compounded zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

Q469. Why do you keep a stock of non-patient-specific compounded zinc sulfate? Please check all that apply.

This question was not displayed to the respondent.

Q470. For which, if any, diseases or conditions do you consider zinc sulfate standard therapy?

This question was not displayed to the respondent.

Q471. Does your specialty describe the use of zinc sulfate in medical practice guidelines or other resources? This question was not displayed to the respondent.

Q16. What is your terminal clinical degree? Please check all that apply.

This question was not displayed to the respondent.

Q17. Which of the following Board certification(s) do you hold? Please check all that apply.

There are eleven (11) substancessubstances containedcontained inin thisthis surveysurvey.. As a medical expert, we appreciate your input regarding the use of these substances 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

Q1. Which of the following substances do you use in your practice? (check all that apply)

Alpha-lipoic acid (ALA)

Dexamethasone acetate

Edetate disodium (EDTA)

Estriol

Malic acid

Methylcobalamin

Methylsulfonylmethane (MSM)

Pregnenolone

Quinacrine

Tranilastranilast

Triamcinoloneriamcinolone diacetatediacetate

None of the above

Q515. What type(s) of product(s) do you use, prescribe, or recommend for alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent.

Q516. Please list any conditions or diseases for which you use compounded alpha lipoic acid (ALA) 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).

This question was not displayed to the respondent.

Q517. Do you use compounded alpha lipoic acid (ALA) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q518. Please list all combination products in which you use compounded alpha lipoic acid (ALA).

This question was not displayed to the respondent.

Q519. For which, if any, diseases or conditions do you consider compounded alpha lipoic acid (ALA) standard therapy?

This question was not displayed to the respondent.

Q520. Does your specialty describe the use of compounded alpha lipoic acid (ALA) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q521. Over the past 5 years, has the frequency in which you have used compounded alpha lipoic acid (ALA) changed?

This question was not displayed to the respondent.

Q522. Why do you use compounded alpha lipoic acid (ALA) instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q523. Do you stock non-patient-specific compounded alpha lipoic acid (ALA) in your practice location?

This question was not displayed to the respondent.

Q524. In what practice location(s) do you stock non-patient-specific compounded alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent.

Q525. How do you obtain your stock of non-patient-specific compounded alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent.

Q526. Why do you keep a stock of non-patient-specific compounded alpha lipoic acid (ALA)? Please check all that apply.

This question was not displayed to the respondent.

Q527. For which, if any, diseases or conditions do you consider alpha lipoic acid (ALA) standard therapy?

This question was not displayed to the respondent.

Q528. Does your specialty describe the use of alpha lipoic acid (ALA) in medical practice guidelines or other resources? This question was not displayed to the respondent.

Q529. What type(s) of product(s) do you use, prescribe, or recommend for dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q530. Please list any conditions or diseases for which you use compounded dexamethasone acetate 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).

This question was not displayed to the respondent.

Q531. Do you use compounded dexamethasone acetate as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q532. Please list all combination products in which you use compounded dexamethasone acetate.

This question was not displayed to the respondent.

Q533. For which, if any, diseases or conditions do you consider compounded dexamethasone acetate standard therapy?

This question was not displayed to the respondent.

Q534. Does your specialty describe the use of compounded dexamethasone acetate in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q535. Over the past 5 years, has the frequency in which you have used compounded dexamethasone acetate changed?

This question was not displayed to the respondent.

Q536. Why do you use compounded dexamethasone acetate instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q537. Do you stock non-patient-specific compounded dexamethasone acetate in your practice location?

This question was not displayed to the respondent.

Q538. In what practice location(s) do you stock non-patient-specific compounded dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q539. How do you obtain your stock of non-patient-specific compounded dexamethasone acetate? Please check all that apply. This question was not displayed to the respondent.

Q540. Why do you keep a stock of non-patient-specific compounded dexamethasone acetate? Please check all that apply.

This question was not displayed to the respondent.

Q541. For which, if any, diseases or conditions do you consider dexamethasone acetate standard therapy?

This question was not displayed to the respondent.

Q542. Does your specialty describe the use of dexamethasone acetate in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q543. What type(s) of product(s) do you use, prescribe, or recommend for edetate disodium (EDTA)? Please check all that apply.

This question was not displayed to the respondent.

Q544. Please list any conditions or diseases for which you use compounded edetate disodium (EDTA) 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).

This question was not displayed to the respondent.

Q545. Do you use compounded edetate disodium (EDTA) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q546. Please list all combination products in which you use compounded edetate disodium (EDTA).

This question was not displayed to the respondent.

Q547. For which, if any, diseases or conditions do you consider compounded edetate disodium (EDTA) standard therapy?

This question was not displayed to the respondent.

Q548. Does your specialty describe the use of compounded edetate disodium (EDTA) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q549. Over the past 5 years, has the frequency in which you have used compounded edetate disodium (EDTA) changed?

This question was not displayed to the respondent.

Q550. Why do you use compounded edetate disodium (EDTA) instead of any FDA-approved drug product?

This question was not displayed to the respondent. Q551. Do you stock non-patient-specific compounded edetate disodium (EDTA) in your practice location?

This question was not displayed to the respondent.

Q552. In what practice location(s) do you stock non-patient-specific compounded edetate disodium (EDTA)? Please check all that apply.

This question was not displayed to the respondent.

Q553. How do you obtain your stock of non-patient-specific compounded edetate disodium (EDTA)? Please check all that apply.

This question was not displayed to the respondent.

Q554. Why do you keep a stock of non-patient-specific compounded edetate disodium (EDTA)? Please check all that apply.

This question was not displayed to the respondent.

Q555. For which, if any, diseases or conditions do you consider edetate disodium (EDTA) standard therapy?

This question was not displayed to the respondent.

Q556. Does your specialty describe the use of edetate disodium (EDTA) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q557. What type(s) of product(s) do you use, prescribe, or recommend for estriol? Please check all that apply.

This question was not displayed to the respondent.

Q558. Please list any conditions or diseases for which you use compounded estriol 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).

This question was not displayed to the respondent.

Q559. Do you use compounded estriol as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q560. Please list all combination products in which you use compounded estriol.

This question was not displayed to the respondent.

Q561. For which, if any, diseases or conditions do you consider compounded estriol standard therapy?

This question was not displayed to the respondent. Q562. Does your specialty describe the use of compounded estriol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q563. Over the past 5 years, has the frequency in which you have used compounded estriol changed?

This question was not displayed to the respondent.

Q564. Why do you use compounded estriol instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q565. Do you stock non-patient-specific compounded estriol in your practice location?

This question was not displayed to the respondent.

Q566. In what practice location(s) do you stock non-patient-specific compounded estriol? Please check all that apply.

This question was not displayed to the respondent.

Q567. How do you obtain your stock of non-patient-specific compounded estriol? Please check all that apply.

This question was not displayed to the respondent.

Q568. Why do you keep a stock of non-patient-specific compounded estriol? Please check all that apply.

This question was not displayed to the respondent.

Q569. For which, if any, diseases or conditions do you consider estriol standard therapy?

This question was not displayed to the respondent.

Q570. Does your specialty describe the use of estriol in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q571. What type(s) of product(s) do you use, prescribe, or recommend for malic acid? Please check all that apply.

This question was not displayed to the respondent.

Q572. Please list any conditions or diseases for which you use compounded malic 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).

This question was not displayed to the respondent.

Q573. Do you use compounded malic acid as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply. This question was not displayed to the respondent.

Q574. Please list all combination products in which you use compounded malic acid.

This question was not displayed to the respondent.

Q575. For which, if any, diseases or conditions do you consider compounded malic acid standard therapy?

This question was not displayed to the respondent.

Q576. Does your specialty describe the use of compounded malic acid in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q577. Over the past 5 years, has the frequency in which you have used compounded malic acid changed?

This question was not displayed to the respondent.

Q578. Why do you use compounded malic acid instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q579. Do you stock non-patient-specific compounded malic acid in your practice location?

This question was not displayed to the respondent.

Q580. In what practice location(s) do you stock non-patient-specific compounded malic acid? Please check all that apply.

This question was not displayed to the respondent.

Q581. How do you obtain your stock of non-patient-specific compounded malic acid? Please check all that apply.

This question was not displayed to the respondent.

Q582. Why do you keep a stock of non-patient-specific compounded malic acid? Please check all that apply.

This question was not displayed to the respondent.

Q583. For which, if any, diseases or conditions do you consider malic acid standard therapy?

This question was not displayed to the respondent.

Q584. Does your specialty describe the use of malic acid in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q585. What type(s) of product(s) do you use, prescribe, or recommend for methylcobalamin? Please check all that apply.

This question was not displayed to the respondent. Q586. Please list any conditions or diseases for which you use compounded methylcobalamin in your practice. Please include the strength(s), dosing frequency(ies), dosage form(s), route(s) of administration, duration of therapy, and patient population (ex. age, gender, comorbidities, allergies, etc).

This question was not displayed to the respondent.

Q587. Do you use compounded methylcobalamin as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q588. In which combination(s) do you use compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q589. For which, if any, diseases or conditions do you consider compounded methylcobalamin standard therapy?

This question was not displayed to the respondent.

Q590. Does your specialty describe the use of compounded methylcobalamin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q591. Over the past 5 years, has the frequency in which you have used compounded methylcobalamin changed?

This question was not displayed to the respondent.

Q592. Why do you use compounded methylcobalamin instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q593. Do you stock non-patient-specific compounded methylcobalamin in your practice location?

This question was not displayed to the respondent.

Q594. In what practice location(s) do you stock non-patient-specific compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q595. How do you obtain your stock of non-patient-specific compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent.

Q596. Why do you keep a stock of non-patient-specific compounded methylcobalamin? Please check all that apply.

This question was not displayed to the respondent. Q597. For which, if any, diseases or conditions do you consider methylcobalamin standard therapy?

This question was not displayed to the respondent.

Q598. Does your specialty describe the use of methylcobalamin in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q655. What type(s) of product(s) do you use, prescribe, or recommend for methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q656. Please list any conditions or diseases for which you use compounded methylsulfonylmethane (MSM) 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).

This question was not displayed to the respondent.

Q657. Do you use compounded methylsulfonylmethane (MSM) as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q658. Please list all combination products in which you use compounded methylsulfonylmethane (MSM).

This question was not displayed to the respondent.

Q659. For which, if any, diseases or conditions do you consider compounded methylsulfonylmethane (MSM) standard therapy?

This question was not displayed to the respondent.

Q660. Does your specialty describe the use of compounded methylsulfonylmethane (MSM) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q661. Over the past 5 years, has the frequency in which you have used compounded methylsulfonylmethane (MSM) changed?

This question was not displayed to the respondent.

Q662. Why do you use compounded methylsulfonylmethane (MSM) instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q663. Do you stock non-patient-specific compounded methylsulfonylmethane (MSM) in your practice location?

This question was not displayed to the respondent. Q664. In what practice location(s) do you stock non-patient-specific compounded methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q665. How do you obtain your stock of non-patient-specific compounded methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q666. Why do you keep a stock of non-patient-specific compounded methylsulfonylmethane (MSM)? Please check all that apply.

This question was not displayed to the respondent.

Q667. For which, if any, diseases or conditions do you consider methylsulfonylmethane (MSM) standard therapy?

This question was not displayed to the respondent.

Q668. Does your specialty describe the use of methylsulfonylmethane (MSM) in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q599. What type(s) of product(s) do you use, prescribe, or recommend for pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q600. Please list any conditions or diseases for which you use compounded pregnenolone 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).

This question was not displayed to the respondent.

Q601. Do you use compounded pregnenolone as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q602. Please list all combination products in which you use compounded pregnenolone.

This question was not displayed to the respondent.

Q603. For which, if any, diseases or conditions do you consider compounded pregnenolone standard therapy?

This question was not displayed to the respondent.

Q604. Does your specialty describe the use of compounded pregnenolone in medical practice guidelines or other resources?

This question was not displayed to the respondent. Q605. Over the past 5 years, has the frequency in which you have used compounded pregnenolone changed?

This question was not displayed to the respondent.

Q606. Why do you use compounded pregnenolone instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q607. Do you stock non-patient-specific compounded pregnenolone in your practice location?

This question was not displayed to the respondent.

Q608. In what practice location(s) do you stock non-patient-specific compounded pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q609. How do you obtain your stock of non-patient-specific compounded pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q610. Why do you keep a stock of non-patient-specific compounded pregnenolone? Please check all that apply.

This question was not displayed to the respondent.

Q611. For which, if any, diseases or conditions do you consider pregnenolone standard therapy?

This question was not displayed to the respondent.

Q612. Does your specialty describe the use of pregnenolone in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q613. What type(s) of product(s) do you use, prescribe, or recommend for quinacrine? 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

Q614. PleasePlease listlist anyany conditionsconditions oror diseasesdiseases forfor whichwhich youyou useuse compoundedcompounded quinacrine inin youryour practice.practice. PleasePlease includeinclude thethe strength(s), dosing frequency(ies), dosage form(s), route(s) of administration, duration of therapy,, andand patientpatient populationpopulation (ex.(ex. age,age, gender,, comorbidities,comorbidities, allergies,allergies, etc).etc). Strength(s) (please include Dosing Route(s) of Duration of units) frequency(ies) Dosage form(s) administration therapy Patient population Condition 1 (please describe)

Systemic lupus

Condition 2 (please describe)

Condition 3 (please describe)

Condition 4 (please describe)

Condition 5 (please describe)

Condition 6 (please describe)

Condition 7 (please describe)

Condition 8 (please describe)

Q615. Do you use compounded quinacrine as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

Single

Combination

Q616. Please list all combination products in which you use compounded quinacrine.

This question was not displayed to the respondent.

Q617. ForFor which,which, ifif anyany,, diseasesdiseases oror conditionsconditions dodo youyou considerconsider compoundedcompounded quinacrine standard therapy?

Q618. DoesDoes youryour specialtyspecialty describedescribe thethe useuse ofof compoundedcompounded quinacrine inin medicalmedical practicepractice guidelinesguidelines oror other resources?

Q619. Over the past 5 years, has the frequency in which you have used compounded quinacrine changed?

Yes - I use it MORE oftenoften nownow (briefly(briefly describedescribe why)why)

Yes - I use it LESS oftenoften nownow (briefly(briefly describedescribe why)why)

No - use has remained consistent

Q620. WhyWhy dodo youyou useuse compoundedcompounded quinacrine insteadinstead ofof anyany FDA-approvedFDA-approved drugdrug product?product?

Intolerance to FDA approved product

Q621. Do you stock non-patient-specific compounded quinacrine in your practice location?

Yes

Q622. In what practice location(s) do you stock non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q623. How do you obtain your stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent.

Q624. Why do you keep a stock of non-patient-specific compounded quinacrine? Please check all that apply.

This question was not displayed to the respondent. Q625. For which, if any, diseases or conditions do you consider quinacrine standard therapy?

This question was not displayed to the respondent.

Q626. Does your specialty describe the use of quinacrine in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q627. What type(s) of product(s) do you use, prescribe, or recommend for tranilast? Please check all that apply.

This question was not displayed to the respondent.

Q628. Please list any conditions or diseases for which you use compounded tranilast 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).

This question was not displayed to the respondent.

Q629. Do you use compounded tranilast as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q630. In which combination(s) do you use compounded tranilast? Please check all that apply.

This question was not displayed to the respondent.

Q631. For which, if any, diseases or conditions do you consider compounded tranilast standard therapy?

This question was not displayed to the respondent.

Q632. Does your specialty describe the use of compounded tranilast in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q633. Over the past 5 years, has the frequency in which you have used compounded tranilast changed?

This question was not displayed to the respondent.

Q634. Why do you use compounded tranilast instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q635. Do you stock non-patient-specific compounded tranilast in your practice location?

This question was not displayed to the respondent.

Q636. In what practice location(s) do you stock non-patient-specific compounded tranilast? Please check all that apply.

This question was not displayed to the respondent. Q637. How do you obtain your stock of non-patient-specific compounded tranilast? Please check all that apply.

This question was not displayed to the respondent.

Q638. Why do you keep a stock of non-patient-specific compounded tranilast? Please check all that apply.

This question was not displayed to the respondent.

Q639. For which, if any, diseases or conditions do you consider tranilast standard therapy?

This question was not displayed to the respondent.

Q640. Does your specialty describe the use of tranilast in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q641. What type(s) of product(s) do you use, prescribe, or recommend for triamcinolone diacetate? Please check all that apply.

This question was not displayed to the respondent.

Q642. Please list any conditions or diseases for which you use compounded triamcinolone diacetate 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).

This question was not displayed to the respondent.

Q643. Do you use compounded triamcinolone diacetate as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply.

This question was not displayed to the respondent.

Q644. Please list all combination products in which you use compounded triamcinolone diacetate.

This question was not displayed to the respondent.

Q645. For which, if any, diseases or conditions do you consider compounded triamcinolone diacetate standard therapy?

This question was not displayed to the respondent.

Q646. Does your specialty describe the use of compounded triamcinolone diacetate in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q647. Over the past 5 years, has the frequency in which you have used compounded triamcinolone diacetate changed?

This question was not displayed to the respondent. Q648. Why do you use compounded triamcinolone diacetate instead of any FDA-approved drug product?

This question was not displayed to the respondent.

Q649. Do you stock non-patient-specific compounded triamcinolone diacetate in your practice location?

This question was not displayed to the respondent.

Q650. In what practice location(s) do you stock non-patient-specific compounded triamcinolone diacetate? Please check all that apply.

This question was not displayed to the respondent.

Q651. How do you obtain your stock of non-patient-specific compounded triamcinolone diacetate? Please check all that apply.

This question was not displayed to the respondent.

Q652. Why do you keep a stock of non-patient-specific compounded triamcinolone diacetate? Please check all that apply.

This question was not displayed to the respondent.

Q653. For which, if any, diseases or conditions do you consider triamcinolone diacetate standard therapy?

This question was not displayed to the respondent.

Q654. Does your specialty describe the use of triamcinolone diacetate in medical practice guidelines or other resources?

This question was not displayed to the respondent.

Q16. 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)

Q17. 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,, DiabetesDiabetes andand MetabolismMetabolism

Family Medicine

Gastroenterology

Hematology

InfectiousInfectious DiseaseDisease

InternalInternal MedicineMedicine

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)