The Clinical Utility of Compounded Bioidentical Hormone Therapy A Review of Safety, Effectiveness, and Use (2020) / Chapter Skim
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8 The Use of Compounded Bioidentical Hormone Therapy
8 The Use of Compounded Bioidentical Hormone Therapy
Pages 173-216
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From page 173... ...
As a framework for this discussion, the chapter begins with a brief overview of the rise of cBHT and rationales for use, and it follows with a discussion on the assessed therapeutic need for cBHT, derived from evidence-based clinical guidance that inform practice. As discussed within the chapter, cBHT medications are marketed to treat a broad spectrum of indications related to patient health and wellbeing.
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. See Appendix H to review boxed warnings for bioidentical hormone therapy (BHT)
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. Effect of WHI on Perceptions and Treatment Options for Hormone Therapy FDA-Approved Bioidentical Hormone Therapy Early analyses and science communication efforts for WHI, coupled with FDA's limited indications for use and requirements for boxed warnings of potential adverse effects, had a lasting effect on clinician- and patientrelated concerns regarding the use of hormone therapy (Barlow, 2014; Thompson et al., 2017)
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Bioidentical hormones may be synthesized from plant or animal sources, or completely chemically synthesized, and are offered as FDA-approved drug products or as preparations that have not undergone FDA approval. See Chapter 4 for an additional discussion on this topic.
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. As illustrated in Box 2 in Figure 8-1, clinicians can prescribe an FDAapproved BHT product for indications that are "off-label."6 In this situation, the prescriber can be informed by clinical guidance and data on the safety and efficacy for the FDA-approved labeled indications.
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b Other cBHT use Not aligned with evidence-based clinical guidance Safety and efficacy not known Box 4 FIGURE 8-1 Use of bioidentical hormone therapy. a This figure does not represent all possible uses of FDA-approved drug products or cBHT preparations.
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(See the section "Professional Guidance and Clinical Practice Guidelines for the Use of cBHT" for an additional discussion.) Purported Indications for the Use of cBHT The vast majority of FDA-approved BHT products have labeled indications related to treating moderate to severe vasomotor symptoms and vulvovaginal atrophy of menopause in women and testosterone deficiency or hypogonadism in men (Crandall, 2019; NLM, 2020; Shifren et al., 2019; see Table 8-1 for a list of labeled indications)
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180 THE CLINICAL UTILITY OF cBHT TABLE 8-1 Common Indications and Contraindications for FDA-Approved Bioidentical Hormone Therapy Products Bioidentical Hormone Brand Name Preparation Label Indications 17β-estradiol Estrace Pill Moderate to severe vasomotor symptoms; moderate to severe symptoms of vulvar and vaginal atrophy; hypoestrogenism due to hypogonadism, castration, or primary ovarian failure; prevention of osteoporosis 17β-estradiol Alora Patch Moderate to severe vasomotor symptoms; moderate to severe symptoms of vulvar and vaginal atrophy; hypoestrogenism due to hypogonadism, castration, or primary ovarian failure; prevention of osteoporosis 17β-estradiol Climara Patch Moderate to severe vasomotor symptoms; moderate to severe symptoms of vulvar and vaginal atrophy; hypoestrogenism due to hypogonadism, castration, or primary ovarian failure; prevention of osteoporosis 17β-estradiol Vivelle-Dot Patch Moderate to severe vasomotor symptoms; moderate to severe symptoms of vulvar and vaginal atrophy; hypoestrogenism due to hypogonadism, castration, or primary ovarian failure; prevention of osteoporosis 17β-estradiol Minivelle Patch Moderate to severe vasomotor symptoms; prevention of osteoporosis 17β-estradiol Menostar Patch Prevention of osteoporosis 17β-estradiol Estrogel Gel Moderate to severe vasomotor symptoms; moderate to severe symptoms of vulvar and vaginal atrophy
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arterial thromboembolic disease; Known hypersensitivity to product or its ingredients Undiagnosed vaginal bleeding; Known, suspected, or history of breast cancer; Known or suspected estrogen-dependent neoplasia; Active deep vein thrombosis, pulmonary embolism, or history of these conditions; Liver dysfunction or disease; Known or suspected pregnancy; Active or history of arterial thromboembolic disease; High risk of venous thrombosis or arterial thrombosis; Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders Undiagnosed vaginal bleeding; Known, suspected, or history of breast cancer; Known or suspected estrogen-dependent neoplasia; Active deep vein thrombosis, pulmonary embolism, or history of these conditions; Liver dysfunction or disease; Known or suspected pregnancy; History of arterial thromboembolic disease; Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders; Known hypersensitivity to product or its ingredients Undiagnosed vaginal bleeding; Known, suspected, or history of breast cancer; Known or suspected estrogen-dependent neoplasia; Active deep vein thrombosis, pulmonary embolism, or history of these conditions; Liver dysfunction or disease; Known or suspected pregnancy; History of arterial thromboembolic disease; Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders; Known hypersensitivity to product or its ingredients Undiagnosed vaginal bleeding; Known, suspected, or history of breast cancer; Known or suspected estrogen-dependent neoplasia; Active deep vein thrombosis, pulmonary embolism, or history of these conditions; Liver dysfunction or disease; Known or suspected pregnancy; History of arterial thromboembolic disease; Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders Undiagnosed vaginal bleeding; Known, suspected, or history of breast cancer; Known or suspected estrogen-dependent neoplasia; Active deep vein thrombosis, pulmonary embolism, or history of these conditions; Liver dysfunction or disease; Known or suspected pregnancy; History of arterial thromboembolic disease; Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders; Anaphylactic reaction or angioedema with product continued
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182 THE CLINICAL UTILITY OF cBHT TABLE 8-1 Continued Bioidentical Hormone Brand Name Preparation Label Indications 17β-estradiol Elestrin Gel Moderate to severe vasomotor symptoms 17β-estradiol Divigel Gel Moderate to severe vasomotor symptoms 17β-estradiol Estrace Vaginal Moderate to severe vulvar and cream vaginal atrophy due to menopause 17β-estradiol Estring Vaginal ring Moderate to severe vulvar and vaginal atrophy due to menopause 17β-estradiol Evamist Spray Moderate to severe vasomotor symptoms 17β-estradiol Imvexxy Vaginal Moderate to severe dyspareunia, tablet a symptom of vulvar and vaginal atrophy, due to menopause Estradiol Depo- Injection Moderate to severe vasomotor cypionate estradiol symptoms; hypoestrogenism due to hypogonadism
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THE USE OF cBHT 183 Contraindications Undiagnosed vaginal bleeding; Known, suspected, or history of breast cancer; Known or suspected estrogen-dependent neoplasia; Active deep vein thrombosis, pulmonary embolism, or history of these conditions; Liver dysfunction or disease; Known or suspected pregnancy; History of arterial thromboembolic disease; Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders; Anaphylactic reaction or angioedema with product Undiagnosed vaginal bleeding; Known, suspected, or history of breast cancer; Known or suspected estrogen-dependent neoplasia; Active deep vein thrombosis, pulmonary embolism, or history of these conditions; Liver dysfunction or disease; Known or suspected pregnancy; History of arterial thromboembolic disease; Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders; Known hypersensitivity to product or its ingredients; Anaphylactic reaction or angioedema with product Undiagnosed vaginal bleeding; Known, suspected, or history of breast cancer; Known or suspected estrogen-dependent neoplasia; Active deep vein thrombosis, pulmonary embolism, or history of these conditions; Liver dysfunction or disease; Known or suspected pregnancy; History of arterial thromboembolic disease; Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders; Anaphylactic reaction or angioedema with product Undiagnosed vaginal bleeding; Known, suspected, or history of breast cancer; Known or suspected estrogen-dependent neoplasia; Active deep vein thrombosis, pulmonary embolism, or history of these conditions; Liver dysfunction or disease; Known or suspected pregnancy; History of arterial thromboembolic disease; Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders; Known hypersensitivity to product or its ingredients; Anaphylactic reaction or angioedema with product Undiagnosed vaginal bleeding; Known, suspected, or history of breast cancer; Known or suspected estrogen-dependent neoplasia; Active deep vein thrombosis, pulmonary embolism, or history of these conditions; Liver dysfunction or disease; Known or suspected pregnancy; History of arterial thromboembolic disease; Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders; Anaphylactic reaction or angioedema with product Undiagnosed vaginal bleeding; Known, suspected, or history of breast cancer; Known or suspected estrogen-dependent neoplasia; Active deep vein thrombosis, pulmonary embolism, or history of these conditions; Liver dysfunction or disease; History of arterial thromboembolic disease; Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders; Anaphylactic reaction or angioedema with product Undiagnosed vaginal bleeding; Known, suspected, or history of breast cancer; Known or suspected estrogen-dependent neoplasia; Active deep vein thrombosis, pulmonary embolism, or history of these conditions; Liver dysfunction or disease; Known or suspected pregnancy; Recent (e.g., within the past year) arterial thromboembolic disease; Known hypersensitivity to product or its ingredients continued
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Micronized Endometrin Ovules To support embryo implantation progesterone and early pregnancy by supplementation of corpus luteal function as part of an assisted reproductive technology (ART) treatment program for infertile women 17β-estradiol Bijuva Pill Moderate to severe vasomotor and micronized symptoms due to menopause progesterone Testosterone Testim Gel Indicated for replacement therapy in males for conditions associated with symptoms of deficiency or absence of endogenous testosterone Testosterone Vogelxo Gel Indicated for replacement therapy in males for conditions associated with symptoms of deficiency or absence of endogenous testosterone Testosterone Androgel Gel Indicated for replacement therapy in males for conditions associated with symptoms of deficiency or absence of endogenous testosterone
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THE USE OF cBHT 185 Contraindications History of arterial thromboembolic disease; Undiagnosed abnormal genital bleeding; Known, suspected, or history of cancer of the breast; Active deep vein thrombosis, pulmonary embolism, or history of these conditions; Liver dysfunction or disease; Known or suspected pregnancy; History of arterial thromboembolic disease Undiagnosed vaginal bleeding; Liver dysfunction or disease; Known or suspected malignancy of the breast or genital organs; Missed abortion; Known sensitivity or hypersensitivity to product or its ingredients Undiagnosed vaginal bleeding; Liver dysfunction or disease; Known or suspected malignancy of the breast or genital organs; Missed abortion; Known sensitivity or hypersensitivity to product or its ingredients History of arterial thromboembolic disease; Known allergic reaction; Undiagnosed vaginal bleeding; Liver dysfunction or disease; History of arterial thromboembolic disease; Known or suspected malignancy of the breast or genital organs; Ectopic pregnancy or missed abortion; Known allergic reactions Undiagnosed vaginal bleeding; Known, suspected, or history of breast cancer; Known or suspected estrogen-dependent neoplasia; Active deep vein thrombosis, pulmonary embolism, or history of these conditions; Liver dysfunction or disease; Known or suspected pregnancy; History of arterial thromboembolic disease; Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders; Known hypersensitivity to product or its ingredients; Anaphylactic reaction or angioedema with product Carcinoma of the breast or known or suspected carcinoma of the prostate; Pregnancy or breastfeeding Carcinoma of the breast or known or suspected carcinoma of the prostate; Pregnancy or breastfeeding Carcinoma of the breast or known or suspected carcinoma of the prostate; Pregnancy or breastfeeding; Pregnant women need to be aware of the potential for transfer of testosterone from men continued
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, Loyd Allen, for a review of all cBHT-related articles published in the IJPC from 1997 to 2018. As summarized in a presentation to this committee on June 27, 2019, Allen noted that special populations using cBHT include patients who cannot tolerate certain components of FDA-approved drug products (e.g., lactose)
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THE USE OF cBHT 187 Contraindications Carcinoma of the breast or known or suspected carcinoma of the prostate; Pregnancy or breastfeeding Carcinoma of the breast or known or suspected carcinoma of the prostate; Pregnancy or breastfeeding Carcinoma of the breast or known or suspected carcinoma of the prostate; Pregnancy or breastfeeding Carcinoma of the breast or known or suspected carcinoma of the prostate; Pregnancy or breastfeeding Carcinoma of the breast or known or suspected carcinoma of the prostate; Pregnancy or breastfeeding Carcinoma of the breast or known or suspected carcinoma of the prostate; Pregnancy or breastfeeding; Known hypersensitivity to the drug; serious cardiac, hepatic, or renal disease Undiagnosed abnormal genital bleeding: Any postmenopausal woman with undiagnosed, persistent, or recurring genital bleeding should be evaluated to determine the cause of the bleeding before consideration of treatment alternate dosage strengths or forms (e.g., for those who have difficulty swallowing solids) , or need preparations to support treatment compliance (e.g., in cases where convenience or personal preference is important)
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In general, the collected statements expressed concerns regarding the quality, safety, and effectiveness of compounded preparations and cautioned against their use if FDA-approved BHT product options were available. In fact, in each of the professional guidance statements reviewed by the committee, FDA-approved BHT products were recommended as the first-line hormone therapy treatments (see Table 8-2 for relevant excerpts from clinical guidance)
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"Our AMA: (1) recognizes the term ‘bioidentical hormone' as a marketing term not grounded in science; use of the term ‘compounded hormone therapy' is preferred; (2)
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. In the absence of an Testosterone available approved product, if a compounded product is Therapy for needed, the compounding pharmacy should be compliant Women with purity of Active Pharmaceutical Ingredients (API)
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were minimal, and the committee could not identify any clinical guidance that outline a therapeutic need for a specific patient population to receive a specific cBHT formulations in lieu of FDA-approved BHT products. Furthermore, based on its review of peerreviewed literature and clinical guidance statements, the committee was
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See Chapter 5 for an additional discussion on the inadequate label requirements for cBHT preparations. Allergies to inactive components in FDA-approved BHT products are commonly expressed rationales for the use of compounded preparations, 11 It should be noted that medical associations, societies, and other relevant health organiza tions that issue clinical guidance are often supported, in part, by the pharmaceutical industry.
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. Female Sexual Dysfunction Currently, there are no available FDA-approved BHT products to treat the diagnostic classifications of FSD.15 In addition, after a review of the evidence, the committee could not identify any professional medical organiza tions with evidence-based clinical guidance that recommend use of cBHT for treating FSD.
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.16 cBHT preparations containing testosterone appear to be an increasingly popular option as a result of the limited number, dosage forms, and dosing options of FDAapproved drug products containing testosterone currently on the market (AMA, 2016; Clayton et al., 2018)
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Conclusion 8-1 Evidence-based clinical guidance recommends use of FDA-approved drug products for treatment of menopause and male hypogonadism. Some, but not all, guidelines reviewed acknowledge the potential for limited use of compounded bioidentical hormone therapy in specific medical circumstances, for example, patients with allergies to specific components of FDA-approved hormone therapy, or patients who require a dosage form not currently available as an FDA-approved drug product.
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Available through the National Academies Public Access File. 20 Testimony was collected from clinicians who self-identified as having a wide range of pro fessional credentials (e.g., M.D., D.O., registered nurse, nurse practitioner, physician assistant)
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. FIGURE 8-2 Age differentials in users of bioidentical hormone therapy: compounded formulations versus FDA-approved drug products.
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In 2015, 87,677 participants were specifically asked for the first time about their use of "bioidentical estrogen," "bioidentical progesterone," and testosterone. In coordination with NHS2 investigators, the committee was able to access data regarding the frequency of use of these bioidentical hormones in this study population (NHS, 2019)
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SOURCE: NHS, 2019. cBHT: Types and Amounts of Use To examine the common types and amounts of cBHT preparations used by patients, the committee gathered descriptive data on dispensed drugs purchased from 503B outsourcing facilities, as well as from information from NABP.
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From its 2016 to 2018 collection of pharmacy inspection application requests, NABP submitted a compiled list of the five most dispensed 25 FDA 2019 email from G Cosel to National Academies staff regarding aggregated volume output of products containing ingredients of interest to compounded bioidentical hormone therapy study.
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26 Although the application form specifically asked pharmacists to list their top compounded preparations, there were certain instances where it was not clear whether pharmacists accidently listed FDA-approved drug products. To address this issue in the analysis of the data, if the complete formulation listed was not found in FDA's list of available hormone therapy products, then formulation was counted in the total tally for compounded preparations.
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Furthermore, no data source exists to capture the use of cBHT by patients who pay out of pocket. Quantifiable data are needed to adequately inform understanding of use and trends, policy decisions related to the clinical utility of cBHT, and other influencing factors, such as financial incentives.27 27 See Chapter 3 for more information on cBHT formulations and conflicts of interest.
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FACTORS DRIVING THE USE OF cBHT While there is limited evidence-based support for the use of cBHT to treat menopausal symptoms, the available data suggest millions of patients use thousands of different cBHT formulations every day. Given this fact, the committee deemed it critical in its examination of clinical utility to explore potential factors influencing interest and use of these non-FDA-approved preparations.
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. For example, a 2017 study of 100 websites promoting or offering cBHT services or products identified through a Google search found that nearly TABLE 8-6 Published Statements and Professional Guidance on the Marketing of C ompounded Bioidentical Hormone Therapy Organization Name Year Concerns and Recommendations American 2016 "There have been some ethical and conflict of interest Medical issues associated with commercial wellness clinics and Association compounding pharmacies that prescribe and dispense CHT.
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. These medical clinics often promoted cBHT preparations as less risky than conventional hormone therapies, with 65 percent of their websites marketing cBHT as having either a lower risk of causing breast cancer risk or even being protective against breast cancer (Yuksel et al., 2017)
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SOURCE: NASEM, 2019c. Patient Perspectives The existing data on motivations for use come primarily from a few qualitative studies exploring women's reported reasons for seeking cBHT to treat their menopausal symptoms (Fishman et al., 2015; Thompson et al., 2017)
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. Beliefs in Safer, More "Natural" Hormone Therapy Alternatives Patients using cBHT have reported that being "natural" makes cBHT safer than conventional hormone therapy, safe when taken long term, and considered safe for use even for breast cancer survivors (Fishman et al., 2015)
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Mistrust in Health Care Institutions There are additional influences that "push" patients away from FDAapproved drug products. Over the past four decades, Gallup polling r evealed that confidence in almost all U.S.
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reported that overall out-of-pocket costs for cBHTs may be higher than those of noncompounded prescriptions. The average out-of-pocket cost reported for cBHTs was $88 in a 2017 survey, whereas the average price of FDA-approved postmenopausal hormone therapy prescriptions was $49 30 A 2019 PCCA national survey of 14 within-network pharmacies concluded that the m edian sales price of select cBHT was lower than the median sales prices of select FDAapproved BHT products (available through the National Academies Public Access File)
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Conclusion 8-3 Drivers of patient interest and use of compounded bioidentical hormone therapy (cBHT) may include, but are not limited to, unsubstantiated marketing claims of superior safety and effectiveness, boutique patient experience, financial costs, and the appeal of "natural" hormones and/or dosage forms.
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However, data suggest there may be millions of patients using cBHT, implying cBHT preparations are being prescribed for reasons outside of recognized therapeutic need. As noted in a 2018 National Academies report, research results that lack clear clinical utility may still have personal meaning to a patient or participant.
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2011. Bioidentical hormones: An evidence-based review for primary care pro viders.
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2019. Position statement: Compounded bioidentical hormone therapy.
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2019b. FDA submitted volume output of 503B facility products containing ingre dients of interest to compounded bioidentical hormone therapy study.
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2016. Compounded bioidentical hormones in endocrinology practice: An Endocrine Society scientific statement.
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2007. Bioidentical hormones: Sound science or bad medicine.
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