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5 Compounded Bioidentical Hormone Preparations
Pages 91-116

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From page 91...
... preparations, including a description of their common formulations (e.g., common active and inactive ingredients) , formulation methods, quality testing, and labeling.
From page 92...
... That is, the content and quality of the final preparation depends completely on what is described in the Master Formulation Record (MFR) as chosen or described by the compounder.3,4 Compounder-specific factors that may influence quality and performance of the final preparation include the choice of active and inactive ingredients, ingredient testing, available compounding equipment, compounder skill, quality systems, facility cleanliness, and environmental controls.
From page 93...
... As a result, and as presented at the study's open session meetings, dispensed cBHT preparations often do not include the boxed warnings, warnings, contraindications, and detailed instructions for use similar to those included with FDA-approved hormone product labeling, despite containing the same active ingredients (NASEM, 2019c)
From page 94...
... . TABLE 5-1 FDA-Approved Drug Products and Availability of Medication Guides and Boxed Warnings Hormone Medication Guides Boxed Warnings Estradiol No Yes Progesterone No NA Testosterone Yes Yes NOTE: NA = no applicable boxed warning for this active ingredient.
From page 95...
... TYPES OF cBHT PREPARATIONS A wide variety of cBHT dosage forms are dispensed to patients, and because of a lack of registries and surveillance of use, it is difficult to obtain specific estimates for the number of available forms of cBHT preparations. To begin to describe the breadth of cBHT preparations dispensed by compounders, the committee found it necessary to compile its own list of cBHT preparations, drawing on available resources.9 This list presents only a small sample of the universe of cBHT preparations and at best provides a snapshot and limited description of available cBHT preparations.
From page 96...
... . Of the 10 hormone ingredients of focus for this report, all are available in cBHT preparations except for estradiol cypionate.11 Table 5-3 provides a summarized list of the different dosage forms available for single active ingredient cBHT preparations, as identified by the committee in its review, and compares them to available dosage forms of FDA-approved single a ­ ctive ingredient BHT products.
From page 97...
... Nasal Gel, metered Drop Spray Solution Suspension Rectal No FDA-approved option Enema  • Gel  • Suspension  • Emulsion Implant Pellet Pellet NOTE: The classification of dosage forms available in FDA-approved products has been adapted from the original table submitted by Reed Smith LLP to mirror the terminology used in FDA's Orange Book. SOURCE: Reed Smith LLP, 2019.
From page 98...
... SOURCE: FDA, 2020b. Available Doses For each of the dosage forms listed in Table 5-3, the compounding process generates preparations of varying strengths, adding to the number of total possible cBHT preparations available for use.
From page 99...
... , cBHT preparation adverse event reports (FDA, 2018a, 2020a) , information provided by compounding practitioners (see the National Academies Public Access File)
From page 100...
... This includes the wide array of different dosage forms, single active ingredient preparations, multiple active ingredient preparations, and an extensive range of different active ingredient doses and dose combinations. Multihormone cBHT Preparations Part of the appeal of compounding bioidentical hormones is that multiple hormones can be combined into a single dosage form that does not exist in a single FDA-approved drug product.
From page 101...
... While FDA does not offer guidance on the development of fixed dose combination drug products, aspects of the agency's guidance on other combined products may offer insight into FDA's thinking on combination drug products. FDA recommends that product de velopers consider and evaluate the potential for interactions between components of the combination product.
From page 102...
... cBHT ACTIVE INGREDIENTS To prepare a cBHT formulation, the compounder must either purchase the pure active ingredient from a wholesaler or obtain the active ingredient from a suitable FDA-approved drug product, should one exist.16 The pure ingredient is referred to as the API or bulk drug substance. FDA-approved drug products are required to use APIs that have been well characterized within an application for approval or in a Drug Master File (DMF)
From page 103...
... BDDCS Monograph Dehydroepiandrosterone 0.0635 NR No Estradiol 0.0036 1 Yes Estradiol cypionate NA NA Yes Estriol 0.02734 NR Yes Estrone 0.03 NR Yes Pregnenolone 0.00706 NR No Progesterone 0.00881 2 Yes Testosterone 0.0234 2 Yes Testosterone cypionate NA NA Yes Testosterone propionate NA NA Yes NOTE: BDDCS = Biopharmaceutics Drug Disposition Classification System; Class 1 = high solubility; high permeability; rapid dissolution; Class 2 = low solubility; high ­ ermeability; p NA = used in only injection products; NR = not reported; USP = United States Pharmacopeia. SOURCES: Committee generated, using data from Benet et al., 2011, and NLM, 2020b.
From page 104...
... In contrast, 503B outsourcing facilities and FDA-approved drug manufacturers
From page 105...
... For comparison, Box 5-4 lists the 10 inactive ingredients incorporated into Estrace Cream, which are all required for prolonged product stability. In contrast, 503A compounding pharmacies are not required to demonstrate that APIs are stable in formulations for the life (i.e., expiry date or beyond-use date)
From page 106...
... . 21  As discussed in Chapters 2 and 8, it is difficult to secure quantitative data on the prescrip tion rates and dispensing practices for specific cBHT formulations, doses, and dosage forms; however, available data suggest that Bi-est and Tri-est, available in varying amounts and d ­ osage forms, are commonly compounded preparations (IJPC, 2018; NABP, 2019)
From page 107...
... and inactive ingredients are mixed together. As pellets slowly dissolve over time, and thereby slowly release hormone(s)
From page 108...
... . There is also evidence of compounding pharmacies substituting inactive ingredients into pellet products (e.g., a cholesterol base for a steric acid base)
From page 109...
... . 25  See Drug Products That Present Demonstrable Difficulties for Compounding Under the Federal Food, Drug, and Cosmetic Act; Establishment of a Public Docket.
From page 110...
... . In contrast, compounded preparations made at 503B outsourcing facilities are required to list inactive ingredients directly on the label, and given FDA's increased oversight role 26  SeeSection 503B(a)
From page 111...
... TABLE 5-5 Inactive Ingredients in Estrace Cream and Their Function Ingredient Purpose Water Solvent Propylene glycol Humectant; preservative; solvent or cosolvent Stearyl alcohol Stiffening agent; emollient; weak emulsifying agent White ceresin wax Stiffening agent Mono and diglycerides Emulsifier; stabilizer; emollient; plasticizer Hypromellose Gelling agent Sodium lauryl sulfate Emulsifier; solubilizer Methylparaben Preservative Edetate disodium Chelating agent; preservative Tertiary-butylhydroquinone Antioxidant of 503B facilities, the agency would likely detect noncompliance with this requirement (see Box 5-4) .29 Some compounding suppliers offer premixed commercial bases (solu­ tions, creams, semisolids)
From page 112...
... In these cases, an estradiol cream preparation purchased from one compounding pharmacy may have different inactive ingredients than a product with the same name purchased from a second compounding pharmacy. Differences in inactive ingredients can affect the availability and absorption of cBHT active ingredients, given their low solubility and high metabolism (Panakanti and Narang, 2012)
From page 113...
... In addition, cBHT active dose ranges are wider, both lower and higher than corresponding bioidentical FDA-approved drug products, and inactive ingredients (e.g., excipients) can be difficult to identify, creating concerns about cBHT safety and efficacy.
From page 114...
... Cosel to National Academies staff regarding aggregated volume output of products containing ingredients of interest to compounded bioidentical hormone therapy study. May 30, 2020 (available through the National Academies Public Access File)
From page 115...
... 2019. Comparison chart of 503A and 503B dosage forms, provided to the com mittee by Reed Smith LLP on behalf of a client, a coalition of six compounding facilities.
From page 116...
... 2014. Strength and stability testing for compounded preparations.


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