Think Twice Before Prescribing Custom-Compounded Bioidentical Hormone Therapy

The Increase in Custom-Compounded Bioidentical Hormone Therapy

Following the release of the Women's Health Initiative's initial findings of increased risk of heart disease, breast cancer, stroke, gallstones, dementia and blood clots, women became concerned about continuing oral conjugated estrogen 0.625/medroxyprogesterone 2.5 mg. As use of approved hormone therapies (HT) sank, primarily due to fear, use of custom-compounded hormone “bioidentical” therapies (CBHT) rose to fill the void, buoyed primarily by misleading claims from marketers and famous figures about CBHT's safety and effectiveness. ^1,2 Some women use CBHT instead of HT approved by the US Food and Drug Administration (FDA) for medical reasons—they might be sensitive to one of the approved drugs' ingredients or unable to take the medication as approved. For these women and for others who cannot use a particular FDA-approved product, pharmacies that offer traditional compounding are indispensible. ³ However, the long-standing absence of federal restrictions on advertising for compounded drugs has contributed to mistaken beliefs that CBHT is safer than FDA-approved pharmaceutical HT and that estriol (the estrogen used in combinations such as TriEst) has been shown to prevent breast cancer. ^4,5,6

The Lack of Safety, Efficacy, Monitoring or Regulation by the FDA of Custom-Compounded BHT

During the rapid increase in custom-compounding of BHT, federal law delegated most of the responsibility for overseeing compounding pharmacies to state pharmacy boards, and the FDA provided minimal monitoring. In most states, the budget allocated to the pharmacy board has been insufficient to regulate the pharmacies closely, and state law limited the boards' enforcement authority. Responding to a citizen's petition sponsored by Wyeth, ⁷ the FDA sent warning letters ⁸ in 2008 to seven pharmacies cautioning them about making misleading claims unsupported by medical evidence and advising them that products containing estriol, which is not FDA-approved, were considered experimental medications and needed an investigational new drug application (IND) to continue being sold. The FDA has never required data on these hormone products from randomized, double-blind clinical trials, so no such studies have ever been performed. ^4,5,6 In addition, no pharmacokinetic data are available for these hormone products. Although evidence is growing that FDA-approved bioidentical transdermal products are safe and effective, with potentially less risk of blood clots or stroke, the data for the FDA-approved products may not apply to compounded transdermal hormones, which have never been tested. ^9,10

As Davis et al. ¹⁰ point out in their review of CBHT, there is a paucity of randomized clinical trial data to support the safety or efficacy of these therapies. Some risks have also been reported, including an increased risk of endometrial cancer. Most of the clinical studies that have been published were typically small, were not randomized or double-blinded, and suffered from poor design (e.g., combined endpoints for women using different doses, delivery methods, or even hormones). More concerning and largely unrecognized is that, in addition to lacking scientific data on safety or efficacy, custom-compounded drugs have risks unique to the compounding process. Analytic evaluation has revealed significant variances between the amount of hormone prescribed and the amount present in the compounded products, which could lead to possible overdosing or underdosing of one of the therapy's components. ^11,12 The resultant hormonal imbalance might increase a user's risk of cancer or blood clots. ¹²

Demonstration of Risk of Compounded Therapies

The lack of FDA oversight for approval, monitoring, and regulating CBHT products has given rise to concerns about safety and efficacy, potential adverse events, consistency of drugs batch-to-batch or within a batch, sterility, or the presence of contaminants. The risk from products distributed by compounding pharmacies was unfortunately most clearly shown when contaminated intrathecal steroids from the New England Compounding Center in Framingham, Massachusetts—which was shut down in 2012—were linked to more than 750 cases of fungal meningitis and associated illnesses and at least 64 deaths. ¹³

Drug Quality and Security Act (DQSA)

In November of 2013, Congress passed the Drug Quality and Security Act (DQSA), ^14,15 which clarifies the FDA's authority to enforce provisions of the Federal Food, Drug, and Cosmetic Act (FFDCA) that apply to pharmacy compounding. Basically, the DQSA differentiates between two types of compounding pharmacies. One is “outsourcing pharmacies,” which have the option of paying a fee to voluntarily register with the FDA so that they can sell compounded sterile drugs in bulk to hospitals or practices without having to obtain a prescription or file for FDA approval of their products. Registered outsourcing pharmacies must agree to observe Current Good Manufacturing Practices, submit to routine inspections, and report adverse events to the FDA. If a compounding pharmacy that sells sterile drugs in bulk declines to register as an outsourcing facility, the law requires the pharmacy to follow all provisions of the FFDCA that apply to manufacturers of conventional drugs. The new regulations specify that drugs should be packaged according to monograph with a label that accurately reports strength, quality, purity, and expiration.

Traditional compounding pharmacies will continue to be regulated as before by the state pharmacy boards. They will be allowed to compound drugs in advance of a prescription but are not allowed to sell them without a prescription. The FDA has the right to inspect unregistered pharmacies but must often obtain a court order to access records. In short, compounding is allowable by a licensed pharmacist or physician based on receipt of a valid prescription order or in limited quantities before receipt if the compounder had previously received valid prescription orders for an individual.

Who Should Be Candidates for CBHT?

Recommendations ^12,16,17 from national organizations providing care for women, including ACOG, NAMS, Endocrine Society and American Society of Reproductive Medicine, are in agreement that evidence is lacking to support claims by compounders that CBHT is safer than FDA-approved products. FDA-approved products, which have been tested in large randomized clinical trials and include an appropriate label (package insert), are recommended over custom-compounded products for most women. Salivary testing has limitations due to intra- and inter-individual variability ¹⁸ and is not recommended by these organizations for determining or following dosing decisions.

According to NAMS, ^16,19 providers should consider CBHT only for those women who cannot take an FDA-approved product due to intolerance or allergy (such as a peanut allergy because the FDA-approved micronized progesterone is in peanut oil), for women who need a lower dose or a different dosing regimen than FDA-approved commercially available products, or for a woman whose provider has decided that a compounded product best serves her specific medical needs.

What About Risks to Prescribers?

Dr. Sellers and Utian ²⁰ discuss the potential medicolegal risks for those who prescribe CBHT, even when done at patient or pharmacy request. They suggest that if an adverse event occurs due to incorrect dosing or contaminants associated with the compounding process, consequences could include loss of malpractice insurance, personal liability, and risk of criminal prosecution.

Summary

FDA-approved hormone therapy is recommended over CBHT unless a medical condition exists that contraindicates use of an FDA-approved therapy. ^12,16,17 Prescribers should remember that CBHT has not been adequately tested for efficacy, safety, quality, purity, or potency and that it should be considered to have similar risks to FDA-approved HT, along with additional risks due to the compounding process. To date, there has been no requirement for compounders to include a “label” (package insert) providing information about proven benefits and risks, contraindications, or warnings; thus, women may not recognize that the drug they are receiving is not FDA-approved or monitored. Other concerns include the absence of any requirement for compounders to provide proof of batch-to-batch or within-batch consistency or even to identify specific batch numbers. For clinicians who elect to prescribe CBHT, it is imperative to recognize that there are inadequate data supporting their use and that concerns about efficacy and safety, including the unique risks raised by the compounding process and lack of FDA monitoring, may increase medicolegal risks. ²⁰