Menopause: The Journal of The North American Menopause Society Vol. 21, No. 12, pp. 1298/1300 DOI: 10.1097/gme.0000000000000376 * 2014 by The North American Menopause Society
NAMS PRACTICE PEARL What are the concerns about custom-compounded Bbioidentical[ hormone therapy? JoAnn V. Pinkerton, MD, NCMP
Unsubstantiated claims, lack of scientific safety and efficacy data, and lack of quality control surround customcompounded bioidentical hormone products. FDA-approved hormone therapy provides tested and regulated therapy without the risks of unregulated and untested custom preparations.
B
ioidentical hormones, a marketing term not recognized by the US Food and Drug Administration (FDA), refers to exogenous hormones biochemically similar to those produced within the body and includes 17A-estradiol (predominant estrogen before menopause), estrone (predominant estrogen after menopause), estriol (from placenta), progesterone (ovaries, placenta, and adrenal glands), testosterone (ovaries and adrenal glands), and their conjugates.1 These are derived from soy and yam precursors and must be chemically processed to make them able to be absorbed by the human body. Hormones that meet the definition of bioidentical are available as FDA-approved prescription therapies and include estradiol (oral, patch, gel, lotion, mist, and vaginal ring, cream, or tablet) and micronized progesterone (oral or vaginal). The FDA has not approved estriol. Custom-compounded bioidentical hormone products are prepared, assembled, and packaged according to a provider_s prescription into gels, creams, lotions, sublingual tablets, subdermal implants, suppositories, or troches.2 Transdermal therapies avoid the first-pass effect through the liver, and there is evidence that they have a lower clotting risk.3 Progesterone may have fewer negative effects than synthetic progestins on lipids, sleep and mood, and breast (density, tenderness, and cancer risk) when combined with estrogen. No FDA-approved testosterone therapy (bioidentical or otherwise) is available for women. LACK OF TESTING FOR EFFICACY, SAFETY, AND QUALITY CONTROL The major difference between FDA-approved hormone products meeting the definition of bioidentical versus customReleased August 6, 2014 From the University of Virginia Midlife Health Center, Charlottesville, VA.
1298
compounded products is that the former are regulated by FDA, tested for purity, potency, and efficacy, and sold with FDA-approved product information that includes boxed warnings. Efficacy and safety data, required for obtaining particular product indications, have been demonstrated in randomized, clinical trials with peer-reviewed published reports for FDA-approved bioidenticals but not for customcompounded products.4,5 No large, long-term studies have been done to determine the effectiveness, safety, or adverse effects of custom-compounded bioidentical hormones. In 2008, because of lack of scientific data on estriol, FDA stated that pharmacies should not compound drugs containing estriol unless the prescriber has a valid investigational new drug application.4 LACK OF BOXED WARNINGS Custom-compounded hormone products may not contain package labeling or the boxed warning about increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary embolism, and deep vein thrombosis that all FDAapproved estrogens must provide.6 LACK OF FDA OVERSIGHT OF COMPOUNDING PHARMACIES Custom-compounding pharmacies have not been closely regulated by FDA. There have been no requirements to test for efficacy, safety, quality, purity, or potency; to provide product information about proven benefits and risks; or to give proof of batch-to-batch consistency.4 Dosing and purity can vary substantially from batch to batch. In 2003, FDA examined 29 compounded pharmaceuticals and found that a third failed a standard quality test and nine had fewer active ingredients than the prescription. In 2012, MORE magazine sent 12 filled prescriptions of Tri-Est with progesterone to Flora Research Laboratories in Grants Pass, Oregon, which specializes in
Menopause, Vol. 21, No. 12, 2014
Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
NAMS PRACTICE PEARL
natural products research.7 Compared with the prescription labels, lower quantities of estriol were present. In 10 out of 12, estrone and estradiol had different doses than prescribed (58.4%-272.5% of estrone and 95.9%-259% of estradiol), with inadequate doses of progesterone in 11 out of 12 (60%-80%), potentially increasing the risk of endometrial cancer. Compounding pharmacies have traditionally fallen under the jurisdiction of state regulators. To date, only 188 out of 7,500 US compounding pharmacies have accreditation by the Pharmacy Compounding Accreditation Board, which requires compliance with strict regulations and periodic renewal (pcab.org lists accredited pharmacies). All drug producers are expected to follow federal Good Manufacturing Practice regulations, but compounded products are not well monitored for these standards.8 In 2012, the New England Compounding Center in Framingham, Massachusetts, was shut down after contaminated intrathecal steroids were linked to more than 750 cases of fungal meningitis or related illnesses and more than 64 deaths. In November of 2013, the Drug Quality and Security Act was passed. It clarifies the FDA_s regulatory authority over drug compounding. BOutsourcing pharmacies[ are allowed to sell products in bulk to hospitals and physician practices in the absence of individual prescriptions but must register with FDA, pay a fee, adhere to good manufacturing standards, subject themselves to routine inspections, and report adverse events. As of January 10, 2014, 11 US compounding pharmacies had registered with FDA under the new legislation.9 Unregistered pharmacies will continue to be regulated by state boards of pharmacy and allowed to compound a product in advance of receiving a prescription but not allowed to sell without a prescription. FDA can inspect unregistered pharmacies in response to a complaint but will need a court order to access records. FDA draft guidance10 available to compounding pharmacies stipulates potential violations if: The product is a Bfilthy, putrid, or decomposed substance, or [is] prepared, packed, or held under insanitary [sic] conditions whereby it may have been contaminated with filth or whereby it may have been rendered injurious to health.[ b. The drug is recognized in an official compendium (U.S. Pharmacopeial Convention [USP] or similar official pharmacopeia), its Bstrength must not differ from, and its quality or purity must not fall below, the standards set forth in the compendium, unless the difference is plainly stated on its label,[ and Bit must be packaged and labeled as prescribed in the compendium.[ c. BThe drug product_s labeling, advertising, and promotion [is] false or misleading.[ Compounding by a licensed pharmacist or licensed physician for an identified patient should be based on receipt of a valid prescription order with a notation that the compounded product is necessary for the identified patient or, in limited quantities, before the receipt of a valid prescription order for an individual patient if there have been prior valid prescription orders.10 a.
SALIVARY TESTING Salivary hormone-level testing to Btailor[ hormone therapy is not considered meaningful. Hormone levels in saliva vary within each woman depending on absorption, diurnal variation, the specific hormone being tested, and other variables. Salivary levels have not been shown to correlate for the purpose of efficacy, safety, or adjusting hormone therapy dose levels.2,5,6 MEDICO-LEGAL RISKS FOR PHYSICIANS Prescribers of compounded products may be personally exposed should there be an adverse event resulting from a product that neither the prescriber nor compounder can prove was the correct dose of the specific product and was free of contaminants. Possible consequences include the invalidation of their malpractice insurance, personal liability, and criminal prosecution.8 THE NORTH AMERICAN MENOPAUSE SOCIETY NAMS recommends well-tested, FDA-approved products over custom-compounded products for most women. NAMS does not recommend saliva testing to determine hormone levels.6 Custom-compounded products should be limited to patients who cannot tolerate an FDA-approved product, need a lower dose than commercially available, have allergic reactions to an ingredient found in the FDA-approved version, or for whom a provider decides that the compounded product best serves specific medical needs.6 There is no scientific evidence to support claims of increased efficacy or safety for Bindividualized[ estrogen or progesterone regimens prepared by compounding pharmacies over conventional FDA-approved hormone therapies.2 Transdermal therapies may have a lower risk of venous thromboembolism, but compounded transdermal products lack scientific testing. The menopause professional should assess the need for hormone therapy and provide adequate education about risks and benefits as well as the lack of quality control, scientific efficacy, and safety data regarding compounded hormone products. Financial disclosure/conflicts of interest: In the past 12 months, Dr. Pinkerton has served as consultant (fees to UVA) for Noven, Novo Nordisk, Shionogi, and Pfizer, research support for multicenter clinical trials (fees to UVA) from Bionovo, Depomed, Endoceutics, TherapeuticsMD and Pfizer, travel fees for consulting from Noven, Novo Nordisk, Shionogi, and Pfizer, and in kind editorial writing support from Noven, Shionogi, and Pfizer.
REFERENCES 1. The Endocrine Society. Position Statement: Bioidentical Hormones. www.endocrine.org/~/media/endosociety/Files/Advocacy%20and% 20Outreach/Position%20Statements/All/BH_Position_Statement_ final_10_25_06_w_Header.pdf. Accessed May 15, 2014. 2. US Food, Drug Administration. Bio-identicals: Sorting Myths from Facts. www.fda.gov/forconsumers/consumerupdates/ucm049311.htm. April 8, 2008. Accessed May 15, 2014. 3. Olie´ V, Canonico M, Scarabin PY. Risk of venous thrombosis with oral versus transdermal estrogen therapy among postmenopausal women. Curr Opin Hematol 2010;17:457-463. 4. US Food and Drug Administration. FDA takes action against compounded menopause hormone therapy drugs [press release]. January 9, 2008. Menopause, Vol. 21, No. 12, 2014
Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
1299
NAMS PRACTICE PEARL www.fda.gov/newsevents/newsroom/pressannouncements/2008/ ucm116832.htm. Last updated April 16, 2013. Accessed May 15, 2014. 5. Boothby LA, Doering PL. Bioidentical hormone therapy: a panacea that lacks supportive evidence. Curr Opin Obstet Gynecol 2008;20: 400-407. 6. North American Menopause Society. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause 2012;19:257-271. 7. Ramin CJ. The hormone hoax thousands fall for. More. October 2013. www.more.com/health/wellness/hormone-hoax-thousands-fall-0. Accessed May 15, 2014.
8. Sellers S, Utian WH. Pharmacy compounding primer for physicians: prescriber beware. Drugs 2012;72:2043-2050. 9. Clarke T. US compounding pharmacies start to register with FDA [news release]. Reuters. January 9, 2014. www.reuters.com/article/2014/01/ 10/us-compounding- pharmacies-fda-idUSBREA0903120140110. Accessed May 15, 2014. 10. US Food and Drug Administration. Draft Guidance; Pharmacy Compounding of Human Drug Products Under Section 503A of the Federal Food, Drug, and Cosmetic Act. December 2013. ww.fda.gov/ downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ ucm377052.pdf. Accessed May 15, 2014.
This Practice Pearl, developed by the author provides practical information on current controversial topics of clinical interest. It is not an official position of The North American Menopause Society (NAMS). Clinicians must always take into consideration the individual patient along with any new data published since the publication of this statement on August 6, 2014. Made possible by donations to the NAMS Education & Research Fund.
1300
Menopause, Vol. 21, No. 12, 2014
* 2014 The North American Menopause Society
Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
NAMS PRACTICE PEARL What are the concerns about custom-compounded Bbioidentical[ hormone therapy? JoAnn V. Pinkerton, MD, NCMP
Unsubstantiated claims, lack of scientific safety and efficacy data, and lack of quality control surround customcompounded bioidentical hormone products. FDA-approved hormone therapy provides tested and regulated therapy without the risks of unregulated and untested custom preparations.
B
ioidentical hormones, a marketing term not recognized by the US Food and Drug Administration (FDA), refers to exogenous hormones biochemically similar to those produced within the body and includes 17A-estradiol (predominant estrogen before menopause), estrone (predominant estrogen after menopause), estriol (from placenta), progesterone (ovaries, placenta, and adrenal glands), testosterone (ovaries and adrenal glands), and their conjugates.1 These are derived from soy and yam precursors and must be chemically processed to make them able to be absorbed by the human body. Hormones that meet the definition of bioidentical are available as FDA-approved prescription therapies and include estradiol (oral, patch, gel, lotion, mist, and vaginal ring, cream, or tablet) and micronized progesterone (oral or vaginal). The FDA has not approved estriol. Custom-compounded bioidentical hormone products are prepared, assembled, and packaged according to a provider_s prescription into gels, creams, lotions, sublingual tablets, subdermal implants, suppositories, or troches.2 Transdermal therapies avoid the first-pass effect through the liver, and there is evidence that they have a lower clotting risk.3 Progesterone may have fewer negative effects than synthetic progestins on lipids, sleep and mood, and breast (density, tenderness, and cancer risk) when combined with estrogen. No FDA-approved testosterone therapy (bioidentical or otherwise) is available for women. LACK OF TESTING FOR EFFICACY, SAFETY, AND QUALITY CONTROL The major difference between FDA-approved hormone products meeting the definition of bioidentical versus customReleased August 6, 2014 From the University of Virginia Midlife Health Center, Charlottesville, VA.
1298
compounded products is that the former are regulated by FDA, tested for purity, potency, and efficacy, and sold with FDA-approved product information that includes boxed warnings. Efficacy and safety data, required for obtaining particular product indications, have been demonstrated in randomized, clinical trials with peer-reviewed published reports for FDA-approved bioidenticals but not for customcompounded products.4,5 No large, long-term studies have been done to determine the effectiveness, safety, or adverse effects of custom-compounded bioidentical hormones. In 2008, because of lack of scientific data on estriol, FDA stated that pharmacies should not compound drugs containing estriol unless the prescriber has a valid investigational new drug application.4 LACK OF BOXED WARNINGS Custom-compounded hormone products may not contain package labeling or the boxed warning about increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary embolism, and deep vein thrombosis that all FDAapproved estrogens must provide.6 LACK OF FDA OVERSIGHT OF COMPOUNDING PHARMACIES Custom-compounding pharmacies have not been closely regulated by FDA. There have been no requirements to test for efficacy, safety, quality, purity, or potency; to provide product information about proven benefits and risks; or to give proof of batch-to-batch consistency.4 Dosing and purity can vary substantially from batch to batch. In 2003, FDA examined 29 compounded pharmaceuticals and found that a third failed a standard quality test and nine had fewer active ingredients than the prescription. In 2012, MORE magazine sent 12 filled prescriptions of Tri-Est with progesterone to Flora Research Laboratories in Grants Pass, Oregon, which specializes in
Menopause, Vol. 21, No. 12, 2014
Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
NAMS PRACTICE PEARL
natural products research.7 Compared with the prescription labels, lower quantities of estriol were present. In 10 out of 12, estrone and estradiol had different doses than prescribed (58.4%-272.5% of estrone and 95.9%-259% of estradiol), with inadequate doses of progesterone in 11 out of 12 (60%-80%), potentially increasing the risk of endometrial cancer. Compounding pharmacies have traditionally fallen under the jurisdiction of state regulators. To date, only 188 out of 7,500 US compounding pharmacies have accreditation by the Pharmacy Compounding Accreditation Board, which requires compliance with strict regulations and periodic renewal (pcab.org lists accredited pharmacies). All drug producers are expected to follow federal Good Manufacturing Practice regulations, but compounded products are not well monitored for these standards.8 In 2012, the New England Compounding Center in Framingham, Massachusetts, was shut down after contaminated intrathecal steroids were linked to more than 750 cases of fungal meningitis or related illnesses and more than 64 deaths. In November of 2013, the Drug Quality and Security Act was passed. It clarifies the FDA_s regulatory authority over drug compounding. BOutsourcing pharmacies[ are allowed to sell products in bulk to hospitals and physician practices in the absence of individual prescriptions but must register with FDA, pay a fee, adhere to good manufacturing standards, subject themselves to routine inspections, and report adverse events. As of January 10, 2014, 11 US compounding pharmacies had registered with FDA under the new legislation.9 Unregistered pharmacies will continue to be regulated by state boards of pharmacy and allowed to compound a product in advance of receiving a prescription but not allowed to sell without a prescription. FDA can inspect unregistered pharmacies in response to a complaint but will need a court order to access records. FDA draft guidance10 available to compounding pharmacies stipulates potential violations if: The product is a Bfilthy, putrid, or decomposed substance, or [is] prepared, packed, or held under insanitary [sic] conditions whereby it may have been contaminated with filth or whereby it may have been rendered injurious to health.[ b. The drug is recognized in an official compendium (U.S. Pharmacopeial Convention [USP] or similar official pharmacopeia), its Bstrength must not differ from, and its quality or purity must not fall below, the standards set forth in the compendium, unless the difference is plainly stated on its label,[ and Bit must be packaged and labeled as prescribed in the compendium.[ c. BThe drug product_s labeling, advertising, and promotion [is] false or misleading.[ Compounding by a licensed pharmacist or licensed physician for an identified patient should be based on receipt of a valid prescription order with a notation that the compounded product is necessary for the identified patient or, in limited quantities, before the receipt of a valid prescription order for an individual patient if there have been prior valid prescription orders.10 a.
SALIVARY TESTING Salivary hormone-level testing to Btailor[ hormone therapy is not considered meaningful. Hormone levels in saliva vary within each woman depending on absorption, diurnal variation, the specific hormone being tested, and other variables. Salivary levels have not been shown to correlate for the purpose of efficacy, safety, or adjusting hormone therapy dose levels.2,5,6 MEDICO-LEGAL RISKS FOR PHYSICIANS Prescribers of compounded products may be personally exposed should there be an adverse event resulting from a product that neither the prescriber nor compounder can prove was the correct dose of the specific product and was free of contaminants. Possible consequences include the invalidation of their malpractice insurance, personal liability, and criminal prosecution.8 THE NORTH AMERICAN MENOPAUSE SOCIETY NAMS recommends well-tested, FDA-approved products over custom-compounded products for most women. NAMS does not recommend saliva testing to determine hormone levels.6 Custom-compounded products should be limited to patients who cannot tolerate an FDA-approved product, need a lower dose than commercially available, have allergic reactions to an ingredient found in the FDA-approved version, or for whom a provider decides that the compounded product best serves specific medical needs.6 There is no scientific evidence to support claims of increased efficacy or safety for Bindividualized[ estrogen or progesterone regimens prepared by compounding pharmacies over conventional FDA-approved hormone therapies.2 Transdermal therapies may have a lower risk of venous thromboembolism, but compounded transdermal products lack scientific testing. The menopause professional should assess the need for hormone therapy and provide adequate education about risks and benefits as well as the lack of quality control, scientific efficacy, and safety data regarding compounded hormone products. Financial disclosure/conflicts of interest: In the past 12 months, Dr. Pinkerton has served as consultant (fees to UVA) for Noven, Novo Nordisk, Shionogi, and Pfizer, research support for multicenter clinical trials (fees to UVA) from Bionovo, Depomed, Endoceutics, TherapeuticsMD and Pfizer, travel fees for consulting from Noven, Novo Nordisk, Shionogi, and Pfizer, and in kind editorial writing support from Noven, Shionogi, and Pfizer.
REFERENCES 1. The Endocrine Society. Position Statement: Bioidentical Hormones. www.endocrine.org/~/media/endosociety/Files/Advocacy%20and% 20Outreach/Position%20Statements/All/BH_Position_Statement_ final_10_25_06_w_Header.pdf. Accessed May 15, 2014. 2. US Food, Drug Administration. Bio-identicals: Sorting Myths from Facts. www.fda.gov/forconsumers/consumerupdates/ucm049311.htm. April 8, 2008. Accessed May 15, 2014. 3. Olie´ V, Canonico M, Scarabin PY. Risk of venous thrombosis with oral versus transdermal estrogen therapy among postmenopausal women. Curr Opin Hematol 2010;17:457-463. 4. US Food and Drug Administration. FDA takes action against compounded menopause hormone therapy drugs [press release]. January 9, 2008. Menopause, Vol. 21, No. 12, 2014
Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
1299
NAMS PRACTICE PEARL www.fda.gov/newsevents/newsroom/pressannouncements/2008/ ucm116832.htm. Last updated April 16, 2013. Accessed May 15, 2014. 5. Boothby LA, Doering PL. Bioidentical hormone therapy: a panacea that lacks supportive evidence. Curr Opin Obstet Gynecol 2008;20: 400-407. 6. North American Menopause Society. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause 2012;19:257-271. 7. Ramin CJ. The hormone hoax thousands fall for. More. October 2013. www.more.com/health/wellness/hormone-hoax-thousands-fall-0. Accessed May 15, 2014.
8. Sellers S, Utian WH. Pharmacy compounding primer for physicians: prescriber beware. Drugs 2012;72:2043-2050. 9. Clarke T. US compounding pharmacies start to register with FDA [news release]. Reuters. January 9, 2014. www.reuters.com/article/2014/01/ 10/us-compounding- pharmacies-fda-idUSBREA0903120140110. Accessed May 15, 2014. 10. US Food and Drug Administration. Draft Guidance; Pharmacy Compounding of Human Drug Products Under Section 503A of the Federal Food, Drug, and Cosmetic Act. December 2013. ww.fda.gov/ downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ ucm377052.pdf. Accessed May 15, 2014.
This Practice Pearl, developed by the author provides practical information on current controversial topics of clinical interest. It is not an official position of The North American Menopause Society (NAMS). Clinicians must always take into consideration the individual patient along with any new data published since the publication of this statement on August 6, 2014. Made possible by donations to the NAMS Education & Research Fund.
1300
Menopause, Vol. 21, No. 12, 2014
* 2014 The North American Menopause Society
Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
