DUAVEE, Hot Flashes and Bone Health

Hot flashes are part of the natural process of menopause, and many women can manage them without resorting to drugs. When medication is needed, women often have turned to standard hormone replacement therapies that are effective at preventing hot flashes and maintaining bone health, but the treatments do so at the expense of serious health risks.

A combination of conjugated estrogens plus bazedoxifene (DUAVEE) was approved by the Food and Drug Administration (FDA) in October 2013 as a new alternative treatment for moderate to severe hot flashes and bone health.[1] Because the drug is less effective than the current standard treatments and its safety is uncertain, Public Citizen’s Health Research Group recommends that patients not use this drug for seven years.

The search for a safer pill for hot flashes

Hot flashes are a temporary sensation of warmth, often with flushing and sweating, caused by the natural hormonal changes of menopause, the time when women’s menstrual periods stop and estrogen production decreases. Many women are able to manage hot flashes using lifestyle-related strategies, such as keeping the core body temperature cool and getting regular exercise. When these methods prove ineffective and symptoms are debilitating, the mainstay of treatment is hormone replacement therapy (HRT), either in the form of estrogen alone (ALORA, CENESTIN, CLIMARA, DELESTROGEN, DIVIGEL, ELESTRIN, ENJUVIA, ESTRACE, ESTRADERM, ESTRASORB, ESTROGEL, EVAMIST, FEMTRACE, MENEST, PREMARIN, VIVELLE, VIVELLE-DOT) or estrogen plus a progestin, which can be taken either separately or together as a combined HRT product (ACTIVELLA, ANGELIQ, CLIMARAPRO, COMBIPATCH, FEMHRT, PREMPHASE, PREMPRO).[2]

HRT is effective in preventing hot flashes and also in increasing bone density to prevent osteoporosis.[3] But it carries serious side effects: Estrogen-only HRT causes endometrial cancer, meaning it should not be used in women with an intact uterus,[4] and also increases the risk of stroke, blood clotting in the legs, gallbladder disease and dementia.[5] The progestin in combination HRT counteracts estrogen’s effects on the uterus, reducing the risk of endometrial cancer,[6] but the drug still carries all of estrogen’s other risks, plus the increased risk of breast cancer.[7]

Because of these risks, pharmaceutical companies have long searched for a better treatment that would behave like estrogen in fighting hot flashes and increasing bone density, but would avoid estrogen’s most serious risks. Unfortunately, so far, no drug has fit this perfect model.

Bazedoxifene fails to work for osteoporosis

DUAVEE combines a new active ingredient, bazedoxifene, with estrogen in an attempt to offer a new HRT alternative for treating hot flashes and increasing bone density. Bazedoxifene was first developed as a stand- alone drug by Wyeth Pharmaceuticals to treat osteoporosis.[8] The medication belongs to a class of drugs known as selective estrogen receptor modulators, drugs that behave like estrogen in some parts of the body but block its effects in other parts.[9]

Like estrogen, bazedoxifene alone increases bone density.[10] But in clinical testing, bazedoxifene proved ineffective in preventing nonvertebral fractures, a category that includes hip fractures, the most harmful type of fracture.[11] The drug also caused a dramatic increase in the rate of blood clotting in the legs, higher than the rates seen with HRT.[12] In part because of these concerns, the FDA in 2007 declined to approve Wyeth’s application to market bazedoxifene as a stand-alone pill.[13]

Can the whole be safer than its parts?

Undaunted, Wyeth tried a new approach, combining bazedoxifene with estrogen to form DUAVEE. While bazedoxifene alone did not prevent hot flashes — in fact, it caused more of them[14] — it seemed to have the potential to combat estrogen’s cancer-causing effects in the uterus.[15],[16] This meant that the drug could potentially be combined with estrogen to create an alternative to traditional combination HRT.

Wyeth tested DUAVEE in five controlled clinical trials.[17] Company-funded reviews presenting the results of these trials claimed that DUAVEE reduces hot flashes; strengthens bones; and does not cause breast cancer, endometrial cancer or blood clots.[18],[19] In short, DUAVEE appears as if it were the perfect drug to replace existing combination HRT products.

Missing trial information and other problems

FDA reviewers were less enthusiastic, and agency review documents describe clinical trials plagued with problems. Establishing an appropriate dose and formulation for the combination pill proved especially challenging.[20] Too small a dose of bazedoxifene would not block estrogen’s effects in the uterus, leading to early endometrial abnormalities that may progress to cancer.[21] Too large a dose undermined estrogen’s effectiveness in reducing hot flashes.[22]

The dose and formulation that the FDA eventually approved are not as effective in treating hot flashes or increasing bone mass as existing combined HRT drugs.[23] Of further concern, women whose bodies process bazedoxifene especially quickly may be at a higher risk of endometrial cancer.[24]

The Wyeth trials also suffered from data quality issues. Natural disasters, clerical errors and various other apparently random events led to the disappearance of important documents for close to 10 percent of subjects in two of the key clinical trials.[25] Such elevated rates of missing information are far higher than those generally seen by the FDA.[26]

Wyeth also made much-higher-than-normal payments to researchers involved in DUAVEE’s development.[27] The company reported to the FDA that half the researchers in the DUAVEE development program stated a financial conflict of interest, with four reporting payments of over half a million dollars each.[28] Such high payments may have led researchers to bias the study results in favor of DUAVEE, intentionally or unintentionally.[29]

Important data also was missing when it came to assessing cancer risk. Key data was missing for nearly 20 percent of patients in the most important clinical trial assessing breast cancer risk.[30] And while clinical tests of DUAVEE did not provide evidence of an increased risk of endometrial cancer or breast cancer at the approved dose, the trials assessing this risk were too small to detect differences in rates of actual cancer cases and instead relied mainly on measurements of breast density and other early risk factors for cancer.[31]

But the biggest potential problem with DUAVEE was the lack of information on blood clotting risk. In previous large randomized, controlled trials, DUAVEE’s two active ingredients each increased the risk of blood clots when used alone.[32],[33] Surprisingly, after completing five large clinical trials of DUAVEE enrolling close to 10,000 subjects, Wyeth reported only 10 cases of blood clotting in the legs and six cases of blood clotting in the brain (stroke).[34] The rates of these adverse events were unusually low, even in the control groups that received a placebo.[35]

Wyeth employees have argued that subjects in these trials were simply very young and healthy, and therefore not prone to blood clots. Yet another explanation is that some of the blood clots were not reported. Regardless of the reason, the fact that there were so few blood clots means that it is impossible to know DUAVEE’s true risk relative to a placebo or combination HRT, particularly worrisome in older and higher-risk patients.

What You Can Do

DUAVEE is less effective than HRT in preventing hot flashes, and clinical trials for DUAVEE suffered from multiple problems, making it difficult to assess the drug’s cancer and blood clotting risks. Combination HRT is known to carry serious risks, but since it is not clear whether DUAVEE is safer or more dangerous, we have applied our "Seven-Year Rule." We urge patients to wait seven years (until 2020) before trying this new drug, as it does not represent a clear clinical breakthrough over existing alternatives. We adopted this rule because research has shown that most of the cases in which a new drug has been pulled from the market or received a black-box warning have occurred within seven years of the drug’s approval.

If you experience hot flashes and wish to prevent osteoporosis, the safest option is to avoid drug treatment entirely. For hot flashes, use lifestyle-related strategies such as keeping your core body temperature cool and getting regular exercise. When hot flash symptoms are severe and nondrug approaches fail, use HRT at the lowest dose and for the shortest time needed to address these symptoms.[36]

If your goal is to prevent bone fractures, regular exercise helps maintain strong bones and prevent osteoporosis, as does eating a healthy, varied diet.[37] Consider drug treatment only if you have been diagnosed with osteoporosis and are at high risk of bone fractures. The bisphosphonates alendronate (BINOSTO, FOSAMAX), ibandronate (BONIVA) and risedronate (ACTONEL, ATELVIA) are effective in preventing both hip and spine fractures and are the best choices for treatment.[38]

References

[1] Letter from the Food and Drug Administration to Wyeth Pharmaceuticals, Inc., a wholly owned subsidiary of Pfizer, Inc. October 3, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2013/022247Orig1s001ltr.pdf. Accessed June 23, 2015.

[2] Food and Drug Administration. Medical review(s): Conjugated estrogens/bazedoxifene (Duavee). June 5, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022247Orig1s000MedR.pdf. Accessed July 20, 2015.

[3] Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMAM. 2013;310(13):1353-1368.

[4] Food and Drug Administration. Medical review(s): Conjugated estrogens/bazedoxifene (Duavee). June 5, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022247Orig1s000MedR.pdf. Accessed July 20, 2015.

[5] Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368.

[6] Food and Drug Administration. Medical review(s): Conjugated estrogens/bazedoxifene (Duavee). June 5, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022247Orig1s000MedR.pdf. Accessed July 20, 2015.

[7] Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368.

[8] Wyeth Receives Approvable Letter from FDA for Bazedoxifene for the Prevention of Postmenopausal Osteoporosis - May 1, 2007. April 2007. http://www.drugs.com/nda/viviant_070424.html. Accessed June 23, 2015.

[9] Morello KC, Wurz GT, DeGregorio MW. SERMs: Current status and future trends. Crit Rev Oncol Hematol. 2002;43:63-76.

[10] Palacios S, Silverman SL, Villiers TJ, et al. A 7-year randomized, placebo-controlled trial assessing the long-term efficacy and safety of bazedoxifene in postmenopausal women with osteoporosis: Effects on bone density and fracture. Menopause. 2015;22(8):000-000. [Epub ahead of print] DOI: 10.1097/gme.0000000000000419].

[11] Ibid.

[12] Food and Drug Administration. Medical review(s): Conjugated estrogens/bazedoxifene (Duavee). June 5, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022247Orig1s000MedR.pdf. Accessed July 20, 2015.

[13] Ibid.

[14] Palacios S, Silverman SL, Villiers TJ, et al. A 7-year randomized, placebo-controlled trial assessing the long-term efficacy and safety of bazedoxifene in postmenopausal women with osteoporosis: Effects on bone density and fracture. Menopause. 2015;22.

[15] Food and Drug Administration. Medical review(s): Conjugated estrogens/bazedoxifene (Duavee). June 5, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022247Orig1s000MedR.pdf. Accessed July 20, 2015.

[16] Pickar JH, Yeh IT, Bachmann G, Speroff L. Endometrial effects of a tissue selective estrogen complex containing bazedoxifene/conjugated estrogens as a menopausal therapy. Fertil Steril. 2009;92(3):1018-1024.

[17] Komm BS, Thompson JR, Mirkin S. Cardiovascular safety of conjugated estrogens plus bazedoxifene: Meta-analysis of the SMART trials. Climacteric. 2015;18:1-9.

[18] Mirkin S, Archer DF, Pickar JH, Komm BS. Recent advances to help understand and improve the safety of menopausal therapies. Menopause. 2014;22(3):351-360.

[19] Komm BS, Thompson JR, Mirkin S. Cardiovascular safety of conjugated estrogens plus bazedoxifene: Meta-analysis of the SMART trials. Climacteric. 2015;18:1-9.

[20]  Food and Drug Administration. Medical review(s): Conjugated estrogens/bazedoxifene (Duavee). June 5, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022247Orig1s000MedR.pdf. Accessed July 20, 2015.

[21] Ibid.

[22] Ibid.

[23] Ibid.

[24] Ibid.

[25] Ibid.

[26] Ibid.

[27] Ibid.

[28] Ibid.

[29] Ibid.

[30] Ibid.

[31] Food and Drug Administration. Medical review(s): Conjugated estrogens/bazedoxifene (Duavee). June 5, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022247Orig1s000MedR.pdf. Accessed July 20, 2015.

[32] Food and Drug Administration. Medical review(s): Conjugated estrogens/bazedoxifene (Duavee). June 5, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022247Orig1s000MedR.pdf. Accessed July 20, 2015.

[33] Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368.

[34] Komm BS, Thompson JR, Mirkin S, Cardiovascular safety of conjugated estrogens plus bazedoxifene: meta-analysis of the SMART trials. Climacteric. 2015;18:1-9.

[35] Food and Drug Administration. Medical review(s): Conjugated estrogens/bazedoxifene (Duavee). June 5, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022247Orig1s000MedR.pdf. Accessed July 20, 2015.

[36] Hormone replacement therapy: Use at the lowest dose and for the shortest amount of time. Worst Pills, Best Pills News. January 2014. /newsletters/view/884. Accessed June 23, 2015.

[37] A guide to treatments for osteoporosis. Worst Pills, Best Pills News. May 2015. /newsletters/view/960. Accessed June 23, 2015.

[38] Ibid.