Postmenopausal Women Should Not Use the Conjugated Estrogens and Bazedoxifene Combination (DUAVEE)

Menopause is a normal stage in a woman’s life when her menstrual period stops. It can be accompanied by bothersome changes due to the loss of production of estrogen and progesterone hormones, resulting in vasomotor symptoms (such as hot flashes [flushes] and night sweats), vaginal or vulvar atrophy (causing dryness and soreness in the genital area) and osteoporosis (bone thinning).

When drug therapy is necessary to manage these changes, short-term use of estrogen (with or without a progestin [progesterone], as appropriate) has been the standard menopausal hormone therapy (hereafter, hormone therapy) in healthy women during the early postmenopausal period (usually from age 50 to 59).[1]

Widespread and long-term use of hormone therapy is no longer recommended because it is associated with serious risks. For example, estrogen causes endometrial (inner lining of the uterus) cancer and increases the risk of cardiovascular disease (mainly stroke and high blood pressure), blood clots in the legs or lungs, gallbladder disease and dementia.[2] Progestin counteracts estrogen’s effects on the uterus, so it is usually combined with estrogen hormone therapy for women with a uterus to reduce the risk of endometrial cancer. But the estrogen-progestin combination still carries all of estrogen’s other risks, in addition to increased risks of heart attack and breast cancer.

In 2013, the Food and Drug Administration (FDA) approved DUAVEE, an oral hormone therapy that combines bazedoxifene (a selective estrogen receptor modulator) with conjugated estrogens for women with a uterus to treat moderate-to-severe vasomotor symptoms associated with menopause and to prevent postmenopausal osteoporosis.[3]

Public Citizen’s Health Research Group has previously designated Duavee as “Do Not Use for Seven Years” because, at the time of its approval, it did not represent a clear clinical breakthrough over standard hormone therapy and its risks were not clear.[4]

We now have designated Duavee as Do Not Use because there is still no new evidence to support its usefulness relative to well-studied standard hormone therapy, which has clearer benefits and risks. The evidence regarding Duavee continues to be limited to four main clinical trials sponsored by the drugmakers (Wyeth and its parent company Pfizer), which mainly compared the effect of the drug on hot flashes, vaginal symptoms, the endometrium or bone-mineral density with that of a placebo.[5] These trials have not been replicated by independent researchers,[6] nor have long-term randomized trials of Duavee been conducted. Therefore, the risks associated with Duavee remain uncertain, particularly among women older than 65.

Effect on hot flashes and vaginal or vulvar atrophy

A small, 12-week clinical trial showed that Duavee reduced the average daily number of moderate-to-severe hot flashes from 10 to 3 per day, compared with 11 to 5 per day for a placebo group.[7] However, no trial compared the drug with systemic estrogen-alone or estrogen-with-progestogen therapy, which have been shown to be highly effective in reducing moderate-to-severe hot flashes in multiple longer trials.[8]

Another trial showed that Duavee had some beneficial effect on some markers of vaginal or vulvar atrophy compared with placebo.[9] However, the clinical significance of this finding is unclear.[10] Furthermore, vaginal estrogen is the recommended first-line treatment for vaginal or vulvar atrophy because its adverse effects are very rare.[11]

One of the proposed benefits of Duavee is decreasing the risk of endometrial hyperplasia (enlargement) or cancer.[12] Pfizer claims that these endometrial disorders occurred in fewer than 1% of Duavee users in two trials.[13] However, the European Medicines Agency (EMA) noted that in one of these trials, four Duavee users with marked endometrial thickening did not have an endometrial biopsy to determine whether they had endometrial disorders.[14] As acknowledged by the agency, had these women had endometrial disorders, the outcome of the trial would have changed from “success to failure.”

The EMA only approved the drug, which is marketed under the brand name DUAVIVE in Europe, for women with a uterus for whom treatment with progestin-containing hormone therapy is not appropriate.[15] The editors of Prescrire International, a highly regarded French source of independent drug information, commented that, instead, “it would have been more reasonable [for the agency] to refuse to” approve the drug altogether.[16]

Effect on osteoporosis prevention

Bazedoxifene was initially developed in the U.S. under the brand name VIVIANT as a standalone drug for osteoporosis.[17] But it proved ineffective in clinical trials for preventing nonvertebral fractures, including hip fractures, the most harmful type of fracture.[18] Bazedoxifene also caused a dramatic increase in the rate of blood clots, higher than the rates seen with standard hormone therapy.[19] In part because of these concerns, the FDA declined to approve the drug in 2008.

Evidence regarding the prevention of osteoporosis with Duavee comes from the two aforementioned endometrial-disorder trials.[20] These trials showed that the drug improved bone-mineral density of the hip and lumbar spine relative to a placebo.[21] However, FDA scientists noted that this effect in one of the two trials was numerically less than that seen with estrogen-plus-progestin therapy. Importantly, these trials did not assess more meaningful outcomes, such as the number of fractures.

Notably, Pfizer withdrew the osteoporosis indication from its drug application in Europe because one of the two trials supporting this claim was deemed “not compliant with good clinical practice” by the EMA.[22]

Inadequate assessment of serious risks

Duavee trials have been criticized because they lacked direct comparison with standard hormone therapy and had small numbers of subjects, short durations and limited information on women older than 65.[23],[24],[25] These limitations preclude adequate assessment of serious adverse events of hormone therapy — including cardiovascular or cerebrovascular events, blood clots and hormone-dependent (breast, ovarian and uterine) cancers.[26]

In fact, an independent FDA committee that assessed adverse events from the Duavee trials acknowledged these serious limitations.[27]

What You Can Do

If you are a menopausal woman who is experiencing hot flashes and wishing to prevent osteoporosis, your safest option is to avoid drug treatment entirely. For hot flashes, try 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, do not use Duavee. Instead, use standard hormone therapy at the lowest dose and for the shortest time needed to address your symptoms if you are younger than 60 and do not have vaginal bleeding, a history of blood clots, cancer, cardiovascular or liver disease, or other conditions.[28] Also, do not use the low-dose version of the antidepressant paroxetine (BRISDELLE) for hot flashes because it has questionable benefits and carries risks of depression and suicidal behavior or thoughts.[29]

For drug therapy to manage postmenopausal vaginal symptoms, consider vaginal estrogen because its adverse events are rare compared with those for oral or other systemic formulations.[30]

To prevent bone fractures, engage in regular exercise because it helps maintain strong bones and prevent osteoporosis, as does eating a healthy diet.[31] Consider drug treatment only if you have been diagnosed with osteoporosis and are at high risk of fractures. Bisphosphonates, including alendronate (BINOSTO, FOSAMAX), are the best medications for preventing osteoporosis-related fractures.
 

References

[1] 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 October 23, 2020.

[2] Food and Drug Administration. Menopause: Medicines to help you. August 22, 2019. https://www.fda.gov/consumers/free-publications-women/menopause-medicines-help-you. Accessed October 23, 2020.

[3] Pfizer Inc. Label: Duavee (DUAVEE). December 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022247s006lbl.pdf. Accessed October 23, 2020.

[4] DUAVEE, hot flashes and bone health. Worst Pills, Best Pills News. September 2015. /newsletters/view/989. Accessed October 23, 2020.

[5] Equine oestrogens + bazedoxifene (duavive) and menopause. Prescrire Int. 2017;26(184):180-182.

[6] Bazedoxifene for HRT? Drug Ther Bull. 2017;55(4):42-44.

[7] National Institute for Health and Care Excellence. Oestrogen deficiency symptoms in oestrogen deficiency symptoms in postmenopausal women: conjugated oestrogens and bazedoxifene acetate. December 22, 2016. https://www.nice.org.uk/advice/es3/resources/oestrogen-deficiency-symptoms-in-postmenopausal-women-conjugated-oestrogens-and-bazedoxifene-acetate-32172999109. Accessed October 23, 2020.

[8] Maclennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev. 2004;4(October 18):CD002978.

[9] National Institute for Health and Care Excellence. Oestrogen deficiency symptoms in oestrogen deficiency symptoms in postmenopausal women: conjugated oestrogens and bazedoxifene acetate. December 22, 2016. December 22, 2016. https://www.nice.org.uk/advice/es3/resources/oestrogen-deficiency-symptoms-in-postmenopausal-women-conjugated-oestrogens-and-bazedoxifene-acetate-32172999109. Accessed October 23, 2020.

[10] Bazedoxifene for HRT? Drug Ther Bull. 2017;55(4):42-44.

[11] National Institute for Health and Care Excellence. Menopause: diagnosis and management. November 12, 2015 https://www.nice.org.uk/guidance/ng23/resources/menopause-diagnosis-and-management-pdf-1837330217413. Accessed October 30, 2020.

[12] National Institute for Health and Care Excellence. Oestrogen deficiency symptoms in oestrogen deficiency symptoms in postmenopausal women: conjugated oestrogens and bazedoxifene acetate. December 22, 2016. https://www.nice.org.uk/advice/es3/resources/oestrogen-deficiency-symptoms-in-postmenopausal-women-conjugated-oestrogens-and-bazedoxifene-acetate-32172999109. Accessed October 23, 2020.

[13] Pfizer Inc. Label: Duavee (DUAVEE). December 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022247s006lbl.pdf. Accessed October 23, 2020.

[14] European Medicines Agency. Assessment report for conjugated oestrogens and bazedoxifene (DUAVIVE). 23 October 2014. https://www.ema.europa.eu/en/documents/assessment-report/duavive-epar-public-assessment-report_en.pdf. Accessed October 23, 2020.

[15] European Medicines Agency. Annex I - Summary of product characteristics for conjugated oestrogens and bazedoxifene (DUAVIVE). June 22, 2020. https://www.ema.europa.eu/en/documents/product-information/duavive-epar-product-information_en.pdf. Accessed October 23, 2020.

[16] Equine oestrogens + bazedoxifene (duavive) and menopause. Prescrire Int. 2017;26(184):180-182.

[17] Viviant (bazedoxifene) FDA approval status. https://www.drugs.com/history/viviant.html. Accessed October 23, 2020.

[18] 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):806-813.

[19] 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 October 23, 2020.

[20] Pfizer Inc. Label: Duavee (DUAVEE). December 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022247s006lbl.pdf. Accessed October 23, 2020.

[21] Food and Drug Administration. Summary review for regulatory action: Conjugated estrogens/bazedoxifene (Duavee). October 3, 2013. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022247Orig1s000SumR.pdf. Accessed October 23, 2020.

[22] European Medicines Agency. Assessment report for conjugated oestrogens and bazedoxifene (DUAVIVE). 23 October 2014. https://www.ema.europa.eu/en/documents/assessment-report/duavive-epar-public-assessment-report_en.pdf. Accessed October 23, 2020.

[23] Bazedoxifene for HRT? Drug Ther Bull. 2017;55(4):42-44.

[24] National Institute for Health and Care Excellence. Oestrogen deficiency symptoms in postmenopausal women: conjugated oestrogens and bazedoxifene acetate. December 22, 2016. https://www.nice.org.uk/advice/es3/resources/oestrogen-deficiency-symptoms-in-postmenopausal-women-conjugated-oestrogens-and-bazedoxifene-acetate-32172999109. Accessed October 23, 2020.

[25] Equine oestrogens + bazedoxifene (duavive) and menopause. Prescrire Int. 2017;26(184):180-182.

[26] The sorcerer’s apprentice. Prescrire Int. 2017;26(184):171.

[27] Food and Drug Administration. Summary review for regulatory action: Conjugated estrogens/bazedoxifene (Duavee). October 3, 2013. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022247Orig1s000SumR.pdf. Accessed October 23, 2020.

[28] 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 October 23, 2020.

[29] Do not use paroxetine (BRISDELLE) for treatment of hot flashes. Worst Pills, Best Pills News. March 2020. /newsletters/view/1321##ref_9. Accessed October 23, 2020.

[30] Study bolsters evidence linking menopausal hormone therapy to breast cancer. Worst Pills, Best Pills News. March 2020. /newsletters/view/1320. Accessed October 23, 2020.

[31] A guide to treatments for osteoporosis. Worst Pills, Best Pills News. May 2015. /newsletters/view/960. Accessed October 23, 2020.