Risks of Ospemifene For Menopause-Related Pain During Intercourse

In February 2013, the Food and Drug Administration (FDA) approved ospemifene (OSPHENA) to treat moderate to severe dyspareunia (pain during sexual intercourse) due to menopause.[1] The drug is now being heavily promoted in direct-to-consumer advertisements as the first non-estrogen pill approved to treat this condition. Yet ospemifene functions on vaginal tissue in ways that mimic estrogen, and the drug’s product label bears a black-box warning for several known risks of estrogen treatment, including risk of uterine (endometrial) cancer and blood clots.

Because much remains unknown about ospemifene’s safety, Public Citizen’s Health Research Group recommends that you do not use the drug for seven years, in keeping with our “Seven-Year Rule” for new drugs that do not represent a clinical breakthrough over existing therapy.

However, since the existing therapy for postmenopausal vaginal pain, estrogen, also carries serious risks, we recommend that you use estrogen only as a last resort, when non-hormonal lubricants have failed and pain interferes significantly with intercourse and other aspects of your life.

Vaginal changes during and after menopause

The estrogen levels in a woman’s body naturally decrease during menopause, causing changes to the vagina that can lead to loss of elasticity and vaginal shortening, narrowing and thinning. Such changes, in turn, may cause pain during sexual intercourse, as well as dryness, vaginal discharge, itching or burning.[2]

While these symptoms affect many women, only about 5 percent of postmenopausal women report experiencing pain during sexual intercourse, and less than 1 percent experience severe pain.[3] Among postmenopausal women with any type of vaginal symptom, including itching and dryness, most report that the symptom interferes with sexual enjoyment.[4] Such symptoms can also interfere with sleep, overall enjoyment of life and relationships with sexual partners.[5] In severe form, these symptoms can be extremely distressing, leading many women who experience them to seek treatment.

Previous drug treatments for pain during intercourse

The FDA has approved several estrogen products (ESTRACE vaginal cream, ESTRING, FEMRING, VAGIFEM) that are applied topically to the vagina as creams, vaginal inserts or dissolving tablets to treat vaginal menopause symptoms. Such products provide relief in 80 percent to 95 percent of women. These vaginal products appear to be as effective at treating vaginal symptoms as products that work by distributing estrogen throughout the body, including estradiol pills, patches, mists and creams/gels applied outside the vagina (ALORA, CLIMARA, DELESTROGEN, ESTRADERM, ESTROGEL, VIVELLE, VIVELLE-DOT).[6]

Estrogen pills are known to increase the risk of blood clots, among other serious side effects. In particular, women who have an intact uterus and use estrogen products are at an increased risk of uterine cancer.[7]

Estrogen products applied to the vagina have not been studied as well as pills. Because estrogen can be absorbed into the body through the vagina, there is a risk that these products may also cause blood clots, uterine cancer and other side effects seen with oral estrogen therapy. (For more on estrogen risks, see our recent article “Hormone Replacement Therapy: Use at the Lowest Dose and for the Shortest Amount of Time” in the January 2014 issue of Worst Pills, Best Pills News.)

Some doctors recommend that women who use a vaginal estrogen product take a progestin such as medroxyprogesterone acetate (PROVERA) to reduce the risk of uterine cancer.[8] Medroxyprogesterone acetate is approved for use in combination with estrogen pills but has not been thoroughly studied to determine appropriate dosing with vaginal products. Moreover, progestin itself may increase certain other dangers, including possible risk of breast cancer.[9]

Questions about ospemifene safety

Ospemifene is a member of a class of drugs known as selective estrogen receptor modulators (SERMs). SERMs are called “selective” because they behave like estrogen in some tissues but block estrogen activity in others.[10]

Because SERMs behave differently on different tissues, the effectiveness and side effects of each SERM may be very different. The SERMs tamoxifen (NOLVADEX, SOLTAMOX) and toremifene (FARESTON) are currently FDA-approved to treat breast cancer by blocking estrogen activity in breast tissue, but both drugs cause uterine cancer and blood clots by acting like estrogen on the uterus and blood components involved in clot formation.

The SERM raloxifene (EVISTA) — approved to treat osteoporosis but ineffective against breast cancer — has more limited effects on the uterus. However, it still has the potential to cause blood clots and menopausal symptoms.[11]

Ospemifene is a SERM very similar to tamoxifen.[12] Early studies indicated that ospemifene might have beneficial effects on vaginal menopause symptoms and possibly avoid some of the more serious risks of estrogen and other SERMs.

Pre-market clinical trials demonstrated ospemifene’s effectiveness at treating vaginal pain during intercourse, but there is some evidence that the drug has adverse effects on the uterus, such as thickening the uterine wall and triggering abnormal cell growth in some patients, which suggests a possible increased risk of uterine cancer.[13] Also, when mice and rats were exposed to doses close to the dose now on the market, there was a significant increase in tumors in multiple organs, indicating potential cancer risk.[14]

While it is not clear yet whether the cancer risk is higher or lower than with estrogen pills, the evidence has prompted the FDA to add a black-box warning to the drug’s label explaining that ospemifene may increase the risk of uterine cancer.[15] The FDA also required a black-box warning describing blood-clotting risks, although there were too few blood-clotting events in the clinical trials to be certain if subjects receiving the drug actually had an increased risk of blood clots relative to these who received a placebo. Also, unlike estrogen, which reduces the occurrence of hot flashes, ospemifene can actually trigger or increase the frequency of this menopausal symptom.

Ospemifene is approved only to treat vaginal menopausal symptoms and should not be used in women who may become pregnant, because it has been shown to cause miscarriages in animals at very low doses.[16]

Treating vaginal changes without drugs

Several steps can be taken to address vaginal changes before trying estrogen or other hormonal drug treatments. One of the first steps is to use an over-the-counter nonhormonal vaginal lubricant during intercourse or to regularly apply a long-acting vaginal moisturizer.[17]

In general, vaginal lubricants have no serious side effects and provide relief to a substantial number of women. However, be cautious in selecting a lubricant, as some may actually irritate the vagina. Certain water-based gels have properties that cause irritation or kill off beneficial bacteria, which may lead to yeast infections. Oil-based lubricants also increase the risk of vaginal infection. The North American Menopause Society recommends using a non-irritating water-based lubricant (GOOD CLEAN LOVE, PRÉ, SLIPPERY STUFF) or a silicone-based lubricant (ASTROGLIDE X, ID MILLENNIUM, K-Y INTRIGUE, PINK, PJUR EROS).[18]

Try several products sequentially if the first fails to provide relief. You should always test out a new lubricant for 24 hours on a small area of skin. Look for redness or signs of irritation before applying vaginally.

Regular sexual activity is also important for preventing vaginal menopausal symptoms, as the vagina can narrow and shorten in the absence of sexual penetration. If this occurs, gentle stretching using lubricated vaginal dilators of graduated sizes may help restore vaginal function.

Benefits of lubricant alone compared to lubricant plus ospemifene

Lubricant use, regular intercourse and waiting to see if symptoms improve may be enough to address symptoms in many women. In the clinical trials for ospemifene — which included women with moderate to severe vaginal pain — women in the placebo group received nothing more than a dummy pill and nonhormonal lubricant to use as needed during sex.[23] Nevertheless, these women experienced substantial relief.

While the placebo group began the study with an average vaginal pain severity of 2.7 on a scale from none (0) to severe (3), after 12 weeks of treatment, the average pain severity for women in the placebo group had dropped to 1.5. By contrast, the average pain score for ospemifene users (who received regular treatment with ospemifene plus the nonhormonal lubricant) dropped only slightly more, from 2.7 to 1.2.

At the beginning of the trial, all women reported moderate to severe pain during sex; at the end, nearly half of the participants in the placebo group reported no or mild vaginal pain. The number of ospemifene users reporting such decreases was modestly higher, at just under two-thirds.

The ospemifene trials showed that the drug is only marginally more effective than placebo. More importantly, they showed that drug treatment is not required in many women, who can achieve relief more safely without drugs.

What You Can Do

We have adopted the Seven-Year Rule for ospemifene. We created this rule because our research has shown that half the cases where the FDA has added a black-box warning or pulled a drug from the market occurred within seven years of the date of the drug’s approval.[24] New safety information about ospemifene is likely to emerge over the next seven years, and it will hopefully help doctors and patients assess whether the drug is safer or more dangerous than vaginal estrogen therapy.

If you experience pain during intercourse, you should first attempt to treat it with a vaginal moisturizer or one of the water- or silicone-based lubricants listed in this article. Continue to have intercourse regularly if possible.

If these methods fail, use a vaginal estrogen-based cream, insert or suppository. Try it until sexual intercourse is pain-free, then work with your doctor to quit the medication while you continue to have regular intercourse and use a nonhormonal lubricant.

While using vaginal estrogen-based creams or suppositories, seek medical help immediately if you have changes in vision or speech or experience a sudden severe headache, severe pains in your chest or legs with or without shortness of breath, weakness and fatigue, or vaginal bleeding.

For women with an intact uterus, we do not recommend adding a progestin product to reduce the risk of uterine cancer while using vaginal estrogen-based creams or suppositories, as this practice is not well studied. Instead, use the vaginal estrogen at the lowest dose and for the shortest time possible, and tell your doctor about any vaginal bleeding, which could be a sign of uterine cancer.[25]

References

[1] Food and Drug Administration, Drug Approval Package: Osphena (ospemifene) Oral Tablets. February 26, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203505Orig1s000TOC.cfm. Accessed April 7, 2014.

[2] Ballagh SA, Vaginal hormone therapy for urogenital and menopausal symptoms. Semin Reprod Med. 2005 May;23(2):126-40.

[3] Pastore LM, Carter RA, Hulka BS, Wells E. Self-reported urogenital symptoms in postmenopausal women: Women_s Health Initiative. Maturitas. 2004;49:292-303.

[4] Kingsberg SA, Wysocki S, Magnus L, Krychman ML. Vulvar and vaginal atrophy in postmenopausal women: Findings from the REVIVE (REal Women’s VIews of Treatment Options for Menopausal Vaginal Changes) Survey. J Sex Med. 2013;10: 1790–9.

[5] Ibid.

[6] Cardozo L, Bachmann G, McClish D, Fonda D, Birgerson L. Meta-analysis of estrogen therapy in the management of urogenital atrophy in postmenopausal women: second report of the Hormones and Urogenital Therapy Committee. Obstet Gynecol. 1998;92:722–727.

[7] Ballagh SA, Vaginal hormone therapy for urogenital and menopausal symptoms. Semin Reprod Med. 2005;23(2):126-40.

[8] Ibid.

[9] Food and Drug Administration. Drug Label: FEMRING. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021367s009lbl.pdf. Revised May 2009.

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

[11] Ibid.

[12] Ibid.

[13] Portman DJ, Bachmann GA, Simon JA, and the Ospemifene Study Group. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy. Menopause. 2013;20(6):623-630.

[14] Food and Drug Administration. Pharmacology Review: Osphena (ospemifene). March 28, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203505Orig1s000TOC.cfm. Accessed April 24, 2014.

[15] Food and Drug Administration. Drug Label: OSPHENA. Revised: 02/2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203505s000lbl.pdf

[16] Ibid.

[17] North American Menopause Society. Position Statement: Management of symptomatic vulvovaginal atrophy: 2013 position statement of the North American Menopause Society. Menopause. 2013;20(9):888-902.

[18] Ibid.

[19] Dezzutti CS, Brown ER, Moncla B, et al. Is Wetter Better? An Evaluation of Over-the-Counter Personal Lubricants for Safety and Anti-HIV-1 Activity. PLoS ONE. 7(11):e48328. doi:10.1371/journal.pone.0048328

[20] Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society. Menopause. 2013;20(9):888-902.

[21] Based on information and/or recommendations from the following two publications: Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society. Menopause. 2013;20(9):888-902; and Dezzutti CS, Brown ER, Moncla B, et al. Is Wetter Better? An Evaluation of Over-the-Counter Personal Lubricants for Safety and Anti-HIV-1 Activity. PLoS ONE. 7(11): e48328. doi:10.1371/journal.pone.0048328.

[22] Based on information and/or recommendations from the following three publications: Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society. Menopause 2013; 20(9): 888-902; Dezzutti CS, Brown ER, Moncla B, et al. Is Wetter Better? An Evaluation of Over-the-Counter Personal Lubricants for Safety and Anti-HIV-1 Activity. PLoS ONE 7(11): e48328. doi:10.1371/journal.pone.0048328; and Fashemi B, Delaney ML, Onderdonk AB, Fichorova RN. Effects of feminine hygiene products on the vaginal mucosal biome. Microb Ecol Health Dis. 2013 Feb 25;24.

[23] Portman DJ, Bachmann GA, Simon JA, and the Ospemifene Study Group. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy. Menopause. 2013;20(6):623-630.

[24] Wolfe, SM. The seven-year rule for safer prescribing. Aust Prescr. 2012;35:138-9.

[25] Food and Drug Administration. Drug Label: OSPHENA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203505s000lbl.pdf. Revised February 2013.