Ospemifene 12-month safety and efficacy in postmenopausal women with vulvar and vaginal atrophy

S R Goldstein, G A Bachmann, P R Koninckx, V H Lin, D J Portman, O Ylikorkala, Ospemifene Study Group, Anna-Maija Antila, Jan Blaakær, Marc Dhont, Gilbert Donders, Agneta Ehrenborg, Risto Erkkola, Jorma Heikkinen, Astrid Højgaard, Dirk Janssens, Liisa Karinen, Philippe R Koninckx, Angelica Lindén-Hirschberg, Tord Naessen, Pernille Ravn, Serge Rozenberg, Göran Samsioe, Peter Sieprath, Philippe Simon, Marjo Tuppurainen, Anne Vanha-Perttula, Olavi Ylikorkala, S R Goldstein, G A Bachmann, P R Koninckx, V H Lin, D J Portman, O Ylikorkala, Ospemifene Study Group, Anna-Maija Antila, Jan Blaakær, Marc Dhont, Gilbert Donders, Agneta Ehrenborg, Risto Erkkola, Jorma Heikkinen, Astrid Højgaard, Dirk Janssens, Liisa Karinen, Philippe R Koninckx, Angelica Lindén-Hirschberg, Tord Naessen, Pernille Ravn, Serge Rozenberg, Göran Samsioe, Peter Sieprath, Philippe Simon, Marjo Tuppurainen, Anne Vanha-Perttula, Olavi Ylikorkala

Abstract

Objective: Assessment of 12-month safety of ospemifene 60 mg/day for treatment of postmenopausal women with vulvar and vaginal atrophy (VVA).

Methods: In this 52-week, randomized, double-blind, placebo-controlled, parallel-group study, women 40-80 years with VVA and an intact uterus were randomized 6 : 1 to ospemifene 60 mg/day or placebo. The primary objective was 12-month safety, particularly endometrial; 12-week efficacy was assessed. Safety assessments included endometrial histology and thickness, and breast and gynecological examinations. Efficacy evaluations included changes from baseline to week 12 in percentage of superficial and parabasal cells and vaginal pH.

Results: Of 426 randomized subjects, 81.9% (n = 349) completed the study with adverse events the most common reason for discontinuation (ospemifene 9.5%; placebo 3.9%). Most (88%) treatment-emergent adverse events with ospemifene were considered mild or moderate. Three cases (1.0%) of active proliferation were observed in the ospemifene group. For one, active proliferation was seen at end of study week 52, and diagnosed as simple hyperplasia without atypia on follow-up biopsy 3 months after the last dose. This subsequently resolved with progestogen treatment and dilatation and curettage. In six subjects (five ospemifene (1.4%), one placebo (1.6%)) endometrial polyps were found (histopathology); however, only one (ospemifene) was confirmed as a true polyp during additional expert review. Endometrial histology showed no evidence of carcinoma. Statistically significant improvements were seen for all primary and secondary efficacy measures and were sustained through week 52 with ospemifene vs. placebo.

Conclusions: The findings of this 52-week study confirm the tolerance and efficacy of oral ospemifene previously reported in short- and long-term studies.

Figures

Figure 1
Figure 1
Summary of safety and efficacy assessments (maturation index, vaginal pH, and visual evaluation). BMI, body mass index; ECG, electrocardiogram; MI, maturation index.*, Estradiol, follicle stimulating hormone, luteinizing hormone, and sex hormone binding globulin; †, endometrial biopsy at visit 3 and visit 4 only if the subject's endometrial thickness was ≥ 4 mm; ‡, mammogram and Papanicolaou smear were conducted at week 52
Figure 2
Figure 2
Subject disposition. *Subject is counted in more than one inclusion/exclusion criterion if multiple criteria were not met for that subject
Figure 3
Figure 3
Visual evaluation of the vagina; percentage of subjects with no abnormalities at week 52 (observed cases; intent-to-treat population). *, p < 0.0001

References

    1. Bachmann GA, Nevadunsky NS. Diagnosis and treatment of atrophic vaginitis. Am Fam Physician. 2000;61:3090–6.
    1. North American Menopause Society. The role of local vaginal estrogen for treatment of vaginal atrophy in postmenopausal women: 2007 position statement of The North American Menopause Society. Menopause. 2007;14:355–69.
    1. Santoro N, Komi J. Prevalence and impact of vaginal symptoms among postmenopausal women. J Sex Med. 2009;6:2133–42.
    1. Pastore LM, Carter RA, Hulka BS, Wells E. Self-reported urogenital symptoms in postmenopausal women: Women’s Health Initiative. Maturitas. 2004;49:292–303.
    1. Simon JA, Komi J. Postmenopausal women’s attitudes: vulvovaginal atrophy and its symptoms [abstract LB-10] Menopause. 2007;14:1107.
    1. Freedman M, Reape KZ, Giblin K. Impact of menopausal symptoms on sex lives: a survey evaluation [abstract LB-12] Menopause. 2007;14:1107.
    1. Levine KB, Williams RE, Hartmann KE. Vulvovaginal atrophy is strongly associated with female sexual dysfunction among sexually active postmenopausal women. Menopause. 2008;15:661–6.
    1. Mac Bride MB, Rhodes DJ, Shuster LT. Vulvovaginal atrophy. Mayo Clin Proc. 2010;85:87–94.
    1. Gass ML, Cochrane BB, Larson JC, et al. Patterns and predictors of sexual activity among women in the Hormone Therapy trials of the Women’s Health Initiative. Menopause. 2011;18:1160–71.
    1. Al-Baghdadi O, Ewies AA. Topical estrogen therapy in the management of postmenopausal vaginal atrophy: an up-to-date overview. Climacteric. 2009;12:91–105.
    1. Barlow DH, Samsioe G, van Geelen JM. A study of European womens’ experience of the problems of urogenital ageing and its management. Maturitas. 1997;27:239–47.
    1. Beral V, Bull D, Reeves G Million Women Study Collaborators. Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2005;365:1543–51.
    1. Effects of hormone replacement therapy on endometrial histology in postmenopausal women: The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA. 1996;275:370–5.
    1. Kagan R. Therapeutic options for the treatment of vaginal atrophy. OBG Management. 2010;22:8–13.
    1. North American Menopause Society. Estrogen and progestogen use in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause. 2010;17:242–55.
    1. Santen RJ, Pinkerton JV, Conaway M, et al. Treatment of urogenital atrophy with low-dose estradiol: preliminary results. Menopause. 2002;9:179–87.
    1. 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.
    1. Nath A, Sitruk-Ware R. Pharmacology and clinical applications of selective estrogen receptor modulators. Climacteric. 2009;12:188–205.
    1. Riggs BL, Hartmann LC. Selective estrogen-receptor modulators − mechanisms of action and application to clinical practice. N Engl J Med. 2003;348:618–29.
    1. Ball L, Levy N, Zhao X, et al. Cell type- and estrogen receptor-subtype specific regulation of selective estrogen receptor modulator regulatory elements. Mol Cell Endocrinol. 2009;299:204–11.
    1. Heldring N, Pike A, Andersson S, et al. Estrogen receptors: how do they signal and what are their targets. Physiol Rev. 2007;87:905–31.
    1. Qu Q, Zheng H, Dahllund J, et al. Selective estrogenic effects of a novel triphenylethylene compound, FC1271a, on bone, cholesterol level, and reproductive tissues in intact and ovariectomized rats. Endocrinology. 2000;141:809–20.
    1. Voipio SK, Komi J, Kangas L, Halonen K, DeGregorio MW, Erkkola RU. Effects of ospemifene (FC-1271a) on uterine endometrium, vaginal maturation index, and hormonal status in healthy postmenopausal women. Maturitas. 2002;43:207–14.
    1. Wurz GT, Read KC, Marchisano-Karpman C, et al. Ospemifene inhibits the growth of dimethylbenzanthracene-induced mammary tumors in Sencar mice. J Steroid Biochem Mol Biol. 2005;97:230–40.
    1. Rutanen EM, Heikkinen J, Halonen K, Komi J, Lammintausta R, Ylikorkala O. Effects of ospemifene, a novel SERM, on hormones, genital tract, climacteric symptoms, and quality of life in postmenopausal women: a double-blind, randomized trial. Menopause. 2003;10:433–9.
    1. Bachmann GA, Komi JO. Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study. Menopause. 2010;17:480–6.
    1. Simon JA, Lin VH, Radovich C, Bachmann GA. One-year long-term safety extension study of ospemifene for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus. Menopause. 2012;20:418–27.
    1. Portman DJ, Bachmann GA, Simon JA. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy. Menopause. 2013;20:623–30.
    1. Mutter GL, Ferenczy A. Anatomy and histology of the uterine corpus. In: Kurman RJ, editor. Blaustein’s Pathology of the Female Genital Tract. 5th edn. New York: Springer-Verlag; 2002. pp. 383–420.
    1. Ellmén J, Hakulinen P, Partanen A, Hayes DF. Estrogenic effects of toremifene and tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res Treat. 2003;82:103–11.
    1. Plouffe L, Jr, Siddhanti S. The effect of selective estrogen receptor modulators on parameters of the hypothalamic-pituitary-gonadal axis. Ann N Y Acad Sci. 2001;949:251–8.
    1. Pinkerton JV, Goldstein SR. Endometrial safety: a key hurdle for selective estrogen receptor modulators in development. Menopause. 2010;17:642–53.
    1. Taylor HS. Designing the ideal selective estrogen receptor modulator − an achievable goal? Menopause. 2009;16:609–15.
    1. Delmanto A, Nahas-Neto J, Nahas EA, de Oliveira ML, Fernandes CE, Traiman P. Effect of raloxifene on the vaginal epithelium of postmenopausal women. Eur J Obstet Gynecol Reprod Biol. 2008;139:187–92.
    1. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 2005;97:1652–62.
    1. Goldstein SR. Not all SERMs are created equal. Menopause. 2006;13:325–7.
    1. Marttunen MB, Cacciatore B, Hietanen P, Pyrhönen S, Wahlström T, Ylikorkala O. Prospective study on gynaecological effects of two antioestrogens tamoxifen and toremifene in postmenopausal women. Br J Cancer. 2001;84:897–902.
    1. Rioux JE, Devlin C, Gelfand MM, Steinberg WM, Hepburn DS. 17beta-estradiol vaginal tablet versus conjugated equine estrogen vaginal cream to relieve menopausal atrophic vaginitis. Menopause. 2000;7:156–61.
    1. Suckling JA, Kennedy R, Lethaby A, Roberts H. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev. 2006;(Issue 4)
    1. Vagifem [package insert] Princeton, NJ: Novo Nordisk Inc; 2012.
    1. Dreisler E, Sorensen SS, Ibsen PH, Lose G. Prevalence of endometrial polyps and abnormal uterine bleeding in a Danish population aged 20–74 years. Ultrasound Obstet Gynecol. 2009; 33:102–8.
    1. Burich RA, Mehta NR, Wurz GT, et al. Ospemifene and 4-hydroxyospemifene effectively prevent and treat breast cancer in the MTag. Tg transgenic mouse model. Menopause. 2012;19:96–103.
    1. Wurz GT, Soe LH, DeGregorio MW. Ospemifene, vulvovaginal atrophy, and breast cancer. Maturitas. 2013 Jan 15
    1. Taras TL, Wurz GT, DeGregorio MW. In vitro and in vivo biologic effects of ospemifene (FC-1271a) in breast cancer. J Steroid Biochem Mol Biol. 2001;77:271–9.
    1. Polin SA, Ascher SM. The effect of tamoxifen on the genital tract. Cancer Imaging. 2008;8:135–45.
    1. McClung MR, Siris E, Cummings S, et al. Prevention of bone loss in postmenopausal women treated with lasofoxifene compared with raloxifene. Menopause. 2006;13:377–86.
    1. Barrett-Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355:125–37.
    1. Johnston CC, Jr, Bjarnason NH, Cohen FJ, et al. Long-term effects of raloxifene on bone mineral density, bone turnover, and serum lipid levels in early postmenopausal women: three-year data from 2 double-blind, randomized, placebo-controlled trials. Arch Intern Med. 2000;160:3444–50.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever