Vulvar And Vaginal Atrophy Research Articles

Effect of Ospemifene on Densitometric and Plasma Bone Metabolism Biomarkers in Postmenopausal Women Reporting Vulvar and Vaginal Atrophy (VVA).

Women reporting VVA symptoms were included. Bone health profile was investigated in 61 subjects treated with OSP (OSPG) (60 mg/day) and compared with a control group (CG) (n = 67) over 12 months. In the CG, BMD and T-score statistically decreased at the femoral neck (FN), total femur (TF), and lumbar spine (L1-L4). In the OSPG, BMD decreased significantly at FN but tended to remain stable at TF and L1-L4. No changes were observed in bone mineral markers after one year in either group, except BAP, which decreased in OSPG. Long-term OSP treatment improves bone mineral markers at TF and LS and slows bone loss at FN compared to the control group. Overall, OSP exerts a protective effect on bone loss in healthy menopausal women with VVA.

Ospemifene (Osphena)


 CADTH recommends that Osphena should be reimbursed by public drug plans for the treatment of postmenopausal women with moderate to severe dyspareunia and/or vaginal dryness, symptoms of vulvar and vaginal atrophy (VVA), a component of genitourinary syndrome of menopause, if certain conditions are met.
 Osphena should only be covered for patients who share the same characteristics as patients who are eligible for vaginal estrogen products that are currently reimbursed by public drug plans for the treatment of postmenopausal VVA.
 Osphena should only be reimbursed if it is not used with other estrogen therapies and if treatment with Osphena does not cost more than treatment with the least costly vaginal estrogen product currently reimbursed for postmenopausal VVA.

Estradiol (Imvexxy)


 CADTH recommends that Imvexxy be reimbursed by public drug plans for the treatment of moderate-to-severe dyspareunia (painful sex) in women who are postmenopausal if certain conditions are met.
 Imvexxy should only be covered in a similar manner as other vaginal estrogen products that include treatment of women who are postmenopausal and have moderate-to-severe painful sex.
 Imvexxy should only be reimbursed if it is cost saving for drug programs compared to the least costly local hormone therapy reimbursed for the treatment of moderate-to-severe painful sex, a symptom of vulvar and vaginal atrophy (VVA) in women who are postmenopausal.

Risk of venous thromboembolism among women receiving ospemifene: a comparative observational study.

The primary aim of this study was to compare the incidence of venous thromboembolism (VTE) among women initiating ospemifene vs other selective estrogen receptor modulator (SERM) therapies for estrogen-deficiency conditions or breast cancer prevention, and vs women with untreated vulvar and vaginal atrophy (VVA). The secondary objective examined numerous additional safety outcomes. This was a retrospective cohort study using the IBM Watson MarketScan claims database. Women receiving ospemifene, another SERM, or with a new diagnosis of VVA with no treatment from 1 May 2013 to 2 October 2018 were followed through the claims for incident adverse outcomes. The primary outcome was the first occurrence of VTE following cohort entry; secondary outcomes included cerebrovascular events and other adverse events potentially associated with SERM use. Cox models compared the risk of VTE between ospemifene and comparators, using a variety of approaches to control for confounding. The incidence of VTE during the first continuous treatment episode was 3.39 (95% confidence interval [CI]: 1.55-6.43) events per 1,000 person-years (PY) for ospemifene (N = 8977), 11.30 (95% CI: 8.81-14.28) events per 1,000 PY for comparator SERM (N = 12,621), and 10.92 (95% CI: 10.49-11.37) events per 1,000 PY for untreated VVA (N = 242,488). Cox models indicated no increase in risk of VTE for ospemifene vs other SERMs (hazard ratio [HR]: 0.40, 95% CI: 0.19-0.82), and vs untreated VVA (HR: 0.47, 95% CI: 0.24-0.91). This real-world safety analysis found no increase in risk of VTE or other adverse events with use of ospemifene in postmenopausal women. Introduction: This study assessed the risk of venous thromboembolism (VTE) among women treated with ospemifene or another selective estrogen receptor modulator (SERM) therapy and women with untreated vulvar and vaginal atrophy (VVA). Numerous additional safety outcomes were examined.Methods: This study was conducted in the IBM Watson MarketScan claims database. Women receiving ospemifene, another SERM, or with a new diagnosis of VVA with no treatment from 1 May 2013 to 2 October 2018 were followed through the claims for adverse outcomes, including VTE, cerebrovascular events (such as stroke), and other outcomes that might occur with use of a SERM. The analyses compared the risk of VTE between ospemifene and the other two groups, using methods that accounted for differences in patient characteristics between the groups. Because few women over 72 years old used ospemifene, the main analyses examined women aged 54-72 years.Results: The analyses included 8,977 ospemifene users, 12,621 other SERM users, and 242,488 women with untreated VVA. Among women aged 54-72 years, only 9 experienced a VTE during ospemifene treatment, while 55 other SERM users and 1,788 women with untreated VVA had a VTE. The analyses that accounted for differences between the groups confirmed that the risk of VTE was no higher in ospemifene users than in either comparison group.Conclusion: This real-world safety analysis found no increase in risk of VTE or other adverse events with use of ospemifene in postmenopausal women.

077 Postmenopausal Women Using a Softgel Estradiol Vaginal Insert to Treat Moderate to Severe Dyspareunia Were Satisfied With it and Preferred it Over a Previous Treatment

In the 12-week, phase 3 REJOICE trial (NCT02253173), the 17β-estradiol (E2), softgel, vaginal insert (TX-004HR) significantly improved percentages of superficial and parabasal cells, vaginal pH, and dyspareunia in menopausal women with vulvar and vaginal atrophy (VVA) and moderate to severe dyspareunia (Constantine G et al, Menopause 2017;24:409-416). The 4-μg and 10-μg E2 doses were approved by the FDA in May 2018 as Imvexxy® (TherapeuticsMD, Boca Raton, FL).

Incidence of venous thromboembolism among postmenopausal women prescribed ospemifene, selective estrogen receptor modulators for noncancer indications, or untreated vulvar and vaginal atrophy.

Ospemifene is a nonsteroidal selective estrogen receptor modulator (SERM) for the treatment of moderate symptomatic vulvar and vaginal atrophy (VVA) due to menopause. A postauthorization safety study is currently examining the incidence of venous thromboembolism (VTE) among postmenopausal women receiving ospemifene or other SERM (raloxifene, bazedoxifene, or tamoxifen, for noncancer indications), or with untreated VVA. This interim analysis used the US MarketScan Commercial and Medicare Supplemental claims database from 2013 to 2017 to identify incident VTE. The incidence rate and 95% confidence interval of VTE during the first continuous course of treatment (or continuous untreated time for the untreated cohort) were calculated for each cohort overall and by age group, with sensitivity analyses examining incidence in the short term (up to 90 days) and long term (all available follow-up, regardless of treatment changes). Analyses included 8,188 ospemifene users, 11,777 other SERM users, and 220,242 women with untreated VVA. The incidence per 1,000 person-years and 95% confidence interval of VTE were 3.7 (1.7-7.1) for ospemifene, 11.5 (8.9-14.6) for other SERM, and 11.3 (10.8-11.7) for untreated VVA. Stratification by age and altering the time frame for analysis produced results with similar patterns to the primary analysis. This interim analysis of an ongoing study suggests a favorable safety profile for ospemifene with respect to VTE. Comparative analyses with covariate adjustment will be performed when data accrual is complete.

Economic Evaluation of Senshio® (Ospemifene) for the Treatment of Vulvovaginal Atrophy in Scotland.

Local oestrogens, the current treatment for vulvar and vaginal atrophy (VVA), are not suitable for all women. Standard of care (SoC) consists of over-the-counter lubricants and moisturisers. Senshio® (ospemifene) provides a treatment option for postmenopausal women who are not candidates for local vaginal oestrogen therapy who would otherwise have an unmet clinical need. The aim of this study was to estimate the cost-effectiveness of ospemifene, a selective oestrogen receptor modulator, for the treatment of moderate to severe symptomatic VVA in postmenopausal women who are not candidates for local vaginal oestrogen therapy. The Scottish Medicines Consortium (SMC) recently evaluated the clinical and cost-effectiveness evidence of ospemifene plus SoC compared with SoC alone. A cost-effectiveness study, from a National Health Service (NHS) Scotland perspective over a lifetime time horizon, was submitted to the SMC. The cohort-based Markov model used robust clinical evidence from two large pivotal phase III randomised controlled studies and included four health states classified by dyspareunia symptom severity: none, mild, moderate and severe. The movement of women between health states was dependent on the effectiveness of treatment in reducing dyspareunia. Extensive sensitivity analyses were undertaken to assess the level of confidence associated with the base-case results. Treatment with ospemifene was associated with an additional cost of £847 per patient and an increase in quality-adjusted life-years (QALY) of 0.06 per patient. Ospemifene had an incremental cost-effectiveness ratio of £14,138 per QALY. In the probabilistic sensitivity analysis, there was a probability of 89% that ospemifene was cost-effective at a threshold of £20,000 per QALY gained. Ospemifene remained cost-effective under all scenario analyses. The SMC reviewed the clinical and economic evidence and judged that the evidence demonstrated a robust case to support prescribing ospemifene in NHS Scotland. Ospemifene is a cost-effective intervention that has recently been accepted by the SMC for the treatment of postmenopausal women with moderate to severe VVA who are not candidates for local oestrogen.

MON-006 Progesterone Receptor Expression in Endometrial Biopsies After 12 Weeks of Exposure to A 4-µg E2 Softgel Vaginal Insert or Placebo

The softgel, vaginal 17β-estradiol (E2) insert (TX-004HR) significantly improved the maturation index of the vaginal epithelium, dyspareunia and vaginal dryness in menopausal women with vulvar and vaginal atrophy (VVA) and moderate to severe dyspareunia, without histological changes to the endometrium (Constantine G et al, Menopause 2017;24:409-416). The 4-μg and 10-μg E2 doses were FDA approved as Imvexxy® (TherapeuticsMD, Boca Raton, FL), for the treatment of moderate to severe dyspareunia, a symptom of VVA, due to menopause. The progesterone receptor (PR) is an estrogen-regulated gene with expression that is very sensitive to E2 exposure (Xiao CW and Goff AK, J Reprod Fertil.1999;115:101-109). Endometrial PR expression in the biopsies of women using the softgel vaginal 4-µg E2 insert was used as a marker of E2 exposure to determine whether sufficient E2 applied with the vaginal insert reaches the endometrium to upregulate PR expression. Our hypothesis posits that there would be insufficient E2 from the 4-µg E2 insert to stimulate an increase in endometrial PR expression.In this post hoc analysis of the REJOICE trial, endometrial biopsies from 25 women who had a normal baseline biopsy, an on-therapy biopsy after study day 70, and tissue readings from all pathologists were randomly selected from the 4-µg E2 vaginal insert and placebo groups. Endometrial tissue sections were stained to visualize PR expression using PgR1294 (Agilent; Santa Clara, CA). Cell staining was quantified using a trainable feature-recognition algorithm and mean expression levels between baseline and week 12 were analyzed by 2-sided t-tests.Acceptable PR expression results were available for 22 women in the 4-µg E2 group (three had insufficient tissue for analysis) and 25 women in the placebo group. For the 4-µg E2 group, mean ± SD (pmol/mg) PR expression was 0.455 ± 0.203 at baseline and 0.506 ± 0.226 at week 12. For the placebo group, mean PR expression was 0.579 ± 0.196 at baseline and 0.563 ± 0.213 at week 12. Mean PR expression levels at baseline and week 12 were not significantly different from each other within the 4-µg E2 (P=0.438) or placebo (P=0.783) group.No meaningful difference in endometrial PR expression was observed with the vaginal 4-µg E2 insert at week 12. These data support our hypothesis and the assertion that low-dose, local vaginal E2 exposure with the insert placed in the lower part of the vagina, does not pose an endometrial safety issue in postmenopausal women.

Ospemifene in the Management of Vulvar and Vaginal Atrophy: Focus on the Assessment of Patient Acceptability and Ease of Use.

Endocrinological changes that occur with menopause lead to a chronic and progressive condition named vulvar and vaginal atrophy (VVA). This disease is characterized by symptoms such as dryness, dyspareunia, itching, burning, and dysuria. According to recent epidemiological studies, VVA has a high prevalence and can also occur in younger women prior to the menopause, negatively affecting quality of life, sexual function, intimacy and relationship with the partner. Accordingly, therapy should be effective, initiated early and continued for as long as possible. Up to recent years, available therapeutic options have included over-the-counter lubricants and moisturizers, vaginal oestrogens and systemic hormones. These products are not indicated for all women. Hormones are mostly contraindicated in women with a history of hormone-sensitive cancer and are frequently not accepted even by women without contraindications. Local therapies are frequently considered uncomfortable, difficult to apply, and messy. Indeed, these treatments have a high spontaneous discontinuation rate, mostly due to dissatisfaction, safety concern, side effects and difficulty in vaginal placement. Recently, ospemifene, a new non-hormonal systemic remedy, was approved by FDA (Food and Drug Administration) and EMA (European Medicines Agency) for the treatment of the two most bothersome symptoms of VVA: dryness and dyspareunia. Because ospemifene is a selective estrogen receptor modulator (SERM), it can be administered also in women with a history of breast cancer, and this makes it more acceptable by any woman. In addition, its route of administration minimizes those bothersome side effects intrinsic to the vaginal route of administration. Available data indicate that women using ospemifene have higher adherence to treatment, higher persistence and lower discontinuation rate. Satisfaction is higher than with other local therapies and overall health care cost is lower.

Vaginal tamoxifen for treatment of vulvar and vaginal atrophy: Pharmacokinetics and local tolerance in a rabbit model over 28 days.

Vaginally delivered tamoxifen is being developed as alternative to estrogen-based therapies for the treatment of vulvar and vaginal atrophy (VVA) symptoms in subjects at high risk for breast cancer, undergoing treatment for breast cancer with aromatase inhibitors or are breast cancer survivors. Tamoxifen (1 or 20 mg) was administered intra-vaginally to female rabbits once-daily over a 28-day period to assess its pharmacokinetics, systemic exposure and local vaginal tolerance. Plasma samples were taken to assess concentrations of tamoxifen and its metabolites 4-hydroxytamoxifen and N-desmethyltamoxifen over the first day of vaginal administration and following the last dose on Day 28. In-life observations included evaluation of the vaginal region for signs of irritation. At necropsy, vaginal irritation was assessed by the method of Eckstein which reflect collective histopathological grading of four parameters within the vagina including epithelial morphology, leukocytic infiltration, congestion, and edema. Uterine effects of vaginal tamoxifen were also assessed. Plasma concentrations of tamoxifen were higher following administration of 20 mg tamoxifen compared to 1 mg tamoxifen at both Day 1 and Day 28. The metabolite 4-hydroxytamoxifen could not be detected on Day 1 and concentrations were low at Day 28 at the 1 mg tamoxifen dose. 4-Hydroxytamoxifen concentrations were low, but detectable at Day 1 and 28 following administration of 20 mg tamoxifen. The metabolite N-desmethyltamoxifen was undetectable at the 1 mg and 20 mg doses on Day 1; it remained undetectable at the 1 mg tamoxifen dose at Day 28. N-desmethyltamoxifen was detected over the first 8 h of Day 28 then fell below the quantitation limits. There was little to no vaginal or systemic accumulation of tamoxifen following once-daily dosing for 28 days. Tamoxifen accounted for more than 85% of the total systemic exposure compared to its metabolites, 4-hydroxytamoxifen, and N-desmethyltamoxifen. There was essentially no detectable vaginal irritation evident over the course of the study. At necropsy the individual Eckstein scores (maximum score of 16) of the proximal, mid, and distal vagina of females in the 1 mg and 20 mg dose groups were generally comparable in both groups and ranged from minimal to mild magnitude (1 mg dose group: ranging from 1 to 3 in the proximal vagina, 4 to 5 in the mid vagina, and 3 to 7 in the distal vagina; 20 mg dose group: ranging from 3 to 5 in the proximal vagina, 4 to 7 in the mid vagina, and 4 to 5 in the distal vagina). Overall, tamoxifen was absorbed and metabolized following vaginal administration and vaginal irritation was minimal to none at both doses.

Incidence of breast cancer in VVA patients treated with ospemifene and those without any VVA related treatments from a us real-world data

Ospemifene has been marketed in the US since 2013 to treat moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy (VVA) due to menopause. This study used real-world data to estimate the incidence rates of breast cancer in VVA patients without a history of breast cancer treated with ospemifene, and in similar patients without any VVA related treatment.

Weekly vaginal administration of tamoxifen for three months in postmenopausal women with vulvar and vaginal atrophy: a possible new treatment approach?

An exploratory study was conducted recruiting four healthy postmenopausal women suffering from vulvar and vaginal atrophy (VVA). Subjects self-administered vaginal suppositories containing tamoxifen (20 mg). Subjects were instructed to insert one suppository vaginally once daily for one week and twice weekly over a period of three months. Vaginal pH and dryness scores using a visual analog scale (VAS) were recorded at enrollment and subsequent assessments were recorded using self-assessment questionnaires over a three-month period. Serum tamoxifen levels were measured after two months of suppository use. After three months, both vaginal pH and vaginal dryness symptoms showed significant improvement. Vaginal pH scores improved approximately 30% compared to baseline by completion of the study. Vaginal dryness scores improved approximately 63% compared to baseline. As expected, serum tamoxifen levels were negligible ranging from 1.0 ng/ml to 10.0 ng/ml determined after eight weeks on the treatment. The present results suggest that delivery of tamoxifen directly to the vaginal epithelium for the treatment of VVA may be a viable new treatment approach. Therefore, this route of administration may offer an important treatment modality for patients with a history of breast cancer, at risk for breast cancer, and who have hormone-receptor-positive breast cancer, including estrogen receptor-positive (ER-positive), and progesterone receptor-positive (PR-positive) in addition to node negative breast cancer.

TX-004HR clinically improves symptoms of vulvar and vaginal atrophy in postmenopausal women

Objective: This study aimed to evaluate improvement of dyspareunia and associated vaginal dryness with a 17β-estradiol softgel vaginal insert (TX-004HR; TherapeuticsMD, Boca Raton, FL, USA) in women with postmenopausal vulvar and vaginal atrophy (VVA).Methods: Postmenopausal women with VVA and moderate to severe dyspareunia received TX-004HR (4, 10, or 25 μg) or placebo in the 12-week, randomized, double-blind, placebo-controlled, phase 3 REJOICE trial. Post hoc analyses examined improvement levels in dyspareunia and concurrent vaginal dryness with TX-004HR and assessed the effects of patient characteristics on vaginal dryness treatment.Results: Significantly more women treated with TX-004HR (all doses) than placebo had complete resolution or substantial improvement in dyspareunia or vaginal dryness (concurrent with dyspareunia) by 12 weeks, observed as early as week 2 with most doses. TX-004HR significantly improved both dyspareunia and vaginal dryness at least one level versus placebo by week 12 in women with both symptoms. Subgroup analyses showed TX-004HR improved vaginal dryness associated with dyspareunia regardless of age, body mass index, uterine status, prior pregnancy, and vaginal birth number.Conclusion: TX-004HR provided clinically meaningful improvements in dyspareunia and vaginal dryness associated with dyspareunia in postmenopausal women with VVA. Clinicians may be able to use this information when discussing patients’ expectations regarding symptom improvement with the estradiol vaginal insert.

Cariprazine, a selective dopamine D3 receptor partial agonist with unique features to treat schizophrenia negative and cognitive symptoms

The multifactorial consequences of menopausal estrogen deficiency affect numerous tissues throughout the body. Supplemental hormonal therapies carry the burden of a risk/benefit ratio that must be highly individualized. Selective estrogen receptor modulators (SERMs) are estrogen receptor (ER) agonist/antagonists designed to induce benefits comparable with estrogen while minimizing adverse effects. Here, we review the estrogen agonist/antagonist profile of ospemifene, a novel triphenylethylene derivative recently approved to treat dyspareunia, a symptom of vulvar and vaginal atrophy (VVA) due to menopause, both preclinically and clinically. Ospemifene binds ERα and ERβ with approximately equal affinities. In preclinical models, ospemifene increased vaginal and uterine epithelial thickness and mucification to the same extent as estrogen. Ospemifene did not induce endometrial hyperplasia in animal models; there also was no stimulatory effect on endometrial cells. In rat and human mammary cells in vitro, ospemifene evokes a dose-dependent inhibition on estrogen-induced cell responses and cell proliferation, supporting an antiestrogenic effect in breast. In contrast, ospemifene has an estrogenic effect on bone, as seen by improved bone mineral density, strength, mass, and histomorphometry in preclinical models, consistent with improvements in markers of bone resorption and formation in postmenopausal women. Based on the preclinical evidence, ospemifene has beneficial estrogen-like effects on the vaginal epithelium, preliminary evidence to support a neutral endometrial profile, antiproliferative effects in breast, and estrogenic effects in bone. Taken together, especially regarding estrogen-like effects on the vaginal epithelium, ospemifene presents a profile of tissue-specific effects that appear novel among available SERMs and well-suited for the treatment of VVA.

Estradiol vaginal inserts (4 µg and 10 µg) for treating moderate to severe vulvar and vaginal atrophy: a review of phase 3 safety, efficacy and pharmacokinetic data

Objective: To review safety, efficacy and pharmacokinetic (PK) data from the phase 3 REJOICE trial, which evaluated a 17β-estradiol (E2) softgel vaginal insert approved in 2018 for moderate to severe dyspareunia associated with menopausal vulvar and vaginal atrophy (VVA).Methods: REJOICE (Clinicaltrials.gov: NCT02253173) was a randomized, double-blind, placebo-controlled trial in which women with moderate to severe dyspareunia due to menopausal VVA received 4 µg, 10 µg or 25 µg of an E2 vaginal insert or placebo for 12 weeks. The published data for the recently approved 4 µg and 10 µg doses of the E2 vaginal insert, including four co-primary efficacy endpoints (change from baseline to week 12 in percentages of superficial and parabasal cells, vaginal pH and severity of dyspareunia), safety and PK (which included serum E2 levels measured by gas chromatography and tandem mass spectrometry), are summarized here.Results: Women were randomized to receive the E2 vaginal insert (4 µg [n = 186] or 10 µg [n = 188]; Imvexxya) or placebo (n = 187) in the modified intention-to-treat population. The E2 vaginal insert (4 µg and 10 µg) significantly improved the percentages of superficial and parabasal cells (p < .0001), vaginal pH (p < .0001), and the severity score for dyspareunia (p < .05) from baseline to week 12 compared with placebo. The recently approved E2 vaginal insert was well tolerated, with no clinically significant differences in treatment-emergent or serious adverse events versus placebo. Systemic absorption of E2 with both doses was minimal.Conclusions: The recently FDA-approved E2 softgel vaginal insert (4 µg and 10 µg) was safe and effective over 12 weeks for treating moderate to severe dyspareunia due to menopausal VVA with minimal systemic E2 levels.

WISDOM survey: attitudes and behaviors of physicians toward vulvar and vaginal atrophy (VVA) treatment in women including those with breast cancer history.

Objective:To evaluate and compare physicians’ behaviors and attitudes regarding vulvar and vaginal atrophy (VVA) treatment in menopausal women, including women with breast cancer, using an internet-based survey.Methods:The WISDOM survey queried obstetricians and gynecologists (OB/GYNs) and primary care physicians (PCPs) with 23 multipart questions assessing behaviors and attitudes towards VVA treatment.Results:Of 2,424 surveys sent, 945 (39%) responded and 644 (27%) were completed. Of the menopausal women seen by OB/GYNs and PCPs, 44% to 55% reported having VVA symptoms. Physicians prescribed VVA treatments primarily because of effectiveness. Only 34% of OB/GYNs and 17% of PCPs felt comfortable prescribing VVA therapies to women with a personal history of breast cancer. In general, the most common VVA treatment recommended by all was prescription therapy (49%; with or without other therapies) in the form of US Food and Drug Administration-approved vaginal estrogen creams. More OB/GYNs (72%) than PCPs (47%) disagreed that VVA was best treated with over the counter than prescription products. Out-of-pocket cost and fear of risks associated with estrogens were believed to be the main barriers for why women choose not to get treated and why they discontinue treatment.Conclusions:More OB/GYNs than PCPs prescribed VVA treatment, especially vaginal estrogens, for menopausal women, but both groups generally had similar attitudes and behaviors regarding VVA treatment. Physician comfort was low when prescribing to women with a history of breast cancer, despite women's health medical societies supporting vaginal estrogen use in women with a history of estrogen-dependent breast cancer who were unresponsive to nonhormonal therapies when offered in consultation with their oncologist.

033 Don't Stop in the Name of Love

Assess patient refill patterns in the treatment of vulvar and vaginal atrophy (VVA). Analysis of compliance metrics of prescriptions for 858,311 women who filled at least one prescription for VVA treatment was longitudinally tracked utilizing LifeLinkTM Longitudal LRx Prescription Data from IMS Health. The study period spanned 34 months (2013-2016), divided into the following: 1) cohort selection period (4-month period to select women who had either a new-to-therapy or continued prescription); 2) look-back period (18-month period preceding the prescription; 3) look-forward (observation) period (12-month period following the prescription used to evaluate adherence). Approximately 33% of women were new to therapy; the majority used Premarin® and Estrace® creams. While vaginal creams are the leaders for new prescriptions, ∼ 60% of women filled only their initial prescription. Women using vaginal ring, tablet, or the oral SERM (Osphena®) were likely to fill more than one prescription (65% vs ∼40% creams). The trend for multiple fills (5+) followed a similar pattern: ∼7% of women using vaginal estrogen creams, ∼22% of women using a vaginal ring or tablet, and 31% using the oral SERM. Overall, the average number of refills for all products is low, ranging from 2.0 (creams) to 3.9 for the SERM. Average time on therapy was: 369 days for creams, 560 and 604 days for tablet and ring, respectively, and 417 days for the SERM.

Ultra-low doses of TX-004HR to improve symptoms of vulvar and vaginal atrophy (VVA) while maintaining serum levels of estradiol within the normal postmenopausal range.

10074Background: More than 60% of postmenopausal breast cancer (BC) patients have symptoms of dyspareunia and vaginal dryness that often result from endocrine therapy, and are challenging to treat....

Endometrial Safety of Low Dose Vaginal Estrogens in Menopausal Women [39P

INTRODUCTION: 2.3 million women use low dose vaginal estrogen products to treat symptomatic vulvar and vaginal atrophy (VVA) in the US. Most women do not take a concomitant progesterone. A systematic literature search was conducted on the risk of endometrial hyperplasia/cancer and the use of unopposed vaginal estrogen products. METHODS: PubMed and EMBASE were searched for journal articles related to the use of vaginal estrogens in postmenopausal women published in the English language. A total of 5,593 abstracts were reviewed; 37 articles reported vaginal estrogen use and endometrial histology. RESULTS: There were 20 randomized studies with a total of 2,747 women exposed to vaginal estrogen for up to one year; there was no evidence of an increased risk of endometrial hyperplasia/cancer in association with vaginal estrogen products. Other interventional and observational studies identified during the systematic review do not support an increased risk of endometrial hyperplasia or endometrial cancer with low dose vaginal estrogen. The exception is a registry from Denmark that was inconsistent with other studies evaluated and of limited applicability to the US. CONCLUSION: The available evidence from systematic review does not support an increased risk of endometrial hyperplasia or endometrial cancer with low dose vaginal estrogen; however, there are limitations with the applicability of current reports to new lower dose products.

Visual improvements in vaginal mucosa correlate with symptoms of VVA: data from a double-blind, placebo-controlled trial.

Objective:To evaluate the response of the vaginal mucosa with TX-004HR and its correlation with vulvar and vaginal atrophy (VVA) symptoms, and whether visual examination is a useful measure for assessing VVA.Methods:REJOICE was a 12-week, phase 3, multicenter, randomized, double-blind, placebo-controlled study of a vaginal, muco-adhesive, 17β-estradiol softgel capsule (TX-004HR 4, 10, and 25 μg) in postmenopausal women with VVA and moderate-to-severe dyspareunia. Treatments were self-administered vaginally once per day for 2 weeks, then twice per week for 10 weeks. The vagina was visually examined at baseline and at weeks 2, 6, 8, and 12; changes were evaluated using a 4-item scale for vaginal color, vaginal epithelial integrity, vaginal epithelial surface thickness, and vaginal secretions.Results:Significant improvements were observed with all three TX-004HR doses versus placebo in vaginal color (least square mean score changes of −0.96 to −1.06 for TX-004HR doses vs −0.60 for placebo at week 12), epithelial integrity (−0.97 to −1.07 vs −0.60), epithelial surface thickness (−0.94 to −1.03 vs −0.61), and secretions (−1.01 to −1.06 vs −0.64) (P < 0.001 for all comparisons at all time points). Both Pearson's correlations and logistic regression receiver-operating characteristic curve analyses significantly correlated the sum of the individual visual assessment scores with dyspareunia (P < 0.0001) and vaginal dryness (P < 0.0001) at 12 weeks.Conclusions:Greater improvements in the vaginal mucosa of postmenopausal women with VVA and moderate-to-severe dyspareunia were observed with TX-004HR versus placebo, and vaginal mucosa assessment scores correlated with vaginal symptoms of dyspareunia and dryness. Visual vaginal assessment by healthcare professionals is a useful measure for diagnosing VVA and assessing response to treatment.