Oral lasofoxifene's effects on moderate to severe vaginal atrophy in postmenopausal women: two phase 3, randomized, controlled trials.

OBJECTIVE: The aim of this study was to demonstrate whether lasofoxifene improves vaginal signs/symptoms of genitourinary syndrome of menopause. METHODS: Two identical, phase 3 trials randomized postmenopausal women with moderate to severe vaginal symptoms to oral lasofoxifene 0.25 or 0.5 mg/d, or placebo, for 12 week. Changes from baseline to week 12 in most bothersome symptom, vaginal pH, and percentages of vaginal parabasal and superficial cells were evaluated. These coprimary endpoints were analyzed using analysis of covariance, except superficial cells, which were analyzed by the nonparametric, rank-based Kruskal-Wallis test. RESULTS: The two studies enrolled 444 and 445 women (mean age, ~60 y), respectively. Coprimary endpoints at week 12 improved with lasofoxifene 0.25 and 0.5 mg/d greater than with placebo ( P < 0.0125 for all). Study 1: most bothersome symptom (least square mean difference from placebo: -0.4 and -0.5 for 0.25 and 0.5 mg/d, respectively), vaginal pH (-0.65, -0.58), and vaginal superficial (5.2%, 5.4%), and parabasal (-39.9%, -34.9%) cells; study 2: most bothersome symptom (-0.4, -0.5), vaginal pH (-0.57, -0.67), and vaginal superficial (3.5%, 2.2%) and parabasal (-34.1%, -33.5%) cells. Some improvements occurred as early as week 2. Most treatment-emergent adverse events were mild or moderate and hot flushes were most frequently reported (lasofoxifene vs placebo: 13%-23% vs 9%-11%). Serious adverse events were infrequent and no deaths occurred. CONCLUSIONS: In two phase 3 trials, oral lasofoxifene 0.25 and 0.5 mg/d provided significant and clinically meaningful improvements in vaginal signs/symptoms with a favorable safety profile, suggesting beneficial effects of lasofoxifene on genitourinary syndrome of menopause.

Pharmacist-driven deprescribing initiative in primary care.

BACKGROUND: Polypharmacy, a broad term to describe the use of numerous and often unnecessary medications, has been connected to frailty, hospital admissions, falls, and even mortality. The Veterans Health Administration (VHA) developed the VIONE (vital, important, optional, not indicated, and every medication has an indication) dashboard to identify patients with polypharmacy and serve as a framework for deprescribing of medications across VHA facilities where it is used in a variety of practice settings by different disciplines. OBJECTIVE: This study aimed to describe the implementation of a pharmacist-led, system-wide, deprescribing initiative in the primary care setting. PRACTICE DESCRIPTION: Interdisciplinary education was provided through academic detailing. Subsequently, patients were identified for inclusion in the project using the VIONE dashboard focusing on those at highest risk of polypharmacy and moving down to the lowest risk. Interested patients underwent a medication reconciliation. A clinical pharmacist practitioner (CPP) then contacted the patient to discuss potential deprescribing options. Recommendations were relayed to the primary care provider (PCP) for final approval and communicated to the patient by the pharmacy team. PRACTICE INNOVATION: Primary care CPPs (n = 3) integrated deprescribing into their standard workload. This service was implemented in the primary care setting across an entire health care system consisting of 16 different primary care teams. EVALUATION METHODS: The initiative's impact was measured by the number of discontinued medications, the acceptance rate of recommendations by the PCP, the potential annualized cost avoidance, and the number of patients referred to CPP medication management clinics. RESULTS: Among 63 patients, a total of 352 medications were deprescribed resulting in a potential annualized cost avoidance of $184,221. The acceptance rate of discontinuation recommendations was 96.7%. Subsequently, 25.4% of patients were referred to pharmacist-led clinics for disease state management. CONCLUSION: Embedding deprescribing into standard CPP workflow within the primary care setting facilitated a way for polypharmacy reduction and allowed the expansion of pharmacy-led services at VA Butler Healthcare System.

Ospemifene: A Novel Oral Therapy for Vulvovaginal Atrophy of Menopause.

Vulvovaginal atrophy (VVA) resulting from estrogen deprivation at menopause often results in distressing vaginal dryness and dyspareunia. Fewer than 25% of affected women seek help for this condition citing embarrassment, cultural values, an aging or unavailable partner and concerns about use of estrogens following the Women's Health Initiative. Available non-hormonal treatments, such as moisturizers, while affording some relief can be messy to apply and do not prevent disease progression. A new oral selective estrogen receptor modulator, ospemifene, has been found to have strong estrogenic activity in vaginal tissues without adverse estrogenic effects at other sites.

Ospemifene for the treatment of menopausal vaginal dryness, a symptom of the genitourinary syndrome of menopause.

Introduction: Vulvovaginal atrophy (VVA), a component of the genitourinary syndrome of menopause, is a progressive condition due to decline in estrogen leading to vaginal and vulvar epithelial changes. Accompanying symptoms of dryness, irritation, burning, dysuria, and/or dyspareunia have a negative impact on quality of life. Ospemifene is a selective estrogen receptor modulator (SERM) approved by the FDA for moderate to severe dyspareunia and vaginal dryness due to postmenopausal VVA. Areas covered: PubMed was searched from inception to March 2019 with keywords ospemifene and vulvar vaginal atrophy to review preclinical and clinical data describing the safety and efficacy of ospemifene for vaginal dryness and dyspareunia due to VVA. Covered topics include efficacy of ospemifene on vaginal cell populations, vaginal pH, and most bothersome VVA symptoms; imaging studies of vulvar and vaginal tissues; effects on sexual function; and safety of ospemifene on endometrium, cardiovascular system, and breast. Expert opinion: Ospemifene is significantly more effective than placebo in all efficacy analyses studied, working through estrogen receptors and possibly androgen receptors. Safety as assessed by adverse events was generally comparable to that with placebo and to other SERMs, and/or adverse events were not clinically meaningful. No cases of endometrial or breast cancer were reported.

Lack of effect of intravaginal dehydroepiandrosterone (DHEA, prasterone) on the endometrium in postmenopausal women.

OBJECTIVE: This study aims to evaluate the effects of intravaginal dehydroepiandrosterone (DHEA, prasterone) on the endometrium in postmenopausal women. METHODS: Intravaginal DHEA (6.5 mg) was administered daily for 52 weeks to 422 women who had endometrial biopsy at baseline and end of study, whereas 15 women were similarly treated for 26 to 52 weeks. Participants in three other studies received 3.25 mg (n = 126), 6.5 mg (n = 129), or 13 mg (n = 30) of DHEA for 12 weeks; women similarly had baseline and end-of-study biopsies. Endometrial biopsy samples were available for 668 women at baseline and end of study, with sufficient material for analysis. RESULTS: Endometrial atrophy or inactive endometrium (668 women) was found in all women treated with intravaginal DHEA. Similar atrophy was observed in 119 of 121 participants with sufficient material for analysis who received placebo. CONCLUSIONS: After cessation of estradiol secretion by the ovaries at menopause, the estrogens made by mechanisms of intracrinology are inactivated intracellularly at their site of formation and action, thus maintaining serum estradiol at biologically inactive concentrations to avoid stimulation of the endometrium. The absence of enzymes that are able to transform DHEA into estrogens in the endometrium explains the typical endometrial atrophy in all normal postmenopausal women in the presence of variable concentrations of circulating endogenous DHEA. According to these mechanisms, the inactive sex steroid precursor DHEA administered intravaginally acts exclusively in the vagina, whereas all serum sex steroids remain well within the biologically inactive postmenopausal reference range, thus avoiding any stimulation of the already atrophic endometrium.

Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and the North American Menopause Society.

INTRODUCTION: The terminology for the genitourinary tract symptoms related to menopause was vulvovaginal atrophy, which does not accurately describe the symptoms nor is a term that resonates well with patients. AIM: In 2012, the Board of Directors of the International Society for the Study of Women's Sexual Health (ISSWSH) and the Board of Trustees of The North American Menopause Society (NAMS) acknowledged the need to review current terminology associated with genitourinary tract symptoms related to menopause. METHODS: The two societies cosponsored a terminology consensus conference, which was held in May 2013. MAIN OUTCOME MEASURE: The development of a new terminology that more accurately described the genitourinary tract symptoms related to menopause. RESULTS: Members of the consensus conference agreed that the term genitourinary syndrome of menopause (GSM) is a medically more accurate, all-encompassing, and publicly acceptable term than vulvovaginal atrophy. GSM is defined as a collection of symptoms and signs associated with a decrease in estrogen and other sex steroids involving changes to the labia majora/minora, clitoris, vestibule/introitus, vagina, urethra, and bladder. The syndrome may include but is not limited to genital symptoms of dryness, burning, and irritation; sexual symptoms of lack of lubrication, discomfort or pain, and impaired function; and urinary symptoms of urgency, dysuria, and recurrent urinary tract infections. Women may present with some or all of the signs and symptoms, which must be bothersome and should not be better accounted for by another diagnosis. CONCLUSION: The term GSM was presented and discussed at the annual meeting of each society. The respective Boards of NAMS and ISSWSH formally endorsed the new terminology--genitourinary syndrome of menopause--in 2014.

Efficacy and safety of an ascending-dose, extended-regimen levonorgestrel/ethinyl estradiol combined oral contraceptive.

OBJECTIVE: To evaluate the efficacy and safety of an ascending-dose, extended-regimen (ADER) combined oral contraceptive consisting of levonorgestrel (LNG) 150 mcg/ethinyl estradiol (EE) 20 mcg for 42 days, LNG 150 mcg/EE 25 mcg for 21 days, LNG 150 mcg/EE 30 mcg for 21 days and EE 10 mcg for 7 days. STUDY DESIGN: This was a multicenter, open-label, phase 3, single-arm study. Sexually active women aged 18-40 years were enrolled and received ADER for up to 1 year (4 consecutive 91-day cycles). Participants kept diaries to record adherence, bleeding/spotting and other contraceptive use. Efficacy was measured using the Pearl Index and the life-table method; safety and tolerability were assessed through reported adverse events (AEs). RESULTS: A total of 3701 women were enrolled and 2144 completed the study. The Pearl Index was 3.19 [95% confidence interval (CI), 2.49-4.03], based on 70 pregnancies that occurred after ADER initiation and ≤ 7 days after the last LNG/EE or EE-only pill in women aged 18-35 years, excluding cycles in which another contraceptive method was used. Life-table pregnancy rate was 2.82% (95% CI, 2.23%-3.57%) for all users aged 18-35 years. Unscheduled bleeding/spotting decreased with increasing EE doses within each cycle and decreased after cycle 1. No unexpected AEs or changes in laboratory parameters were reported. CONCLUSION: This study demonstrated that ADER effectively prevented pregnancy with a favorable safety and tolerability profile.

Long-term safety of ospemifene (52-week extension) in the treatment of vulvar and vaginal atrophy in hysterectomized postmenopausal women.

OBJECTIVE: To examine the long-term safety of oral ospemifene, a non-estrogen tissue-selective estrogen agonist/antagonist, for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy (VVA) due to menopause. STUDY DESIGN: This multicenter, long-term, open-label, safety extension study was conducted in women without a uterus aged 40-80 years (N=301) who received oral ospemifene 60 mg/day for 52 weeks. Participants either continued their 60-mg/day ospemifene dose from the initial 12-week pivotal efficacy study or switched from blinded placebo or ospemifene 30 mg/day to open-label ospemifene 60 mg/day. The 52-week open-label extension period plus initial 12-week treatment period totaled up to 64 weeks of ospemifene exposure. A 4-week posttreatment follow-up ensued (68 weeks total). MAIN OUTCOME MEASURES: Safety assessments included adverse events, laboratory studies, physical and gynecologic examination, vital signs, breast palpation, and mammography. RESULTS: Most treatment-emergent adverse events (TEAEs) during the extension study were mild or moderate in severity. The most common TEAE related to study drug was hot flushes (10%; leading to discontinuation for 2% of patients). One serious TEAE, a non-ST-elevation myocardial infarction in a patient with pre-existing cardiac disease, was considered possibly related to study medication. One mild breast-related TEAE, considered unrelated to study drug, was ongoing at study completion. There were no instances of pelvic organ prolapse, incontinence, venous thromboembolism, fractures, breast cancers or death. No clinically significant adverse changes were observed in other safety parameters. CONCLUSIONS: Ospemifene is clinically safe and generally well tolerated in postmenopausal patients with dyspareunia, a symptom of VVA.

Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy.

OBJECTIVE: The aim of this work was to study the role of ospemifene, a novel selective estrogen receptor modulator, in the treatment of vulvar and vaginal atrophy in postmenopausal women with moderate to severe dyspareunia and physiological vaginal changes. METHODS: This multicenter phase 3 study used a randomized, double-blind, parallel-group design to compare the efficacy, safety, and tolerability of oral ospemifene 60 mg/day versus placebo. A total of 605 women aged 40 to 80 years who self-reported a most bothersome symptom of dyspareunia and had a diagnosis of vulvar and vaginal atrophy were randomized to take a once-daily dose of ospemifene (n = 303) or placebo (n = 302) for 12 weeks. RESULTS: Analysis of the intent-to-treat (n = 605) population found the efficacy of ospemifene to be significantly greater than that of placebo for each of the following coprimary endpoints: percentages of parabasal and superficial cells, vaginal pH, and severity of dyspareunia. With ospemifene, the percentage of parabasal cells and vaginal pH significantly decreased; the percentage of superficial cells significantly increased; and dyspareunia was significantly reduced versus placebo (all P < 0.0001, except for dyspareunia: P = 0.0001). Among the randomized women, 186 (61.4%) in the ospemifene group and 154 (51.0%) in the placebo group reported at least one treatment-emergent adverse event. Hot flushes were the most frequently reported treatment-related adverse event (ospemifene 6.6% vs placebo 3.6%); only one participant discontinued in each group. As determined by the investigators, no serious adverse events related to the study drug were reported. CONCLUSIONS: In this study, once-daily oral ospemifene 60 mg was effective for the treatment of vulvar and vaginal atrophy in postmenopausal women with dyspareunia.

Adding low-dose estrogen to the hormone-free interval: impact on bleeding patterns in users of a 91-day extended regimen oral contraceptive.

BACKGROUND: A cross-study analysis of contraceptive clinical trials for two different 91-day oral contraceptive (OC) regimens was performed to examine the impact on bleeding patterns when supplementing the 7-day hormone-free interval with 10 mcg ethinyl estradiol (EE) daily. STUDY DESIGN: Two separate 1-year Phase 3 clinical programs were conducted using similar study designs. The percentages of subjects reporting bleeding and spotting using electronic diaries for each 91-day cycle were compared. RESULTS: Scheduled bleeding with the EE regimen was less than that reported with the regimen utilizing placebo during Days 85-91, with significant differences noted for all four 91-day cycles. Unscheduled bleeding decreased more quickly with the 91-day regimen containing low-dose EE in place of placebo, with significant differences noted during the third cycle. CONCLUSIONS: This cross-study comparison suggests that the administration of low-dose estrogen in place of placebo in a 91-day extended regimen OC improves the bleeding profile.

A retrospective managed care claims data analysis of medication adherence to vaginal estrogen therapy: implications for clinical practice.

OBJECTIVES: This study sought to assess refill-based treatment duration and adherence to vaginal estrogen therapy (VET) in clinical practice and to compare treatment duration in women prescribed vaginal tablets (VT) or vaginal creams (VC) in clinical trials with that in clinical practice. METHODS: Adults initiating VET between January and June 2004 were identified in 57 commercial health plans in the United States and followed for up to 10 months after treatment initiation. Treatment duration (Kaplan-Meier analysis) and adherence (medication possession ratio [MPR]) were examined for VC and VT cohorts and compared with a weighted average of treatment duration calculated for seven clinical trials identified in the literature. RESULTS: Of 13,074 women (mean age 54 +/- 9.1 years) identified, patients on VT had significantly longer treatment duration compared with patients on VC (149.1 +/- 101.1 days vs. 91.6 +/- 30.0 days, p < 0.01). Among 5,599 patients receiving multiple prescriptions, higher treatment durations were observed for both VT-treated and VC-treated patients (198.5 +/- 82.4 days vs. 177.1 +/- 86.7 days, p < 0.01) compared with 165 days observed in clinical trials. Medication adherence (MPR > or = 80%) was significantly higher among VT users compared with VC users (74% +/- 27% vs. 52% +/- 32%], p < 0.01); OR, 3.24, 95% CI 2.84-3.70). CONCLUSIONS: Duration of VET among patients receiving multiple prescriptions was longer in real-world clinical practice than in clinical trials. Newly treated patients initiating VT were more likely to continue treatment for longer periods and exhibited greater medication adherence than did those on VC.

A randomized, double-blind, placebo-controlled, multicenter study that assessed the endometrial effects of norethindrone acetate plus ethinyl estradiol versus ethinyl estradiol alone.

OBJECTIVE: The purpose of this study was to determine the incidence of endometrial hyperplasia in subjects who receive continuous norethindrone acetate and ethinyl estradiol combinations versus unopposed ethinyl estradiol. STUDY DESIGN: Nine hundred forty-five postmenopausal women were randomly selected for 12 months of treatment with one of six blinded norethindrone acetate/ethinyl estradiol combinations (milligrams of norethindrone acetate/micrograms of ethinyl estradiol: 0/5, 0.25/5, 1/5, 0/10, 0.5/10, or 1/10) or to open-label 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate. Endometrial hyperplasia and endometrial proliferation were assessed by biopsy at screening, months 6 and 12. RESULTS: Endometrial hyperplasia developed in 26 subjects: Placebo, 0/5 and 0.25/5 (1 subject each) and 0/10 (23 subjects). Significantly less endometrial proliferation was measured in the 1/5 norethindrone acetate/ethinyl estradiol and other norethindrone acetate/ethinyl estradiol combination groups and in the 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate group, than in unopposed ethinyl estradiol groups (6 months: P <.004; 12 months: P <.001). Treatment with 1/5 norethindrone acetate/ethinyl estradiol and with other norethindrone acetate/ethinyl estradiol combinations significantly reduced endometrial proliferation compared with 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate (6 and 12 months: P <.02). CONCLUSION: Norethindrone acetate protects the endometrium from estrogen-induced hyperplasia and changes in proliferative status. In addition, norethindrone acetate/ethinyl estradiol-treated subjects had significantly less endometrial proliferation compared with 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate-treated subjects.