Safety of vaginal tamoxifen capsule for vulvovaginal atrophy

Safety of vaginal tamoxifen capsule for vulvovaginal atrophy | Image Credit: © bukhta79 - © bukhta79 - stock.adobe.com.

According to a recent study published in Climacteric, a vaginal tamoxifen capsule (DARE-VVA1) is safe for use in postmenopausal women with vulvovaginal atrophy (VVA).

VVA, presenting as vaginal dryness, itching, and painful intercourse, is caused by reduced mucosal estrogenization in the vaginal epithelium. This thins the vaginal epithelium, leading to a severe impact on quality of life.

To treat VVA, doctors often prescribe forms of localized micro-dose estrogen therapy, which has proven effective in treating VVA. Women with hormone receptor-positive breast cancer or contraindications to systemic estrogen therapy may not receive this therapy because of associated safety risks, presenting a need for alternative therapy.

Tissue-dependent responses may be accomplished in tissues and organs such as the endometrium, breasts, and vagina using tamoxifen. However, there is a need for a non-hormonal, selective estrogen receptor modulator, non-estradiol, local VVA treatment.

To determine the safety and plasma pharmacokinetics (PK) of DARE-VVA1 vaginal inserts, investigators conducted a phase 1/2, randomized, double-blind, placebo-controlled trial. Participants included menopausal women aged 40 to 75 years without exogenous hormone use.

Menopause was defined as, “12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with a serum follicle stimulating hormone concentration of 40 mIU/ml or higher.” Symptom severity was determined using a 4-point Likert scale, with women needing to report moderate or severe symptoms to be included in the study.

Exclusion criteria included diseases which prevented participation, such as pulmonary, renal, cardiovascular, hepatic, and neurological diseases, along with the use of anticoagulant drugs and presence of uncontrolled hypertension. Women with cancer at any point in the past 5 years, estrogen-dependent neoplasia, or undiagnosed vaginal bleeding were also excluded.

Treatment involved a self-administered vaginal soft gel capsule per day for the first 2 weeks, followed by twice weekly administration for 6 weeks. Data on PK, pharmacodynamics, and acceptability was collected throughout 10 visits during treatment.

Study groups included a placebo group and DARE-VVA1 1 mg, 5 mg, 10 mg, and 20 mg groups, with participants randomized through a permuted block algorithm. Investigators and participants were blinded during study procedures.

Treatment emergent adverse events (TEAEs) were evaluated to measure safety. Adverse events included pelvic pain, vaginal discharge, and vaginal or vulvar irritation. Adverse drug reactions (ADRs) were poor reactions to a product which were not intended as part of the treatment. ADRS not consistent with product information were considered unexpected.

Clinical laboratory assessments were used to measure safety, with changes in severity evaluated. Pharmacokinetic evaluations were performed at baseline, 24 hours following administration on days 4, 7, 10, 18, 28, 42, and 56, the final day of treatment. A follow-up sample was also collected on day 63.

Investigators also evaluated efficacy of the treatment by measuring changes in vaginal maturation index (VMI) and vaginal pH. Vaginal epithelial cells were collected and used to categorize the ratio of the 3 cell types, allowing VMI to be calculated. Vaginal VMI and vaginal pH screenings were performed at baseline, every 2 weeks of treatment, and 1 week after treatment.

There were 17 women included in the final analysis, 14 of which completed the study. Compliance for treatment was greater than 95% in most participants, with no severe adverse events or TAEs leading to study discontinuation reported. However, the presence of at least 1 TAE was reported by 88.2% of patients.

TAEs were most often seen in participants receiving 20 mg DARE-VVA1, followed by those receiving placebo. Of participants, 47% reported at least 1 TAE considered related to treatment, with the highest amount reported by participants receiving placebo. ADRs were reported in 29% of participants, none of which were unexpected.

Median plasma concentrations were greatest in participants receiving 20 mg DARE-VVA1, with a peak median measurement of 8.29 ng/ml on day 10 of treatment. Overall, a significant decrease in vaginal pH was seen at the end of treatment compared to baseline in participants receiving DARE-VVA1. 

The greatest decrease in median vaginal pH was seen in the 20 mg DARE-VVA1 group. An increase in VMI was also observed, with the greatest shift also occurring in the 20 mg DARE-VVA1 group.

While research was not focused on efficacy, an overall decrease in symptoms was observed among patients taking DARE-VVA1. The primary endpoint of safety was also met for DARE-VVA1 groups. Investigators recommended future studies on DARE-VVA1 in women with VVA.

Reference

Thurman A, Hull L, Stuckey B, et al. Pharmacokinetics, safety and preliminary pharmacodynamic evaluation of DARE-VVA1: a soft gelatin capsule containing tamoxifen for the treatment of vulvovaginal atrophy. Climacteric. 2023. doi:10.1080/13697137.2023.2211763