Determination of estradiol and progesterone content in capsules and creams from compounding pharmacies.

OBJECTIVES: To analytically characterize the doses of estradiol and progesterone found in compounded combined forms of oral capsule and transdermal cream formulations, and determine the consistency of the hormone formulations within a batch. METHODS: Prescriptions for combined estradiol/progesterone capsules (0.5 and 100 mg, respectively) and creams (0.5 and 100 mg/g, respectively) were sent to 15 custom-compounding pharmacies. Estradiol and progesterone levels were measured by radioimmunoassays. Hormone levels were measured in 2 capsules and 2 creams from each pharmacy; 10 capsules from 3 pharmacies; and top/middle/bottom layer of cream containers to assess consistency. The magnitude and sources of variation for the measurements were examined by analysis of variance models. RESULTS: Thirteen pharmacies filled the prescriptions. Measured estradiol levels were 0.365 to 0.551 mg for capsules and 0.433 to 0.55 mg/g for creams, and progesterone levels were 90.8 to 135 mg for capsules and 93 to 118 mg/g for creams. Greater variations in estradiol levels were observed between pharmacies for estradiol in capsules than in creams; however, measured estradiol levels within pharmacies were more consistent in the capsules than the creams. Similar results were obtained for progesterone levels. CONCLUSION: The variations in estradiol and progesterone levels observed in compounded hormone therapy formulations justify concerns regarding risks as a result of variability, which have been outlined by The North American Menopause Society, the American College of Obstetricians and Gynecologists, and the US Food and Drug Administration (FDA) in their statements regarding compounded hormone use. These data support the need for an US FDA-approved bioidentical hormone therapy. : Video Summary: Supplemental Digital Content 1, http://links.lww.com/MENO/A425.

A vaginal estradiol softgel capsule, TX-004HR, has negligible to very low systemic absorption of estradiol: Efficacy and pharmacokinetic data review.

This paper reviews the efficacy, safety, and systemic absorption of estradiol with TX-004HR, an investigational, low-dose 17ß-estradiol vaginal softgel capsule, designed to treat vulvar and vaginal atrophy (VVA) in postmenopausal women, with an improved user experience. In phase 2 (NCT02449902) and phase 3 REJOICE (NCT02253173) studies, TX-004HR significantly improved the proportions of vaginal superficial and parabasal cells and vaginal pH, and in the phase 3 study decreased the severity of dyspareunia, vaginal dryness, and vulvar and/or vaginal itching or irritation. In two randomized, phase 1 trials, estradiol Cmax and AUC0-24 were significantly lower with 10µg and 25µg TX-004HR than with the same doses of an approved vaginal estradiol tablet. A substudy (n=72) of the REJOICE trial showed that estradiol Cavg and AUC0-24 with 4µg and 10µg TX-004HR were not different from placebo on days 1 and 14. While TX-004HR 25µg was associated with higher Cavg and AUC0-24 versus placebo on days 1 and 14, these levels remained within the postmenopausal range. Estradiol day-84 values for all three doses were not different from placebo, demonstrating no estradiol accumulation. All TX-004HR doses were well tolerated and had an acceptable safety profile in all reviewed studies. The local vaginal efficacy of TX-004HR was significantly better than that of placebo, while the overall safety profile was similar to that of placebo. Negligible to very low systemic estradiol absorption was observed whether given at 4, 10, or 25µg. If approved, TX-004HR may be an alternative option for women with symptomatic VVA without increasing mean systemic estradiol absorption above postmenopausal levels.

A randomized, double-blind, placebo-controlled phase 2 pilot trial evaluating a novel, vaginal softgel capsule containing solubilized estradiol.

OBJECTIVE: The aim of the study was to evaluate the safety and efficacy of vaginal estradiol (E2) softgel capsules for moderate-to-severe symptoms of vulvar and vaginal atrophy (VVA). Previous phase 1 studies showed lower systemic estrogen concentrations with this softgel capsule compared with an approved low-dose vaginal E2 tablet. METHODS: In this randomized, double-blind, placebo-controlled phase 2 study, 50 postmenopausal women (aged 40-75 y) with at least1 moderate-to-severe VVA symptom received 10 µg vaginal E2 softgel capsules or placebo daily for 14 days. Changes from baseline in vaginal maturation index, investigator's assessment of vaginal mucosa (secretions, epithelial integrity, epithelial surface thickness, color), vaginal pH, and most bothersome symptom were assessed. Adverse events were evaluated. RESULTS: Compared with placebo, the percentage of superficial (35.2 percentage points [pp] vs 8.75 pp; P = 0.0002) and intermediate (18.7 pp vs -3.54 pp; P = 0.0017) cells increased from baseline significantly more with vaginal E2 capsules, and parabasal cells decreased significantly more (-54.4 pp vs -4.80 pp; P < 0.0001). Vaginal pH decreased significantly more with vaginal E2 capsules (-0.974 vs -0.339; P = 0.0002). Decreases in severity of atrophic effects on vaginal epithelial integrity (-0.342 vs 0.176; P = 0.0001) and secretions (-0.643 vs -0.274; P = 0.0401) were significantly greater with vaginal E2 capsules vs placebo. There was no statistical difference in most bothersome symptom severity change from baseline. No serious adverse events were reported. CONCLUSIONS: Vaginal E2 softgel capsules are a safe, effective, local treatment option for postmenopausal women with moderate-to-severe VVA, with lower systemic estrogen absorption than currently available intravaginal treatments.

Pharmacokinetics of the first combination 17ß-estradiol/progesterone capsule in clinical development for menopausal hormone therapy.

OBJECTIVE: This study aims to compare the pharmacokinetics and oral bioavailability of a capsule combining 17ß-estradiol and progesterone in a non-peanut oil-containing formulation with those of widely used and approved separate formulations of estradiol and progesterone coadministered to healthy postmenopausal women. METHODS: This was an open-label, balanced, randomized, single-dose, two-treatment, three-period, three-sequence, cross-over, partial-replicate, reference-scaled study. Postmenopausal women (aged 40-65 y) were randomly assigned to one of three dosing sequences of test and reference products (TRR, RTR, or RRT, where T is the test drug and R is the coadministered reference product), with each of the three periods separated by a 14-day washout. The primary pharmacokinetic endpoints were Cmax, AUC(0-t), and AUC(0-inf) for the test and reference products, assessed for bioequivalence using the scaled average bioequivalence or unscaled average bioequivalence method. Safety was assessed by clinical observation, participant-reported adverse events, and laboratory data, including blood levels of hormones. RESULTS: Sixty-six women were randomly assigned, and 62 women (94.0%) completed all three study periods. All AUC and Cmax parameters met bioequivalence criteria for all analytes (estradiol, progesterone, and estrone), except Cmax for total estrone. The extent of estradiol and progesterone absorption was similar between the test product and the reference products. Four adverse events--all considered mild and unrelated to the study drugs--were reported. CONCLUSIONS: The combination 17ß-estradiol/progesterone product demonstrates bioavailability similar to those of the respective reference products of estradiol and progesterone. If regulatory approval is obtained, this new hormone therapy would be the first treatment of menopause symptoms to combine progesterone with 17ß-estradiol in an oral formulation.

17ß-Estradiol and natural progesterone for menopausal hormone therapy: REPLENISH phase 3 study design of a combination capsule and evidence review.

Several formulations combining estrogens and progestins for hormone therapy (HT) have been approved worldwide for the treatment of menopausal symptoms, yet recent data indicate a decline in their use and an increase in compounded bioidentical HT. Up to now, no single product combining natural 17ß-estradiol and progesterone has been approved by the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA). A phase 3 trial (REPLENISH) is underway to study a novel oral formulation of solubilized 17ß-estradiol and natural progesterone combined in a single gelatin capsule (TX-001HR; TherapeuticsMD, Inc, Boca Raton, FL) for treating vasomotor symptoms (VMS) in postmenopausal women. The REPLENISH trial evaluates the efficacy and safety of TX-001HR (4 doses) versus placebo for the reduction of moderate to severe VMS frequency and severity at 4 and 12 weeks and evaluates the endometrial safety of the combinations at 1 year. TX-001HR contains hormones that are molecularly identical to endogenous estradiol and progesterone and is intended as an option for women who prefer bioidentical hormones; further, it does not contain peanut oil, a common allergen. The constituents of TX-001HR, in a pharmacokinetic report, showed similar bioavailability and safety compared with reference estradiol tablets and micronized progesterone capsules administered together. Published data suggest a safer profile of estradiol and natural progesterone compared with HT containing conjugated equine estrogens and progestins. This report summarizes the methodology of the REPLENISH trial and reviews the evidence suggesting clinical differences between HT containing progesterone or progestins, and estradiol or conjugated equine estrogens.