Estradiol-Intranasal

Estradiol-intranasal is a nasal spray formulation containing an aqueous solution of 17β-estradiol that has a unique pulse-like pharmacokinetic profile. In a well designed, placebo-controlled trial estradiol-intranasal 200 to 400 μg/day significantly reduced the incidence and severity of climacteric symptoms in women with moderate to severe menopausal symptoms after 4 and 12 weeks’ treatment. The efficacy of estradiol-intranasal 300 μg/day was similar to that of oral estradiol 2 mg/day in this and another double-blind placebo-controlled trial. This equivalent efficacy was maintained in a subgroup of women with initially severe symptoms, and in smokers.

Reductions in the incidence of atrophic vaginal mucosa and genitourinary symptoms and increases in the karyopyknotic index achieved with estradiol-intranasal 300 μg/day were also similar to those observed with oral estradiol 2 mg/day.

Assessments of the effects of estradiol-intranasal on the complications of menopause (increased risk of cardiovascular disease and osteoporosis) are ongoing; however, estradiol-intranasal (sequentially combined with a progestogen) produced significant beneficial effects on some lipid parameters and on markers of bone resorption and formation, and bone mineral density in postmenopausal women. Estradiol-intranasal had no significant effects on serum levels of most of the assessed haemostatic factors, or on angiotensinogen or insulin levels.

Estradiol-intranasal 100 to 600 μg/day was generally well tolerated in clinical trials and most adverse events were mild to moderate. The most commonly reported events were nasal symptoms and mastalgia. There was no evidence of endometrial hyperplasia with up to 1 year’s treatment with estradiol-intranasal 300 μg/day combined with a progestogen. The incidence of mastalgia and withdrawal or breakthrough bleeding was lower with estradiol-intranasal 300 μg/day than with oral estradiol 2 mg/day (both administered with a progestogen) in one trial. In another trial, the incidence of mastalgia was lower with estradiol-intranasal 300 μg/day than with estradiol transdermal 50μg (both administered with a progestogen). However, the overall incidence of adverse events was similar between the two treatments in this trial.

Follicle stimulating hormone (FSH) levels described a U curve with a nadir occurring about 8 hours after administration of estradiol-intranasal. There was also a time-dependent decrease in predose FSH levels over 28 days. In a 12-week study, blood levels of FSH decreased after treatment with estradiol-intranasal 100 to 400 μg/day compared with baseline, but serum levels of sex hormone-binding globulin were only slightly increased compared with placebo. In comparison, oral estradiol 1 and 2 mg/day produced higher serum levels of estrone than of estradiol and reduced FSH levels from baseline, but serum levels of sex hormone-binding globulin were markedly higher than those observed with placebo.

Estradiol-intranasal 100 to 400 μg/day significantly reduced urinary levels of a marker of bone resorption and increased serum levels of some markers of bone formation versus placebo for up to 3 months in a study in 326 postmenopausal women. In the short term, the decrease in bone formation was delayed in recipients of intranasal-estradiol compared with those receiving oral estradiol and this may be related to different effects on serum insulin-like growth factor-1 (IGF-1) levels. In those receiving intransal-estradiol no significant effects were observed on serum levels of IGF-1 or insulin-like growth factor binding protein-3 (IGFBP-3) were observed, while estradiol oral resulted in a marked decrease in IGF-1. After 1 year of estradiol-intranasal 300 μg/day bone turnover was normalised to premenopausal levels. In a nonblind crossover trial in 353 postmenopausal women that compared estradiol-intranasal 300 μg/day with transdermal delivery of estradiol 50 μg/day the urinary marker collagen C-telopeptides was significantly reduced after 3 months with both treatments, (31 % and 28% respectively). After one year bone metabolism was normalised, with a significant and similar decrease from baseline for all markers. In the same study, bone mineral density at the spine and hip was significantly increased after one year of treatment; equivalent to 50μg estradiol transdermal.

Estradiol-intranasal 300 μg/day (cyclically combined with dydrogesterone) significantly reduced serum levels of lipoprotein(a), apolipoprotein B and total cholesterol from baseline in a 24-week comparative study in 120 postmenopausal women. Increases in high density lipoprotein-cholesterol and decreases in low density lipoprotein-cholesterol levels were significantly smaller with estradiol-intranasal than with oral estradiol 2 mg/day, but increases in triglyceride levels were also significantly smaller. This is consistent with the lack of first-pass metabolism associated with intranasal administration.

No significant changes were observed with estradiol-intranasal 300 μg/day on serum levels of antithrombin III, activated factor VII, D-dimer, angiotensinogen or insulin serum levels compared with baseline, but fibrinogen levels significantly increased at 23 weeks in a study in 136 to 153 postmenopausal women. In contrast, oral estradiol 2 mg/day significantly decreased serum antithrombin III levels and doubled serum angiotensinogen levels, but only effects on angiotensinogen levels differed significantly between the two treatments.

Estradiol administered by the nasal route leads to a pulsed pharmacokinetic profile characterised by rapid attainment of maximum plasma concentration (C_max), rapid distribution and a short absorption half-life. The main pharmacokinetic parameters were obtained from a study of 36 postmenopausal women treated with estradiol-intranasal 100 to 450μg administered as a single daily dose, or two divided doses 12 hours apart. C_max occurred within 10 to 30 minutes and the distribution half-life of estradiol-intranasal was short (<10 minutes). Plasma levels of estradiol returned to those seen in untreated postmenopausal women within 8 to 12 hours of the dose. The mean C_max of estrone was about one-third to one-quarter that of estradiol and the time to reach C_max was longer.

Systemic exposure to exogenous estradiol was proportional to dose after estradiol-intranasal (50 to 450μg), and did not differ between once daily and twice daily regimens [based on mean area under the plasma concentration-time curve (AUC) at steady state]. The bioavailability of estradiol-intranasal was 25%.

Estradiol-intranasal does not undergo first-pass metabolism (the ratio of AUC during the first 24 hours for estrone to that of estradiol was 0.8 to 1.1). The apparent terminal elimination half-life (1.5 to 3.7 hours) and apparent plasma clearance (198 to 288 L/h) of exogenous estradiol appeared to be independent of dose.

The mean C_max of estradiol was considerably lower after oral estradiol 2mg or transdermal estradiol 50μg than that observed after all dosages of estradiol-intranasal, whereas the mean C_max of estrone was generally higher after oral estradiol and lower after transdermal estradiol versus estradiol-intranasal. In addition, the time to reach C_max of estradiol and estrone was longer with both oral and transdermal estradiol. Compared with estradiol-intranasal, mean ratios of the AUC for estrone to those for estradiol over the first 48 (tablet) or 72 (patch) hours were about 4-fold higher with oral estradiol, but similar with transdermal estradiol. Systemic exposure to exogenous estradiol after oral 2mg and transdermal 50μg estradiol was similar to that achieved after estradiol-intranasal 300μg. Daily administration of 300μg of intranasal estradiol for two 28-day cycles demonstrated a low intra and inter-patient variability over 24 hour exposure.

The efficacy of estradiol-intranasal has been assessed in two well designed comparative trials with placebo and/or oral estradiol and in a nonblind, comparative trial with transdermal estradiol in 358 to 659 women with moderate to severe menopausal symptoms. Estradiol-intranasal 200 to 400 μg/day was significantly more effective than placebo at reducing Kupperman index (KI) scores and the daily frequency of hot flushes after 4 and 12 weeks’ treatment in one trial. In the other two trials estradiol-intranasal 300 μg/day reduced KI scores and the incidence of hot flushes relative to baseline after 12 to 23 weeks’ treatment.

Estradiol-intranasal 300 μg/day had similar efficacy to that of oral estradiol 2 mg/day after 4 to 23 weeks’ treatment in two trials; this equivalent efficacy was maintained in a subgroup of women with initially severe symptoms and in smokers in terms of KI scores. In addition, reductions in KI scores appeared to be similar between estradiol-intranasal 200 μg/day and oral estradiol 1 mg/day in the dose-ranging trial.

Estradiol-intranasal 300 μg/day also reduced the incidence of atrophic vaginal mucosa, increased the karyopyknotic index and reduced the incidence of genitourinary symptoms, which were similar to effects observed with oral estradiol 2 mg/day.

Estradiol-intranasal 100 to 600 μg/day administered for up to 1 year was generally well tolerated in three trials which included a total of 1435 postmenopausal women, and the majority of adverse events were mild to moderate. Nasal symptoms (itching, rhinorrhoea, sneezing, nosebleeds and application site reactions) and mastalgia were the most commonly reported events, and led to premature withdrawal in 3.4% of cases. Application site reaction of moderate severity occurred in a similar percentage of estradiol-intranasal 100–400 μg/day and placebo recipients (4.1 vs 3.3%). The overall incidence of adverse events was similar between estradiol-intranasal 300 μg/day and oral estradiol 2 mg/day in one trial but mastalgia occurred in 13% more oral estradiol than estradiol-intranasal recipients. Similarly, severe mastalgia was reported in significantly more patients receiving oral estradiol than estradiol-intranasal (5.2 vs 1 %). The overall incidence of adverse events was also similar between estradiol-intranasal 300 μg/day and transdermal estradiol 50 μg/day, but moderate and severe mastalgia was significantly more common in transdermal estradiol recipients (15.5 vs 7.2%; p = 0.02).

No endometrial hyperplasia was reported with estradiol-intranasal (300 μg/day in most patients) combined with a progestogen, administered for at least 1 year in 311 patients.

The incidence of withdrawal bleeding was significantly lower with estradiol-intranasal 300 μg/day than with oral estradiol 2 mg/day (49 vs 69%) and that of breakthrough bleeding also tended to be lower (22.6 vs 26.6%) in one trial in which patients additionally received cyclical progestogen for 6 months. In a trial in which patients received unopposed estradiol-intranasal for 12 weeks followed by 2 weeks of therapy supplemented with medroxyprogesterone the incidence of vaginal bleeding was similar between recipients of estradiol-intranasal 100 to 400 μg/day, oral estradiol 1 and 2 mg/day and placebo. The incidence of withdrawal bleeding (69.3 vs 64.4% of patients) and breakthrough bleeding (13.9 vs 16.7% of patients) did not differ significantly between estradiol-intranasal 300 μg/day and transdermal estradiol 50 μg/day in a 3-month study.

No clinically relevant changes were observed in laboratory safety parameters, bodyweight or diastolic or systolic blood pressure in any treatment group.

The usual recommended dosage is 300 μg/day which can be decreased to 150 μg/day or increased to 450 μg/day if signs of hyper- or hypoestrogenisation occur. The maximum recommended dosage is 600 μg/day. A progestogen should be given in conjunction with estradiol-intranasal for at least 12 days of each cycle in women with an intact uterus.

Estradiol-intranasal can be administered temporarily buccally (at twice the intranasal dosage) in patients with severely blocked nasal passages.

Although the efficacy of estrogens is reduced by the coadministration of enzyme inducers, it is unclear whether these drugs interact with estradiol-intranasal. It is likely, however, that any such interaction will be of less clinical significance than that occurring with estrogens given via the oral route because hepatic first-pass metabolism is avoided with estradiol-intranasal. Estradiol-intranasal may potentially interact with other intranasally administered drugs, but this may be prevented by leaving >30 minutes between administration of the two agents.