Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
Pharmacotherapeutic group: Natural and semisynthetic oestrogens, plain
ATC Code: G03CA03
Vaginally applied oestrogen alleviates the symptoms of vaginal atrophy due to oestrogen deficiency in postmenopausal women.
ESTRING vaginal delivery system is a vaginal ring, which delivers approximately 7.5 microgram/24 hours of 17 ß-estradiol for 3 months. ESTRING vaginal delivery system is only suitable for the treatment of urogenital complaints due to oestrogen deficiency. Its pharmacokinetic profile shows that it is not suitable for postmenopausal complaints which require a systemically active dose of oestrogen (e.g. vasomotor symptoms), neither is it suitable for osteoporosis prevention.
The active ingredient, synthetic 17ß-estradiol, is chemically and biologically identical to endogenous human estradiol. The estradiol from the vaginal ring substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms. It acts locally to restore vaginal pH and to eliminate or reduce symptoms and signs of post-menopausal urogenital oestrogen deficiency.
ESTRING vaginal delivery system presumably increases local estradiol target concentrations, while maintaining very low and stable systemic plasma concentrations. There is limited clinical trial data beyond 2 years and therefore the maximum recommended duration of continuous therapy is 2 years.
The pharmacokinetic properties of estradiol in humans are well known and depend, in large part, on the extent to which estradiol is taken up by the systemic circulation. The clinical effects of ESTRING are therefore governed by the release characteristics of the vaginal ring delivery system.
After a brief initial peak, the release of estradiol from ESTRING vaginal delivery system is constant (7.5 microgram/24 h), for at least 90 days, as governed by Fick’s law of diffusion. As a consequence of the initial release, peak plasma levels of estradiol reach about 55 pg/mL (Cmax) within 3 hours (Tmax) when the patient applies the first ring to a previously untreated, atrophic vagina. This initial peak dissipates rapidly, and plasma estradiol concentrations return to postmenopausal levels (defined as <20 pg/mL) within 4 hours, and achieve a constant level of approximately 10 pg/mL or less within 2-3 days. This level is maintained for the duration of the 90-day treatment period and is below the serum estradiol levels typically seen with use of transdermal oestrogen therapy (approximately 40 to 70 pg/mL). No data are available on the absolute bioavailability of estradiol from ESTRING.
The distribution of exogenous oestrogens is similar to that of endogenous oestrogens. Circulating, unbound oestrogens are known to modulate pharmacological response. Oestrogens circulate in blood bound to sex-hormone binding globulin (SHBG) and albumin. A dynamic equilibrium exists between the conjugated and the unconjugated forms of estradiol and estrone, which undergo rapid interconversion.
Estradiol is mainly metabolized in the liver. Its main metabolites are estriol, estrone, and their conjugates. The plasma half life of estradiol is 1-2 hours. Metabolic plasma clearance varies between 450-625 ml/min/m². The metabolites are mainly excreted via the kidneys as glucuronides and sulfates. Oestrogens also undergo enterohepatic circulation. The vaginal delivery of oestrogens avoids first-pass metabolism and there is limited systemic absorption.
The urinary excretion of total estradiol in the 24-hour urine, 4 and 12 weeks post application of estradiol vaginal ring in a Phase 1 study was 7.23 ± 4.82 nmoles and 8.20 ± 5.45 nmoles, respectively.
Estradiol follows apparent linear kinetics for systemic concentrations up to 550 pmoles/L following administration of vaginal ring containing doses of 2 to 400 mg.
The toxicity profile of estradiol is well known. There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC
Studies on the silicone elastomer indicated that it was non-toxic in in-vitro studies, and non-pyrogenic, non-irritant, and non-sensitizing in short term in-vivo tests. Long-term implantation induced encapsulation equal to or less than the negative control (polyethylene). No toxic reaction or tumour formation was observed with the silicone elastomer.
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