Divigel Mechanism of Action

Pharmacotherapeutic Group: Natural and semisynthetic estrogens, plain. ATC Code: G03CA03.
Pharmacology: The active ingredient in Divigel, synthetic 17β-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of estrogen production in menopausal women and alleviates menopausal symptoms. Estrogens prevent bone loss following menopause or ovariectomy.
Clinical Trial Information: The pharmacodynamics of Divigel are similar to those of oral estrogens, but the major difference to oral administration lies in the pharmacokinetic profile. The clinical efficacy of Divigel in the treatment of menopausal symptoms is comparable to that of per oral estrogen.
Relief of Estrogen Deficiency Symptoms and Bleeding Patterns: Relief of menopausal symptoms was achieved during the 1st few weeks of treatment.
Prevention of Osteoporosis: Estrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. The effect of estrogens on the bone mineral density is dose-dependent. Protection appears to be effective for as long as treatment is continued. After discontinuation of hormone replacement therapy (HRT), bone mass is lost at a rate similar to that in untreated women.
Evidence from the Women's Health Initiative (WHI) trial and meta-analyzed trials shows that current use of HRT, alone or in combination with a progestagen, given to predominantly healthy women, reduces the risk of hip, vertebral, and other osteoporotic fractures. Hormone replacement therapy may also prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for that is limited.
Pharmacokinetics: Divigel is an alcohol-based estradiol gel. When applied to the skin, the alcohol evaporates rapidly and estradiol is absorbed through the skin, into the circulation. Application of Divigel on area of 200-400 cm² (size of 1-2 hands) does not affect the amount of estradiol absorbed. However, if Divigel is applied to larger area, absorption decreases significantly. To some extent, however, the estradiol is stored in SC tissue from where it is released gradually into circulation. Percutaneous administration circumvents the hepatic first-pass metabolism. For these reasons, the fluctuations in the plasma estrogen concentrations with Divigel are less pronounced than with per oral estrogen.
A 0.5-, 1-, and 1.5-mg percutaneous dose of estradiol (Divigel 0.5, 1, 1.5 g) results in a plasma concentration (C_max) of about 143, 247 and 582 pmol/L, respectively. The corresponding mean C average concentrations over the dosing interval are 75, 124 and 210 pmol/L. The corresponding mean minimum plasma concentration (C_min) concentrations were 92, 101 and 152 pmol/L, respectively.
During Divigel treatment, the estradiol/estrone ratio remains between 0.4 and 0.7, while for oral estrogen treatment, it usually drops to <0.2. The mean estradiol exposure at steady state of Divigel is 82% compared with an equivalent oral dose of estradiol valerate.
Otherwise the metabolism and excretion of transdermal estradiol follow the fate of natural estrogens.
Toxicology: Preclinical Safety Data: Estradiol is a natural female hormone with an established clinical use. Therefore, no toxicological studies have been performed with Divigel. The necessary studies on the irritant effects of the gel have been studied in rabbits and skin sensitization in guinea pig. Based on the results from these studies, it can be concluded that Divigel very infrequently could cause mild skin irritation. Skin irritation can be reduced by daily change of the application site.