ESTRADERM Transdermal patch Ref.[27763] Active ingredients: Estradiol

Absorption

Steady-state serum oestradiol concentrations are reached within 8 hours after application of Estraderm MX 50 to the skin, and remain stable during 4 days. The mean E2 concentration during steady-state of Estraderm MX 50 is 41 pg/mL in healthy postmenopausal women, corresponding to a mean increase of 37 pg/mL over the mean baseline value of 4 pg/mL (range 2.1 to 9.0 pg/mL). The E2:E1 ratio increases from a postmenopausal value of 0.3 to a value of 1.3, similar to the physiological ratio of E2 to E1 observed before the menopause in women with normally functioning ovaries. During continuous treatment of postmenopausal women with Estraderm MX 50 twice weekly for 12 weeks, mean E2 plasma concentrations rise by 36 pg/mL above baseline at the end of the treatment phase, without any indication that accumulation of E2 levels occurs.

With Estraderm MX 25, E2 plasma levels half those observed with Estraderm MX 50 are measured, and with Estraderm MX 100 plasma E2 levels are slightly more than double those measured with Estraderm MX 50.

Plasma oestradiol concentrations return to baseline value within 24 hours after removal of the patch.

Distribution

In plasma, oestradiol is largely bound to sex hormone binding globulin (SHBG) and albumin. Only a fraction is free and biologically active.

Metabolism

Transdermally applied oestradiol is metabolised in the same way as the endogenous hormone. Oestradiol is metabolised to oestrone, then later – primarily in the liver – to oestriol, epioestriol and catechol oestrogens, which are then conjugated to sulphates and glucoronides. Cytochrome 450 isoforms CYP1A2 and CYP3A4 catalyse the hydroxylation of oestradiol forming oestriol. Oestriol is glucuronidated by UGT1A1 and UGT2B7 in humans. Metabolic plasma clearance ranges from 650 to 900 L/(day x m²). Oestradiol metabolites are also subject to enterohepatic circulation. Oestradiol metabolites are far less active than oestradiol.

Elimination

Oestradiol and its metabolites are mainly excreted in the urine. The plasma elimination half-life of oestradiol is about 1 hour. Oestradiol conjugates excreted in the urine return to pre-application levels on the second or third day after removal of the system.

Animal studies with oestradiol have only shown effects which can be expected from an estrogenic substance.

Acute toxicity of oestrogens is low. Because of marked differences between animal species and between animals and humans, preclinical results possess a limited predictive value for the application of oestrogens in humans.

In experimental animals oestradiol displayed an embryolethal effect at relatively low doses; malformations of the urogenital tract and feminisation of male foetuses were observed.

Long-term, continuous administration of natural and synthetic oestrogens in certain animal species increases the frequency of carcinomas of the mammary gland, uterus, cervix, vagina, testis, and liver.