DERMESTRIL SEPTEM Transdermal patch Ref.[51029] Active ingredients: Estradiol

The average half-life of estradiol in plasma is about one hour. Plasma clearance is 650-900 litre/day/m². Estradiol is metabolised mainly in the liver, the most important metabolites are estriol, estrone and their conjugates (glucuronides, sulphates), which are much less active than estradiol.

The metabolites of estradiol are eliminated mainly by the kidney as glucuronides and sulphates. The metabolites of estradiol are also found in faeces, due to an entero-hepatic circulation.

Following cutaneous application of DERMESTRIL-Septem, estradiol is released from the drug-containing adhesive matrix through the skin and reaches the systemic circulation directly, avoiding first-pass metabolism by the liver. Consequently, the estradiol:estrone ratio in plasma, which falls to values below 1 after the menopause and during oral oestrogen replacement therapy, return to pre-menopausal levels (approximately 1) with transdermal estradiol.

The nominal daily in vivo release rate of DERMESTRIL-Septem 25 is 25 microgram of estradiol; the system is active for one week. This release rate results in physiological estradiol serum concentrations, i.e. in the range of those observed during the premenopausal early follicular phase, which are constantly maintained throughout the patch application period.

Physiological concentrations of estradiol were achieved 6 hours after application of DERMESTRIL-Septem 25 in postmenopausal women, with average concentrations (C_average) over 147 pmol/l after 12 hours.

Following repeated applications of DERMESTRIL-Septem 25 patches at one week intervals, mean maximum serum (C_max) estradiol concentrations of 169 pmol/l were obtained at steady-state. The serum concentration of estradiol remained within the physiological levels of premenopausal women throughout the seven days of application and returned to baseline within 12-24 hours after removal of the patch.

The average concentration (C_average) of estradiol in steady-state conditions was 95 pmol/l. The C_min(trough) of estradiol, shown to be at the steady state, was 48 pmol/l.

Animal studies with estradiol have shown expected oestrogenic effects There are no preclinical data of relevance to the prescriber that are additional to those already included in other sections of the SPC.

Local tolerance studies performed in the rabbit have demonstrated the good skin tolerability of the transdermal patch after single and repeated applications. The patch did not show any sensitisation potential in the guinea pig.