Source: Health Products and Food Branch (CA) Revision Year: 2017
OESCLIM delivers estradiol-17β, a physiologic hormone, transdermally into the systemic circulation. Consequently, the estradiol-17β does not undergo first-pass liver and intestinal metabolism and estradiol-17β serum levels are comparable to those seen in premenopausal women in the early follicular phase of the menstrual cycle. Estradiol-17β stimulates target tissues such as the uterus, breast and vagina.
OESCLIM contains estradiol-17β in an adhesive transdermal therapeutic system designed for application to an area of intact skin. It is designed to release controlled amounts of estradiol-17β continuously through the skin at a rate sufficient to raise circulating estradiol to premenopausal blood levels. Thus, OESCLIM provides a replacement for physiological estradiol.
Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) through a negative feedback mechanism and estrogen replacement therapy acts to reduce the elevated levels of these hormones seen in postmenopausal women.
The pharmacokinetics of transdermally administered estradiol using OESCLIM have been evaluated in a total of 138 healthy postmenopausal women in nine clinical and biopharmaceutic studies.
Approximately twenty-four hours after the application, the mean values of estradiol maximal concentrations (Cmax) are 25, 81 and 108 pg/mL respectively with OESCLIM 25, 50 and 100, and estimated Cmax values are 38 and 75 pg/mL for OESCLIM 37.5 and 75 respectively. Serum levels then remain practically constant throughout the application period (3-4 days). Seventy-two hours (3 days) after application, estradiol serum levels are practically the same as the mean values measured throughout the application period, i.e. 18, 46 and 64 pg/mL, respectively for OESCLIM 25, 50 and 100, and the estimated average serum estradiol concentrations over 72 hours are 31 and 52 pg/mL for OESCLIM 37.5 and 75 respectively.
Repeated applications over three weeks do not lead to accumulation of estradiol.
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estradiol and other naturally occurring estrogens are bound mainly to sex hormone binding globulin (SHBG), and to lesser degree to albumin.
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
Since transdermally absorbed estradiol is not subject to first-pass liver metabolism, the ratio of serum concentrations of estradiol to either of its major metabolites, estrone or estrone sulfate, is closer to those observed in premenopausal women than when administered by the oral route of administration.
Mean ratios for E2/E1 (estradiol/estrone) serum concentrations during OESCLIM patch application are similar to those observed in women before menopause, approximately equal to one.
Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Estradiol serum concentrations return to baseline values within eight hours after patch removal.
Estrogens (naturally occurring, their derivatives or synthetic estrogens) are the basis of postmenopausal Hormonal Replacement Therapy (HRT). Mashchak et al.16 compared the metabolic effects of different estrogens given orally and reported that the physiological hormone estradiol induced the least metabolic disturbances.
It has been clearly demonstrated that estradiol is metabolised to a lesser extent when administered by the transdermal route than by the oral route. The transdermal route, by avoiding “first-pass” metabolism, allows a considerable reduction in the quantity of estradiol administered. Treatment with a patch that delivers 100 μg of estradiol per day results in mean serum levels of estradiol comparable to those obtained with 2 mg/day of micronised estradiol given orally. Moreover, oral estradiol administration results in serum concentrations of estrone, estrone glucuronide and estrone sulphate that are 3, 13 and 4 fold higher respectively, than after transdermal administration. Thus, after transdermal estradiol administration, the estradiol/estrone ratio in the serum is close to 1, the normal value present before menopause (this ratio is approximately 0.2 when estradiol is administered orally).21
Similarly, serum levels of estradiol glucuronides and sulphates, as well as oestriol glucuronides and sulphates, are 11, 5, 7 and 10 fold higher, respectively, after oral treatment than after transdermal treatment.25
The transdermal administration of estradiol provides dose levels of estradiol and estradiol metabolites that more closely approach the physiological than the oral route.
The significant difference in estradiol metabolism between the oral and transdermal routes is also evident in the results of urinary elimination. The concentration of estradiol and estrone conjugates in the urine is in fact 56 μg/g and 183 μg/g of creatinine, respectively, after 3 days of treatment with 2 mg/day of oral estradiol. After a 3-day application of a patch which delivers 100 μg/day, the urinary conjugates of estradiol and estrone did not exceed 4.2 μg/g and 11.3 μg/g of creatinine, respectively.4
A similar situation exists for estradiol distribution studies. Estrogens in the blood stream are bound to albumin, sex hormone-binding globulin (SHBG), cortisol-binding globulin and alpha-1 glycoproteins. It has been shown that three months treatment with 0.1 mg/day of estradiol by the transdermal route does not significantly modify estradiol or estrone binding to plasma transport proteins.10
Moreover, the transdermal route avoids unwanted metabolic effects following oral administration, such as an increase in angiotensinogen or a decrease in antithrombin III.10,11
Excess estradiol is one of the pre-disposing factors in the development of certain tumours, principally in the uterus, mammary and pituitary glands. These effects have been studied after long-term administration in rodents. Exposure in dogs and in primates has not been sufficiently long to reveal this type of activity. However, hyperplasia of the endometrium and the mammary glands, and increased secretory activity of the pituitary suggest that effects occurred at these sites in the above species.
In hamsters, tumour-inducing effects of mesenchymatous origin were observed in the kidneys. No such effects occur in rats, mice or humans. Hepatocarcinomas have been reported in rats after 9 and 12 months treatment with synthetic estrogens such as ethynyl estradiol and mestranol. Such effects have not been reported for estradiol-17β. Furthermore, estradiol administered by the transdermal route does not undergo “first pass” effect through the liver and thus avoids deleterious metabolic effects.
Estradiol is devoid of any mutagenic and/or clastogenic potential. Aneuploidy effects have been observed in vitro.
The carcinogenic potential (uterus, mammary glands and pituitary) of estradiol has been clearly established in animals. Its pre-neoplastic effects on the endometrium are reduced if a progestogen is associated with the estradiol.
No relationship has been established between the risk of pituitary tumours and estrogen treatment in postmenopausal women. Estradiol is contra-indicated in women presenting with tumours of the breast or the pituitary.
The OESCLIM transdermal system was tested in the rabbit and the guinea-pig to evaluate its irritative and sensitizing potential. Three duplicate studies, two acute and two sub-acute local tolerability studies in rabbits and two sensitization studies in guinea-pigs, were performed. The patch was found to be only slightly irritating and had no sensitizing potential.
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