Source: Health Products Regulatory Authority (ZA) Revision Year: 2021 Publisher: Adcock Ingram Limited, 1 New Road, Erand Gardens, Midrand 1685, South Africa
Pharmacological classification: A 21.8.2 Progesterones with estrogens
EVOREL CONTI contains estradiol hemihydrates (17β-estradiol), which is a synthetically prepared estrogen and norethisterone acetate, the acetate ester or norethisterone, a synthetic progestin.
After application to the skin the patch delivers 17ß-estradiol, a physiological hormone, transdermally into the systemic circulation and consequently, the 17β-estradiol does not undergo first pass liver metabolism. In postmenopausal women, EVOREL CONTI raise the estradiol concentrations to levels similar to those in the early follicular phase and maintain these levels over the application period of 3-4 days.
The estradiol/estrone ratio in the plasma of post-menopausal women is between 0,2 to 0,5 which increases after the transdermal application of estradiol to approximately 1 (normal pre-menopausal levels; early follicular phase).
Norethisterone acetate, used in the EVOREL CONTI, is hydrolysed to norethisterone, a synthetic 19-nortestosterone derivative of the 13-methyl gonane group with potent progestational activity. Transdermal norethisterone acetate administration prevents estrogen related endometrial proliferation.
Estradiol distributes widely in the body tissues and is bound to albumin (about 60-65%) and sexhormone-binding globulin (about 35-45%) in serum.
Serum protein binding fractions remain unaltered following transdermal delivery of estradiol. Estradiol is promptly eliminated from the systemic circulation.
Estradiol is metabolised principally into the less pharmacologically active estrone and its conjugates.
Estradiol, estrone and estrone sulphate are interconverted to each other and are excreted in urine as glucuronides and sulphates. The skin metabolises estradiol only to a small extent.
Norethisterone acetate is hydrolysed to the active progestogen, norethisterone. Transdermal delivery of norethisterone acetate produces a sustained level of norethisterone in the systemic circulation.
Norethisterone distributes widely in the body tissues and is bound to albumin (about 61%) and sex hormone binding globulin (about 36%) in serum.
Norethisterone is primarily metabolised by the liver by reduction of the α, β unsaturated ketone structure in ring A of the molecule.
Among the four possible stereoisomeric tetrahydrosteroids, the 5β-, 3α-hydroxy-derivative appears to be the predominant metabolite.
These compounds are primarily excreted in urine and faeces as sulphates and glucuronide conjugates.
In a single and multiple application study in post-menopausal women, serum estradiol concentrations increased rapidly from pre-treatment levels (about 5 pg/ml) after application of an EVOREL CONTI.
At four hours after application, the mean serum estradiol concentration was about 19 pg/ml. A mean peak serum estradiol concentration of about 41 pg/ml above the pre-treatment level was observed at about 23 hours following application.
Serum estradiol concentrations remained elevated for the 3,5 day application period. Concentrations returned rapidly to pre-treatment levels within 24 hours following removal of the patch.
A serum half-life of about 6,6 hours was determined following removal of the patch. Multiple application of the patch resulted in little or no accumulation of estradiol in the systemic circulation.
During use of EVOREL CONTI, the E2/E1 ratios increased rapidly and were maintained at physiological levels at approximated 1. The E2/E1 ratios returned to pre-treatment levels within 24 hours after removal of the patch.
In a single and multiple application study in postmenopausal women, serum norethisterone concentrations rose within 1 day after application of an EVOREL CONTI to a mean steady state level of about 199 pg/ml. Mean steady state serum norethisterone concentrations ranging between about 141–224 pg/ml were maintained for the entire 3,5 day application period following multiple applications. Mean concentrations declined rapidly to the lower limit of assay quantitation at 24 hours after removal of the patch.
A serum half-life of about 15 hours was determined following removal of the patch, indicative of the skin depot effect. As expected from the transdermal delivery only a transient and limited increase in serum norethisterone concentrations was observed following multiple application of the patch.
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