Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Progestagens and oestrogens, fixed combinations, ATC code: G03FA01.

Estradiol: The active ingredient, synthetic 17β-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of oestrogen production in postmenopausal women, and alleviates menopausal symptoms.

Norethisterone acetate: Synthetic progestagen with actions similar to those of progesterone, a natural female sex hormone. As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestagen reduces the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

Relief of menopausal symptoms is achieved during the first few weeks of treatment. By Week 3, the decrease in mean number of moderate to severe hot flushes for the 0.5 mg estradiol treatment group was statistically significant (p≤0.001) when compared to the placebo group. This reduction remained until the conclusion of the study at week 24.

Eviana is a continuous combined HRT product containing 17β-estradiol and norethisterone acetate with the intent of avoiding the regular withdrawal bleeding associated with cyclic or sequential HRT.
Amenorrhoea (no bleeding or spotting) was seen in 89% of the women in month 6 of treatment.
Bleeding and/or spotting was observed in 11 to 15% of the women during the first 6 months of treatment.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Following oral administration of Eviana, 17β-estradiol is absorbed from the gastrointestinal tract, undergoes a first-pass metabolism in the liver and other enteric organs, and reaches a peak plasma concentration within 5-8 hours. After administration of 2 Eviana tablets, the average peak plasma concentration was 24 pg/ml (CV 38 %). The half-life of 17β-estradiol is about 15 hours. It circulates bound to SHBG (37%) and to albumin (61%), while only approximately 1-2% is unbound.
Metabolism of 17β-estradiol, occurs mainly in the liver and the gut but also in target organs, and involves the formation of less active or inactive metabolites, including oestrone, catecholoestrogens and several oestrogen sulfates and glucuronides. Conjugated oestrogens are excreted with the bile, hydrolysed and reabsorbed (enterohepatic circulation), and mainly eliminated in urine in biologically inactive form.

After oral administration, norethisterone acetate is rapidly absorbed and transformed to norethisterone (NET). It undergoes first-pass metabolism in the liver and other enteric organs, and reaches a peak plasma concentration of approximately 2.4 ng/ml CV 41% (after administration of 2 Eviana tablets) within 0.5 -1.5 hours. The terminal half-life of NET is about 9-11 hours. NET binds to SHBG (36%) and to albumin (61%). The most important metabolites are isomers of 5α-dihydro-NET and of tetrahydro-NET, which are excreted mainly in the urine as sulfate or glucuronide conjugates.

The pharmacokinetics of estradiol is not influenced by norethisterone acetate.

The pharmacokinetic properties in the elderly have not been studied.