Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

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

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.
Oestrogens prevent bone loss following menopause or ovariectomy.

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.

Pharmacodynamic effects

In clinical trials with Activelle, the addition of the norethisterone acetate component enhanced the vasomotor symptom relieving effect of 17β-estradiol.

Relief of menopausal symptoms is achieved during the first few weeks of treatment.

Activelle is a continuous combined HRT given with the intent of avoiding the regular withdrawal bleeding associated with cyclic or sequential HRT. Amenorrhoea (no bleeding or spotting) was seen in 90% of the women during months 9-12 of treatment. Bleeding and/or spotting was observed in 27% of the women during the first 3 months of treatment and in 10% during months 10-12 of treatment.

Oestrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass.
The effect of oestrogens on the bone mineral density is dose-dependent. Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women.

Evidence from the WHI trial and meta-analysed trials shows that current use of HRT, alone or in combination with a progestagen – given to predominantly healthy women – reduces the risk of hip, vertebral and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for that is limited.

The effects of Activelle on bone mineral density were examined in 2 two-year, randomised, double-blind, placebo-controlled clinical trials in postmenopausal women (n=327 in one trial, including 47 on Activelle and 48 on Kliogest (2 mg estradiol and 1 mg norethisterone acetate); and n=135 in the other trial, including 46 on Activelle). All women received calcium supplementation ranging from 500 to 1,000 mg daily.
Activelle significantly prevented bone loss at the lumbar spine, total hip, distal radius and total body in comparison with calcium supplemented placebo-treated women. In early postmenopausal women (1 to 5 years since last menses), the percentage change from baseline in bone mineral density at lumbar spine, femoral neck and femoral trochanter in patients completing 2 years of treatment with Activelle was 4.8+0.6%, 1.6+0.7% and 4.3+0.7% (mean + SEM), respectively, while with the higher dose combination containing 2 mg E2 and 1 mg NETA (Kliogest) it was 5.4+0.7%, 2.9+0.8% and 5.0+0.9%, respectively. The percentage of women who maintained or gained bone mineral density during treatment with Activelle and Kliogest was 87% and 91%, respectively, after 2 years of treatment. In a study conducted in postmenopausal women with a mean age of 58 years, treatment with Activelle for 2 years increased the bone mineral density at lumbar spine by 5.9+0.9%, at total hip by 4.2+1.0%, at distal radius by 2.1±0.6%, and at total body by 3.7+0.6%.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption and distribution of 17β-estradiol

Following oral administration of 17β-estradiol in micronised form, rapid absorption from the gastrointestinal tract occurs. It undergoes extensive first-pass metabolism in the liver and other enteric organs, and reaches a peak plasma concentration of approximately 35 pg/ml (range 21-52 pg/ml) within 5-8 hours. The half-life of 17β-estradiol is about 12-14 hours. It circulates bound to SHBG (37%) and to albumin (61%), while only approximately 1-2% is unbound.

Biotransformation and elimination of 17β-estradiol

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. Oestrogens are excreted with the bile, hydrolysed and reabsorbed (enterohepatic circulation), and mainly eliminated in urine in biologically inactive form.

Absorption and distribution of norethisterone acetate

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 3.9 ng/ml (range 1.4-6.8 ng/ml) within 0.5-1.5 hours. The terminal half-life of NET is about 8-11 hours. NET binds to SHBG (36%) and to albumin (61%).

Biotransformation and elimination of norethisterone acetate

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 pharmacokinetic properties in the elderly have not been studied.