Source: Health Products Regulatory Authority (IE) Revision Year: 2022 Publisher: Novo Nordisk A/S, Novo Allé, DK-2880, Bagsværd, Denmark
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 menopausal 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.
Relief of menopausal symptoms is achieved during the first few weeks of treatment.
Kliogest is a continuous combined HRT given with the intent of avoiding the regular withdrawal bleeding associated with cyclic or sequential HRT. Amenorrhoea (no bleeding and spotting) was seen in 94% of the women during months 10-12 of treatment. Bleeding and/or spotting was observed in 30% of the women during the first 3 months of treatment and in 6% 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-analysis of trials show that current use of HRT, oestrogen 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 Kliogest on bone mineral density were examined in a 2-year, randomised, double-blind, placebo-controlled clinical trial in postmenopausal women (n=327, including 48 on Kliogest). All women received calcium supplementation 1,000 mg daily. Kliogest 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 after 2 years of treatment with Kliogest 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 Kliogest was 91% after 2 years of treatment.
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 44 pg/ml (range 30-53 pg/ml) within 6 hours after intake of 1 Kliogest tablet. The half-life of 17β-estradiol is about 18 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. 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 9 ng/ml (range 6-11 ng/ml) within 1 hour after intake of 1 mg. The terminal half-life of NET is about 10 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.
The toxicity profiles of estradiol and norethisterone acetate are well-known. There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the summary of product characteristics.
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