Source: Health Products Regulatory Authority (IE) Revision Year: 2016 Publisher: Pfizer Healthcare Ireland, 9 Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24
Pharmacotherapeutic group: Progestagen and oestrogen in combination
ATC code: G03FA16
The active ingredient, synthetic 17-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.
Trimegestone is a 19-norpregnane progestagen, with an in vitro affinity for the progesterone receptor approximately 6 times that of progesterone. Trimegestone has no significant androgenic, oestrogenic, mineralocorticoid, glucocorticoid, or antiglucocorticoid activity in vivo.
As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestagen reduces, but does not eliminate the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.
Relief of menopausal symptoms was achieved during the first few weeks of treatment.
The incidence of amenorrhea (no bleeding or spotting) increased over time in women treated with Totelle.
Amenorrhea was seen in 86% of women during months 10 –12 treatment. Break through bleeding and/or spotting appeared in 41% of the women during the first three months and in 14% of women during months 10-12 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 show 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.
After 2 years of treatment with Totelle, the increase in lumbar spine bone mineral density (BMD) was 5.32% ± 3.63%. The percentage of women who maintained or gained BMD in the lumbar zone during treatment was 92%.
Totelle also had an effect on hip BMD. The increase after 2 years was 2.84% ± 3.01% at femoral neck and 2.93% ± 2.62% at total hip. The percentage of women who maintained or gained BMD in femoral neck and total hip during treatment was 82% and 89%, respectively.
Following oral administration of 1 mg estradiol in micronized form, rapid absorption from the gastrointestinal tract occurs. Concomitant intake of food moderately increases the extent of absorption of estradiol when administered as Totelle. Estradiol undergoes extensive first-pass metabolism in the liver and small intestine and reaches peak plasma concentrations of approximately 14 to 72 pg/ml within 4 to 8 hours after a single dose. Oestrogens are mainly excreted in urine in a biologically inactive form; they are also excreted in bile, where they are hydrolysed and reabsorbed (enterohepatic circulation). After repeated administration of 1 mg estradiol, the average plasma concentration is approximately 50 pg/ml with minimum plasma concentrations of 20 pg/ml. There were no alterations in the pharmacokinetics of estradiol when it was co-administered with trimegestone. Estradiol is highly bound to plasma proteins (98%), mainly albumin. Metabolism of estradiol occurs mainly in the liver and gut but also in target organs, and involves the formation of less active or inactive metabolites, including estrone, catecholoestrogens and several oestrogen sulfates and glucuronides.
After single oral doses of 0.125 mg administered under fasting conditions to postmenopausal women, trimegestone is rapidly and completely absorbed with peak plasma concentrations of 2 to 5 ng/ml reached within 30 minutes. Food decreases the rate of absorption of trimegestone and reduces Cmax by approximately 50% but does not affect the extent of its absorption when administered as Totelle. The absolute bioavailability after oral administration is approximately 100%. The terminal elimination half-life is approximately 17 hours (range 7 to 37 hours). The pharmacokinetics of trimegestone are dose proportional within the dose range of 0.0625 to 1 mg. After repeated once-a-day administration of 0.125 mg, steady state is reached by the third administration with average concentrations around 0.5 ng/ml and minimum plasma concentrations of 0.2 ng/ml. The pharmacokinetics of trimegestone after repeated administration can be predicted from single dose pharmacokinetics.
Trimegestone and its main metabolite trimegestone sulfate are highly bound to human plasma proteins (98%). Over the range of the concentrations reached after administration of the doses used in the clinical studies, the binding is constant and nonsaturable. The volume of distribution at steady state after intravenous administration is 1.8 l/kg.
Trimegestone is highly metabolised. The major metabolic pathway is sulfoconjugation; a minor pathway is oxidation via the CYP3A4 isoenzyme based on in vitro data. Trimegestone sulfate has 10 times greater plasma concentrations and a longer half-life (30 hours) than trimegestone, but less than one-tenth the progestin receptor-binding affinity of trimegestone. In plasma trimegestone sulfate is the main constituent of AUC after an oral single dose (approximately 55%). Unchanged trimegestone constitutes approximately 8% of AUC, while trimegestone glucuronide and 1- and 6-hydroxylated metabolites together constitute approximately 5% of AUC. After oral administration of radiolabeled trimegestone, 38% of the dose is excreted in urine while 54% is excreted in faeces. No unchanged trimegestone is excreted in urine.
No differences in pharmacokinetic parameters for estradiol, trimegestone, and trimegestone sulfate were observed in elderly women (>65 years) compared with younger postmenopausal women.
In women with mild to moderate renal dysfunction (creatinine clearance >30 ml/min/1.73 m²) no effect on plasma concentrations of estradiol, trimegestone, and trimegestone sulfate were seen. In women with severe renal dysfunction (creatinine clearance <30 ml/min/1.73 m²) data are scarce but indicate an increase in plasma concentrations of estradiol and trimegestone sulfate.
No pharmacokinetic studies have been conducted in women with liver disease.
In reproductive toxicity studies estradiol showed embryotoxic effects and induced feminisation of male foetuses. The relevance of these data for human exposure is unknown (see section 4.6).
Six (6) month toxicology studies in the rat and monkey showed no specific target organ toxicity other than effects associated with the progestomimetic action of the compound. Embryotoxicity studies were conducted with high dosages of trimegestone alone in rats and rabbits. Histological examinations in rabbits showed a dose dependent masculinization of some female foetuses at all doses tested. This effect has been reported for other progestagens, and the relevance of this observation to humans is unknown.
In long-term studies in monkeys, estradiol/trimegestone induced reversible dose- and time-dependent hyperglycaemia at exposures that were approximately 6 or more times greater than those occurring in women. In specific clinical studies at the recommended dosage, no adverse effect on glucose and insulin metabolism has been seen. Carcinogenicity studies in the mouse and rat showed only dose-related hormone-dependent neoplasms, an effect recognised for other oestrogen/progestagen combinations.
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