Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom
Pharmacotherapeutic group: Progestogens and estrogens, fixed combinations
ATC Code: G03FA12 (Medroxyprogesterone & estrogen)
The active ingredients are primarily the sulfate esters of estrone, equilin sulfates, 17α-estradiol and 17β-estradiol. These substitute for the loss of estrogen production in menopausal women, and alleviate menopausal symptoms.
As estrogens promote the growth of the endometrium, unopposed estrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestogen reduces but does not eliminate the estrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.
In a 1-year clinical trial (n=2,808), vasomotor symptoms were assessed for efficacy during the first 12 weeks of treatment in a subset of symptomatic women (n=241) who had at least 7 moderate or severe hot flushes daily or 50 moderate to severe hot flushes during the week before randomisation. Premique 0.625mg/2.5mg (conjugated estrogens/medroxyprogesterone acetate) was shown to be statistically better than placebo at weeks 4, 8 and 12 for relief of both frequency and severity of moderate to severe vasomotor symptoms.
In two clinical trials, the incidence of amenorrhoea (no bleeding or spotting) increased over time in women treated with Premique 0.625 mg/2.5 mg. Amenorrhoea was seen in 68% of women at cycle 6 and 77% of women at cycle 12. Breakthrough bleeding and/or spotting appeared in 48% during the first 3 months, and in 24% of women during months 10-12 of treatment.
Premique Low Dose contains a formulation of medroxyprogesterone acetate (MPA) that is immediately released and conjugated estrogens that are slowly released over several hours.
Following single dose administration of Premique under fasting conditions, the time taken to reach the peak plasma concentration (Tmax) was 6-9 hours and the peak plasma concentration (Cmax±SD) was 149±52 pg/ml and 83± 32pg/ml for the unconjugated estrogens, estrone and equilin, respectively. Peak plasma concentration (Cmax±SD) of 724±475 pg/ml was reached at 2 hours (Tmax) for MPA.
When single doses of Premique were administered with a high-fat meal, there was a two-fold increase in MPA Cmax (1830±1050 pg/ml) and AUC was increased by approximately 30%. Food had little or no significant effect on the exposure of unconjugated and conjugated estrogens. These changes to MPA Cmax and AUC after a high fat meal are not considered to be clinically meaningful as the pharmacokinetics of MPA are highly variable and safety of a wide range of MPA doses up to 10mg have been demonstrated.
Premique can be administered with or without food.
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. MPA is approximately 90% bound to plasma proteins but does not bind to SHBG.
Exogenous estrogens are metabolised in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women a significant proportion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Metabolism and elimination of MPA occur primarily in the liver via hydroxylation, with subsequent conjugation and elimination in the urine.
Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Most metabolites of MPA are extracted as glucuronide conjugates with only minor amounts secreted as sulfates.
Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, cervix, vagina and liver.
In a two-year oral study in which female rats were exposed to MPA dosages of up to 5000μg/kg/day in their diets (50 times higher – based on AUC values – than the level observed in women taking 10mg of MPA), a dose-related increase in pancreatic islet cell tumours (adenomas and carcinomas) occurred. Pancreatic tumour incidence was increased at 1000 and 5000μg/kg/day, but not at 200μg/kg/day.
The cortisol activity of MPA at these high doses is thought to increase serum glucose in rats which reactively stimulates the beta cells of the pancreatic islets to produce insulin. This repeated stimulation is thought to cause the tumours in rats. Similar lesions are not likely to occur in humans since the endocrine system of rats is more sensitive to hormones than that of women. When MPA is combined with estrogen, MPA binds to fewer glucocorticosteriod receptors and thus has less effect on plasma glucose. In humans, the diabetogenic response to MPA at therapeutic doses is slight. Moreover, an extensive literature search revealed no evidence that MPA causes pancreatic tumours in humans.
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