Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Nordic Group B.V., Siriusdreef 22, 2132 WT Hoofddorp, The Netherlands
Pharmacotherapeutic group: Other sex hormone and modulation of the reproductive function/antiprogestogen
ATC code: GO3XB01
Mifepristone is a synthetic steroid with an antiprogestational action as a result of competition with progesterone at the progesterone receptors.
At doses ranging from 3 to 10 mg/kg orally, it inhibits the action of endogenous or exogenous progesterone in different animal species (rat, mouse, rabbit and monkey). This action is manifested in the form of pregnancy termination in rodents.
In women at doses of greater than or equal to 1mg/kg, mifepristone antagonises the endometrial and myometrial effects of progesterone. During pregnancy it sensitises the myometrium to the contraction-inducing action of prostaglandin. During the first trimester, pre-treatment with mifepristone allows the dilatation and opening of the cervix uteri. While clinical data have demonstrated that mifepristone facilitates dilatation of the cervix, no data is available to indicate that this results in a lowering of the rate of early or late complications to the dilatation procedure.
In the event of an early termination of pregnancy, the combination of a prostaglandin analogue used in a sequential regimen after mifepristone leads to an increase in the success rate to about 95 per cent of the cases and accelerates the expulsion of the conceptus.
In clinical trials, according to the prostaglandin used and the time of application, the results vary slightly.
The success rate is around 95% when 600 mg mifepristone is combined with misoprostol 400 μg orally up to 49 days of amenorrhea, and with gemeprost applied vaginally, it reaches 98% up to 49 days of amenorrhea and 95% up to 63 days of amenorrhea.
According to the clinical trials and to the type of prostaglandin used, the failure rate varies. Failures occur in 1.3 to 7.5% of the cases receiving sequentially Mifegyne followed by a prostaglandin analogue, of which:
In pregnancies up to 49 days of amenorrhea, comparative studies between 200 mg and 600 mg of mifepristone in combination with 400 μg misoprostol orally cannot exclude a slightly higher risk of continuing pregnancies with the 200 mg dose.
In pregnancies up to 63 days of amenorrhea, comparative studies between 200 mg and 600 mg of mifepristone:
Combinations of mifepristone with prostaglandin analogues other than misoprostol and gemeprost have not been studied.
During the termination of pregnancy for medical reasons beyond the first trimester, mifepristone administered at a 600- mg dose, 36 to 48 hours prior to the first administration of prostaglandin, reduces the induction-abortion interval, and also decreases the prostaglandin doses required for the expulsion.
When used for labour induction of foetal death in utero, mifepristone alone induces expulsion in about 60% of cases within 72 hours following the first intake. In that event, the administration of prostaglandin or ocytocics would not be required.
Mifepristone binds to the glucocorticoid receptor. In animals at doses of 10 to 25 mg/kg it inhibits the action of dexamethasone. In man the antiglucocorticoid action is manifested at a dose equal to or greater than 4.5 mg/kg by a compensatory elevation of ACTH and cortisol. Glucocorticoid bioactivity (GBA) may be depressed for several days following a single administration of 200 mg mifepristone for termination of pregnancy. The clinical implications of this are unclear, however vomiting and nausea may be increased in susceptible women.
Mifepristone has a weak anti-androgenic action which only appears in animals during prolonged administration of very high doses.
After oral administration of a single dose of 600 mg mifepristone is rapidly absorbed. The peak concentration of 1.98 mg/l is reached after 1.30 hours (means of 10 subjects).
After oral administration of low doses of mifepristone (20 mg), the absolute bioavailability is 69%.
In plasma mifepristone is 98% bound to plasma proteins: albumin and principally alpha-1-acid glycoprotein (AAG), to which binding is saturable. Due to this specific binding, volume of distribution and plasma clearance of mifepristone are inversely proportional to the plasma concentration of AAG.
N-Demethylation and terminal hydroxylation of the 17-propynyl chain are primary metabolic pathways of hepatic oxidative metabolism.
There is a non-linear dose response. After a distribution phase, elimination is at first slow, the concentration decreasing by a half between about 12 and 72 hours, and then more rapid, giving an elimination half-life of 18 hours. With radio receptor assay techniques, the terminal half-life is of up to 90 hours, including all metabolites of mifepristone able to bind to progesterone receptors.
Mifepristone is mainly excreted in faeces. After administration of a 600 mg labelled dose, 10% of the total radioactivity is eliminated in the urine and 90% in the faeces.
In toxicological studies in rats and monkeys up to a duration of 6 months, mifepristone produced effects related to its antihormonal (antiprogesterone, antiglucocorticoid and antiandrogenic) activity.
In reproduction toxicology studies, mifepristone acts as a potent abortifacient. No teratogenic effect of mifepristone was observed in rats and mice surviving foetal exposure. In rabbits surviving foetal exposure, however, foetal anomalies were observed (cranial vault, brain and spinal cord). The effect was dose-dependent. In monkeys, the number of foetuses surviving the abortifacient action of mifepristone was insufficient for a conclusive assessment. No evidence of teratogenicity was observed in postimplantation rat and monkey embryos exposed to mifepristone in vitro.
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