No case of overdose has been reported.
In the event of accidental massive ingestion, signs of adrenal failure might occur. Signs of acute intoxication may require specialist treatment including the administration of dexamethasone.
4 years
Not applicable.
Silica, colloidal anhydrous (E551)
Maize starch
Povidone (E1201)
Magnesium stearate (E572)
Cellulose microcrystalline (E460)
The frequencies of occurrence of side effects are classified as follows:
Very common (> 1/10)
Common (> 1/100 to < 1/10)
Uncommon (> 1/1,000 to < 1/100)
Rare (> 1/10,000 to < 1/1,000)
Very rare (< 1/10,000)
Not known (cannot be estimated from the available data)
Infections and infestations
Common:
- Infection following abortion. Suspected or confirmed infections (endometritis, pelvic inflammatory disease) have been reported in less than 5% of women.
Very rare:
- Very rare cases of serious or fatal toxic and septic shock (caused by Clostridium sordellii or Escherichia coli), which can be with or without fever or other obvious symptoms of infection, have been reported after medical abortion with the use of unauthorised vaginal or buccal administration of misoprostol tablets for oral use. - special warnings and special precautions for use).
Nervous system disorders
Rare:
- Headache
Vascular disorders
Uncommon:
- Hypotension (0.25%)
Gastrointestinal disorders
Very common:
- Nausea, vomiting, diarrhoea (these gastro intestinal effects related to prostaglandin use are frequently reported).
Common:
- Cramping, light or moderate.
Skin and subcutaneous tissue disorders
Uncommon
- Hypersensitivity: Skin rashes uncommon (0.2%).
Rare
- Single cases of urticaria, erythroderma, erythema nodosum, toxic epidermal necrolysis have also been reported.
Very rare
- Angioedema
Reproductive system and breast disorders
Very common:
- Very common uterine contractions or cramping (10 to 45%) in the hours following prostaglandin intake.
Common:
- Heavy bleeding occurs in about 5% of the cases and may require haemostatic curettage in up to 1.4% of the cases.
Rare:
- During induction of second trimester termination of pregnancy or labour induction for foetal death in utero within the third trimester, uterine rupture has been uncommonly reported after prostaglandin intake. The reports occurred particularly in multiparous women or in women with a caesarean section scar.
General disorders and administration site conditions
Rare:
- Malaise, vagal symptoms (hot flushes, dizziness, chills), fever.
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.
Pharmacotherapeutic group: OTHER SEX HORMONE AND MODULATOR OF THE REPRODUCTIVE FUNCTION/ ANTIPROGESTOGEN
ATC code : GO3 X B01.
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:
- 0 to 1.5% of ongoing pregnancies
- 1.3 to 4.6% of partial abortion, with incomplete expulsion
- 0 to 1.4% of haemostatic curettage
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 in combination with 1 mg gemeprost vaginally suggest that 200 mg mifepristone may be as effective as 600 mg mifepristone:
- Complete abortion rates with 200 mg and 600 mg were 93.8% and 94.3%, respectively, in women with < 57 days of amenorrhea (n=777. WHO 1993), and 92.4% and 91.7%, respectively, in women with 57 to 63 days of amenorrhea (n=896, WHO 2001).
- Rates of ongoing pregnancies with 200 mg and 600 mg were 0.5% and 0.3%, respectively, in women with < 57 days of amenorrhea, and 1.3% and 1.6%, respectively, in women with 57 to 63 days of amenorrhea.
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.
Absorption
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%.
Distribution
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.
Biotransformation
N-Demethylation and terminal hydroxylation of the 17-propynyl chain are primary metabolic pathways of hepatic oxidative metabolism.
Elimination
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.
26/03/2015
EXELGYN
216, Boulevard Saint-Germain
75007 Paris
France
/
PVC/aluminium perforated unit dose blister packs of 1, 3 x 1, 15 x 1 or 30 x 1 tablets.
Not all pack sizes may be marketed.
PL 16152/0001
No data showing an effect on the ability to drive or using machines are known. Dizziness could occur as a side effect inherent of the abortion process. When driving or using machines one should take this possible side effect into account.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
19/08/2009
