Mifegyne 200 mg Tablets

Each tablet contains 200 mg mifepristone.

For a full list of excipients, see section 6.1

Tablet.

Light yellow, cylindrical, bi-convex tablets

1 - Medical termination of developing intra-uterine pregnancy.

In sequential use with a prostaglandin analogue, up to 63 days of amenorrhea.

2 - Softening and dilatation of the cervix uteri prior to surgical termination of pregnancy during the first trimester.

3 - Preparation for the action of prostaglandin analogues in the termination of pregnancy for medical reasons (beyond the first trimester).

4 - Labour induction in foetal death in utero.

In patients where prostaglandin or oxytocin cannot be used.

1 - Medical termination of developing intra-uterine pregnancy

The method of administration will be as follows:

• Up to 49 days of amenorrhea:

600 mg of mifepristone (i.e. 3 tablets of 200 mg each) is taken in a single oral dose, followed 36 to 48 hours later, by the administration of a prostaglandin analogue; misoprostol 400 µg orally, or gemeprost 1 mg per vaginam.

Alternatively, 200 mg of mifepristone can also be used in a single oral dose, followed 36 to 48 hours later, by the administration of the prostaglandin analogue gemeprost 1 mg per vaginam (see section 5.1. pharmacodynamic properties)

• Between 50-63 days of amenorrhea

600 mg of mifepristone (i.e. 3 tablets of 200 mg each) is taken in a single oral dose, followed 36 to 48 hours later, by the administration of the prostaglandin analogue gemeprost 1 mg per vaginam.

Alternatively, 200 mg of mifepristone can also be used in a single oral dose, followed 36 to 48 hours later, by the administration of the prostaglandin analogue gemeprost 1 mg per vaginam (see section 5.1. pharmacodynamic properties)

2 - Softening and dilatation of the cervix uteri prior to surgical termination of pregnancy during the first trimester.

200 mg of mifepristone (one tablet), followed 36 to 48 hours later (but not beyond) by surgical termination of pregnancy.

3 - Preparation for the action of prostaglandin analogues in the termination of pregnancy for medical reasons (beyond the first trimester)

600 mg of mifepristone (i.e. 3 tablets of 200 mg each) taken in a single oral dose, 36 to 48 hours prior to scheduled prostaglandin administration which will be repeated as often as indicated.

4 - Labour induction in foetal death in utero

600 mg of mifepristone (e.g. 3 tablets of 200 mg each) in a single oral daily dose, for two consecutive days.

Labour should be induced by the usual methods if it has not started within 72 hours following the first administration of mifepristone.

This product SHOULD NEVER be prescribed in the following situations.

IN ALL INDICATIONS

- chronic adrenal failure,

- hypersensitivity to the active substance or to any of the excipients,

- severe asthma uncontrolled by therapy,

- inherited porphyria.

In the indication: medical termination of developing pregnancy

- pregnancy not confirmed by ultrasound scan or biological tests,

- pregnancy beyond 63 days of amenorrhea,

- suspected extra-uterine pregnancy,

- contra-indication to the prostaglandin analogue selected.

In the indication: softening and dilatation of the cervix uteri prior to surgical termination of pregnancy:

- pregnancy not confirmed by ultrasound scan or biological test,

- pregnancy of 84 days of amenorrhea and beyond

- suspected extra-uterine pregnancy.

Preparation for the action of prostaglandin analogues in the termination of pregnancy for medical reasons (beyond the first trimester)

- contra-indications to the prostaglandin analogue selected

Labour induction in foetal death in utero

Should prostaglandin combination be required, refer to contra-indications to the prostaglandin analogue selected.

Warnings

1 - Medical termination of developing intra-uterine pregnancy

This method requires an active involvement of the woman who should be informed of the method's requirements:

- the necessity to combine treatment with prostaglandin to be administered at a second visit,

- the need for a follow-up visit (3^rd visit) within 14 to 21 days after intake of Mifegyne in order to check for complete expulsion,

- the possible failure of the method, leading to a pregnancy termination by another method.

In the case of a pregnancy occurring with an intra-uterine device in situ, this device must be removed before administration of Mifegyne.

The expulsion may take place before prostaglandin administration (in about 3% of cases). This does not preclude the need for the follow-up visit in order to check that the abortion is complete.

• Risks related to the method

- Failures

The non-negligible risk of failure, which occurs in 1.3 to 7.5 % of the cases, makes the follow-up visit mandatory in order to check that the expulsion is complete.

In rare case of non complete expulsion, a surgical revision may be necessary.

The efficacy of the method decreases with parity, and consequently increasing age of the woman.

- Bleeding

The patient must be informed of the occurrence of prolonged vaginal bleeding (an average of about 12 days or more after Mifegyne intake) which may be heavy. Bleeding occurs in almost all cases and is not in anyway a proof of complete expulsion.

The patient should be informed not to travel far away from the prescribing centre as long as complete expulsion has not been recorded. She should be given precise instructions as to whom she should contact and where to go, in the event of any problems, particularly in the case of very heavy vaginal bleeding.

Persistence of vaginal bleeding at this point could signify incomplete abortion, or an unnoticed extra-uterine pregnancy, and appropriate treatment should be considered.

In the event of an ongoing pregnancy diagnosed after the follow-up visit, termination by another method should be proposed to the woman.

Since heavy bleeding requiring haemostatic curettage occurs in 0 to 1.4% of the cases during the medical method of pregnancy termination, special care should be given to patients with haemostatic disorders with hypo-coagulability, or with anaemia. The decision to use the medical or the surgical method should be decided with specialised consultants according to the type of haemostatic disorder and the level of anaemia.

- Infection

Very rare cases of fatal toxic shock caused by Clostridium sordellii endometritis presenting without fever or other obvious symptoms of infection, have been reported after medical abortion with the use of 200 mg mifepristone followed by non authorised vaginal administration of misoprostol tablets for oral use. Clinicians should be aware of this potentially fatal complication.

2 - Softening and dilatation of the cervix uteri prior to surgical pregnancy termination

For the full efficacy of therapy, the use of Mifegyne must be followed, 36 to 48 hours later and not beyond, by surgical termination.

• Risks related to the method

- Bleeding

The woman will be informed of the risk of vaginal bleeding which may be heavy, following intake of Mifegyne. She should be informed of the risk of abortion prior to surgery (although minimal): she will be informed on where to go in order to check for the completeness of expulsion, or in any case of emergency.

Since heavy bleeding requiring curettage occurs in about 1% of patients, special care should be given to patients with hemostatic disorders, hypocoagulability, or severe anemia.

- Other risks

They are those of the surgical procedure.

3 - In all instances

The use of Mifegyne requires rhesus determination and hence the prevention of rhesus allo-immunisation as well as other general measures taken usually during any termination of pregnancy.

During clinical trials, pregnancies occurred between embryo expulsion and the resumption of menses.

To avoid potential exposure of a subsequent pregnancy to mifepristone, it is recommended that conception be avoided during the next menstrual cycle. Reliable contraceptive precautions should therefore commence as early as possible after mifepristone administration.

Precautions for use

1 - In all instances

In case of suspected acute adrenal failure, dexamethasone administration is recommended. 1 mg of dexamethasone antagonises a dose of 400 mg of mifepristone.

Due to the antiglucocorticoid activity of mifepristone, the efficacy of long-term corticosteroid therapy, including inhaled corticosteroids in asthmatic patients, may be decreased during the 3 to 4 days following intake of Mifegyne. Therapy should be adjusted.

A decrease of the efficacy of the method can theoretically occur due to the antiprostaglandin properties of non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin (acetyl salicylic acid). Limited evidence suggests that co-administration of NSAIDs on the day of prostaglandin administration does not adversely influence the effects of mifepristone or the prostaglandin on cervical ripening or uterine contractility and does not reduce the clinical efficacy of medical termination of pregnancy.

2 - Medical termination of developing intra-uterine pregnancy

Rare but serious cardiovascular accidents have been reported following the intra muscular administration of prostaglandin analogue. For this reason, women with risk factors for cardiovascular disease or established cardiovascular disease should be treated with caution.

Method of prostaglandin administration

During intake and for three hours following the intake, the patient should be monitored in the treatment centre, in order not to miss possible acute effects of prostaglandin administration. The treatment centre must be equipped with adequate medical facilities.

On discharge from the treatment centre all women should be provided with appropriate medications as necessary and be fully counselled regarding the likely signs and symptoms she may experience and have direct access to the treatment centre by telephone or local access.

3 - For the sequential use of Mifegyne - Prostaglandin, whatever the indication

The precautions related to the prostaglandin used should be followed where relevant.

No interaction studies have been performed. On the basis of this drug's metabolism by CYP3A4, it is possible that ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampicin, dexamethasone, St. John's Wort and certain anticonvulsants (phenytoin, phenobarbital, carbamazepine) may induce mifepristone metabolism (lowering serum levels of mifepristone).

Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia.

In animals (see section 5.3 Pre-clinical safety data), the abortifacient effect of mifepristone precludes the proper assessment of any teratogenic effect of the molecule.

With subabortive doses, isolated cases of malformations are observed in rabbits, but not in rats or mice, and are too few to be considered significant, or attributable to mifepristone.

In humans, the few reported cases of malformations do not allow a causality assessment for mifepristone alone or associated to prostaglandin. Therefore, data is too limited to determine whether the molecule is a human teratogen.

Consequently:

- Women should be informed, that due to the risk of failure of the medical method of pregnancy termination and to the unknown risk to the foetus, the control visit is mandatory (see Section 4.4 special warnings and special precautions for use).

- Should a failure of the method be diagnosed at the control visit (viable ongoing pregnancy), and should the patient still agree, pregnancy termination should be completed by another method.

- Should the patient wish to continue with her pregnancy, the available data is too limited to justify a systematic termination of an exposed pregnancy. In that event, a careful ultrasonographic monitoring of the pregnancy should be carried out.

Lactation

Mifepristone is a lipophilic compound and may theoretically be excreted in the mother's breast milk. However, no data is available. Consequently, mifepristone use should be avoided during breast-feeding.

No studies on the effects on the ability to drive and use machines have been performed.

Nervous system disorders

Rare:

- Headache

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.

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 fatal toxic shock caused by Clostridium sordellii endometritis, presenting without fever or other obvious symptoms of infection, have been reported after medical abortion with the use of 200 mg mifepristone followed by non authorised vaginal administration of misoprostol tablets for oral use. Clinicians should be aware of this potentially fatal complication (see section 4.4. – special warnings and special precautions for use).

Vascular disorders

Uncommon:

- Hypotension (0.25%)

General disorders and administration site conditions

Rare:

- malaise, vagal symptoms (hot flushes, dizziness, chills), fever.

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 hemostatic 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 during 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.

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.

OTHER SEX HORMONE AND MODULATOR OF THE REPRODUCTIVE FUNCTION/ ANTIPROGESTOGEN : 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 prostaglandins, 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 oxytocics 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).

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.

After administration of low doses of mifepristone (20 mg orally or intravenously), 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.

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, isolated cases of severe abnormalities occurred (cranial vault, brain and spinal cord). The number of foetal anomalies was not statistically significant and no dose-effect was observed. In monkeys, the number of foetuses surviving the abortifacient action of mifepristone was insufficient for a conclusive assessment.

Anhydrous colloidal silica, maize starch, povidone, magnesium stearate, microcrystalline cellulose

None known

3 years

No special precautions

3 tablets in a blister strip (PVC/aluminium)

1 tablet in a blister strip (PVC/aluminium)

Any unused product or waste should be disposed of in accordance with local requirements.

EXELGYN

216, Boulevard Saint-Germain

75007 Paris

France

PL 16152/0001

19/08/2009

21/04/2011