4.1 Contraindications
This product SHOULD NEVER be prescribed in the following situations.
In all indications
Suspected ectopic pregnancy
Pregnancy not confirmed by ultrasound scan or biological tests
Chronic adrenal failure
Hypersensitivity to the active substance or to any of the excipients
Severe Asthma not uncontrolled by therapy
Known allergy to mifepristone or any component of the product
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.
IN THE INDICATION: TERMINATION OF PREGNANCY BEYOND THE FIRST TRIMESTER
- contra-indications to the prostaglandin analogue selected
In the indication: Labour induction in foetal death in utero
Should prostaglandin combination be required, refer to contra-indications to the prostaglandin analogue selected.
If gemeprost is used, any contraindication to gemeprost (see gemeprost product information).
4.2 Special Warnings and Precautions for Use
WARNINGS
In the absence of specific studies, Mifegyne is not recommended in patients with:
- Renal failure
- Hepatic failure
- Malnutrition
Patients with prosthetic heart valves or who have had one previous episode of infective endocarditis should receive chemoprophylaxis according to the current UK recommendations.
1) Medical termination of pregnancy of developing intra-uterine pregnancy up to 63 days gestation
The method requires active involvement of the woman who should be informed of the requirements of the method:
- the necessity to combine treatment with prostaglandin to be administered at a second visit.
- The need for a follow up visit within 10 14 to 14 21days after intake of mifepristone Mifegyne to check that abortion is complete.
- The possibility of failure of the method which may require 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 mifepristone.
The expulsion may take place before prostaglandin administration (in about 3% of cases). This does not preclude the follow up visit 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 cases, makes the follow up visit mandatory to check that abortion is complete.
- Bleeding
The patient must be informed of the occurrence of prolonged vaginal bleeding (an average of about 12 days after up to 12 days after intake of mifepristone Mifegyne intake) which may be heavy. Bleeding occurs in almost all cases and it not in any way 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 receive precise instructions on whom she should contact and where to go in the event of any problems, particularly in the case of very heavy vaginal bleeding.
A follow-up visit must take place within a period of 10 to 14 to 21 days after administration of mifepristone to verify by the appropriate means (clinical examination, ultrasound scan, and Beta-HCG measurement) that expulsion has been completed and that vaginal bleeding has stopped or substantially reduced. In case of persistent bleeding (even light) beyond the control visit, its disappearance should be checked within a few days.
If continuing pregnancy is suspected, a further ultrasound scan may be required to evaluate its viability.
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 continuing pregnancy diagnosed after the control visit, termination by another method will be proposed to the woman.
Since heavy bleeding requiring hemostatic 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 hemostatic disorders with hypocoagulability, or with anaemia. The decision to use the medical or the surgical method should be decided with specialised consultants according to the type of hemostatic 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 Mifepristone 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 mifepristone 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 hemostatic 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 hemostatic disorders with hypocoagulability, or with anaemia
Other risks
They are those of the surgical procedure.
3) For use with gemeprost for termination of pregnancy between 13 – 24 weeks.
For the full efficacy of therapy, Mifepristone must be followed, 36 to 48 hours later by initiation of gemeprost.
Risks related to the method
- Bleeding
The woman will be informed of the risk of vaginal bleeding following intake of mifepristone. She should be informed of the risk of abortion prior to surgery administration of gemeprost (although minimal): she will be informed on where to go in case of emergency.
Other risks
They are those of gemeprost administration.
A follow-up visit is recommended at an appropriate interval after delivery of the fetus to verify that vaginal bleeding has stopped or has substantially reduced. Persistence of vaginal bleeding could signify incomplete abortion and appropriate investigation/treatment should be considered.
3) In all instances
The use of mifepristone 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
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 mifepristone. 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.
Use non-NSAI analgesics.
2) Medical termination of developing intra-uterine pregnancy with mifepristone and gemeprost
Rare serious cardiovascular accidents have been reported following the intra muscular administration of the prostaglandin analogue sulprostone (withdrawn in 1992). No such cases have been reported since analogues of PGE1 (gemeprost or misoprostol) have been used. For these this reasons women with risk factors for cardiovascular disease or established cardiovascular disease should be treated with caution and as a special precautionary measure, the medical method is not recommended for use in women over 35 years of age and who smoke more than 10 cigarettes a day.
Method of prostaglandin administration
During administration intake and for a minimum of three hours following administration the intake, and in accordance with clinical judgement the patient should be monitored in the treatment centre, in order not to miss possible acute effects of prostaglandin administration. which The treatment centre must be equipped with the appropriate equipment 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 mifepristone - prostaglandin, whatever the indication
The precautions related to the prostaglandin used should be followed where relevant.
The treatment procedure should be fully explained and completely understood by the patient. There is a Patient Information Leaflet available for each of the indications in the tablet carton. Prior to administration of mifepristone the appropriate leaflet should be given to the patient to read.
4.5 Interactions with Other Medicaments and Other Forms of Interaction
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 anticonvulsivants (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 view of the single dose administration, no specific interactions have been studied. However, there could be interactions with drugs which modulate or inhibit prostaglandin synthesis and metabolism. See PRECAUTIONS above.
4.7 Effects on ability to drive and to use machines
No studies on the effects on the ability to drive and use machines have been performed.
None known.
4.8 Undesirable Effects
Most frequently reported undesirable effects (mifepristone)
· Urogenital
- Bleeding
Heavy bleeding occurs in about 5% of the cases and may require hemostatic curettage in up to 0.7% 1.4% of cases.
- Very common uterine contractions or cramping (10 to 45%) in the hours following prostaglandin intake.
- During induction of second trimester termination of pregnancy and induction of labour for fetal death in utero, uterine rupture has been uncommonly reported after prostaglandin intake. The reports occurred particularly in multiparous women or in women with a caesarean section scar.
- Infection following abortion. Suspected or confirmed infections (endometritis, pelvic inflammatory disease) have been reported in less than 5% of women.
- 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).
· Gastrointestinal
- Cramping, light or moderate (common).
- Nausea, vomiting. diarrhoea (these gastro intestinal effects related to prostaglandin use are frequently reported).
· Rarely hypotension (0.25%)
Other undesirable effects (mifepristone)
· Hypersensitivity and skin
- Hypersensitivity: uncommon incidences of skin rashes uncommon (0.2%), single cases of urticaria. and facial oedema
- Single cases of erythroderma, erythema nodosum, epidermal necrolysis have also been reported.
· Other systems
- Rare cases of headaches, malaise, vagal symptoms (hot flushes, dizziness, chills have been reported) and fever.
Undesirable effects (gemeprost)
- nausea, vomiting or diarrhoea, and rarely hypotension (0.25%)
4.9 Overdosage
No case of overdose has been reported.
Tolerance studies have shown that administration of doses of mifepristone of up to 2g caused no unwanted reactions. Nevertheless, In the event of massive ingestion signs of adrenal failure might occur. Signs of acute intoxication may require specialist treatment including the administration of dexamethasone. Any suggestion of acute intoxication, therefore, requires treatment in a specialist environment.
PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic Properties
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 10mg/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 prostaglandins. 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
Mifepristone induces softening and dilatation of the cervix, softening and dilatation has been shown to be detectable from 24 hours after administration of mifepristone and increases to a maximum at approximately 36 – 48 hours after administration.
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 hemostatic 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 between 13 and 24 weeks gestation, 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 dose of gemeprost 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.
Preclinical safety data
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.
6. PHARMACEUTICAL PARTICULARS
6.1 List of Excipients
Anhydrous colloidal silica 3mg, Maize Starch 102mg, Povidone 12mg, Microcrystaline cellulose 30mg, Magnesium Stearate 3mg.
6 Special precautions for disposal <and other handling>
Instructions for Use/Handling
The treatment procedure should be fully explained and completely understood by the patient.
