Active ingredients: Mifepristone
MIFEGYNE 200 mg tablets
Mifegyne package inserts are available for pack sizes:- MIFEGYNE 200 mg tablets
- MIFEGYNE® 600 mg tablets
Why is Mifegyne used? What is it for?
Mifegyne tablets contain mifepristone which is an anti-hormone that works by blocking the effects of progesterone, a hormone necessary for pregnancy to continue. Mifegyne can therefore lead to pregnancy termination. It can also be used to soften and widen the access (cervix) to the uterus. Mifegyne is recommended for the following uses:
- For the medical termination of an intrauterine pregnancy in progress: no later than the 63rd day following the first day of the last menstrual cycle; in combination with a second drug, a prostaglandin (a substance that triggers the contraction of the uterus and softens the cervix) to be taken 36-48 hours after taking Mifegyne.
- To soften and dilate the cervix before surgical termination of pregnancy during the first trimester.
- As a pre-treatment before the administration of prostaglandins for the therapeutic termination of pregnancy beyond the third month of gestation.
- To induce labor in cases where the fetus has died inside the uterus and in cases where it is not possible to use other medical treatments (prostaglandin or oxytocin).
Contraindications When Mifegyne should not be used
Do not take Mifegyne:
In all cases
- if you are allergic to mifepristone or any of the other ingredients of this medicine
- if you suffer from adrenal insufficiency
- if you have severe asthma which cannot be treated properly with medication
- if you have hereditary porphyria.
In addition, for the termination of pregnancy until the 63rd day after the last menstrual cycle:
- if the pregnancy has not been confirmed by laboratory tests or an ultrasound examination
- if the first day of the last menstrual cycle is more than 63 days old
- if your doctor suspects an ectopic pregnancy (the egg is implanted outside the uterus)
- if you cannot take your chosen prostaglandin analog.
To soften and open the cervix before surgical termination of pregnancy:
- if the pregnancy has not been confirmed by laboratory tests or an ultrasound examination
- if your doctor suspects an ectopic pregnancy
- if the first day of the last menstrual cycle was 84 days or more.
For termination of pregnancy beyond the 3rd month of pregnancy:
If you cannot take your chosen prostaglandin analogue.
Precautions for use What you need to know before taking Mifegyne
Talk to your doctor before taking Mifegyne:
- if you have liver or kidney disease
- if you suffer from anemia or malnutrition
- if you have cardiovascular disease (heart or circulatory disease)
- if you are at increased risk of cardiovascular disease. Risk factors include being over the age of 35, being a smoker or having high blood pressure, high blood cholesterol or diabetes.
- if you have a disease which can affect blood clotting
- if you suffer from asthma.
If you are using the contraceptive coil it must be removed before taking Mifegyne.
Before taking Mifegyne, the Rh factor of the blood must be identified. In case of Rh negative, your doctor will advise you on the required routine treatment.
Interactions Which drugs or foods can modify the effect of Mifegyne
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including those available without a prescription.
In particular, tell your doctor if you are taking any of the following medicines:
- corticosteroids (used to treat asthma or to treat other inflammation)
- ketoconazole, itraconazole (used against fungal infections)
- erythromycin, rifampicin (antibiotics)
- St. John's wort (natural remedy used to treat mild forms of depression)
- phenytoin, phenobarbital, carbamazepine (used in the treatment of seizures; epilepsy)
- non-steroidal anti-inflammatory drugs (NSAIDs) such as acetylsalicylic acid or diclofenac.
Grapefruit juice cannot be taken during treatment with Mifegyne.
Warnings It is important to know that:
PREGNANCY, BREASTFEEDING AND FERTILITY
Pregnancy
Failure to terminate pregnancy (continuation of pregnancy) after taking Mifegyne alone or in combination with prostaglandin has been associated with birth defects. The risk of failure increases:
if prostaglandin is not administered in accordance with the respective prescribing information
with the duration of pregnancy
with the number of pregnancies previously had
If termination of pregnancy is not successful after taking this medicine or combination of medicines, there is an unknown risk to the fetus. If you decide to continue the pregnancy you will need to undergo careful prenatal monitoring and repeated ultrasound examinations, with particular attention to the limbs, at a specialized clinic. Your doctor will provide you with further information.
If you decide to continue with the termination of pregnancy, another method will be used. Your doctor will advise you of the options available.
Feeding time
If you are breastfeeding tell your doctor before using this medicine. Do not breastfeed while taking Mifegyne as the medicine passes into breast milk.
Fertility
This medicine does not affect fertility. It is possible to become pregnant again immediately after termination of pregnancy is completed. Contraception should therefore be started immediately upon confirmation of termination by the doctor.
Driving and using machines
Dizziness may occur as a side effect of the abortion procedure. Be especially careful while driving or using machines after taking this medicine until you know how Mifegyne affects you.
Dosage and method of use How to use Mifegyne: Dosage
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
Medical termination of an ongoing intrauterine pregnancy (IMG)
Termination of pregnancy up to 49 days after the last menstrual cycle
Dosage in adults
- 3 tablets to be taken orally
Taking the tablet
- Swallow the tablet whole with a glass of water in the presence of a doctor or a member of his / her medical staff.
- Take the prostaglandin analog, 36-48 hours after Mifegyne. Prostaglandin can be given as tablets to be swallowed with water (misoprostol 400 micrograms) or as a vaginal suppository (gemeprost 1mg).
- If you vomit within 45 minutes after taking the mifepristone tablet, contact your doctor immediately. You will need to take the tablets again.
Termination of pregnancy up to 50-63 days after the last menstrual cycle
Dosage in adults
- 3 tablets to be taken orally
Taking the tablet
- Swallow the tablets whole with a glass of water in the presence of a doctor or a member of his medical staff.
- Take the prostaglandin analog, 36-48 hours after Mifegyne. Prostaglandin is a vaginal egg (gemeprost 1 mg).
- If you vomit within 45 minutes after taking the mifepristone tablets, contact your doctor immediately. You will need to take the tablets again.
This method requires your active participation and you must therefore be informed that:
- You need to take the second medicine (which contains prostaglandin) for the treatment to be effective.
- You must have a follow-up visit (3rd visit) within 14 - 21 days of taking Mifegyne to check that your pregnancy has been completely expelled and that you are well.
The following schedule will be followed for medical termination of pregnancy.
- Mifegyne will be delivered to you at the prescribing center and will need to be taken orally.
- 36-48 hours later, you will be given the prostaglandin analogue. You must rest for 3 hours after taking the prostaglandin analogue.
- The embryo can be expelled within a few hours after taking the prostaglandin analogue or in the days immediately following. After taking Mifegyne you will have vaginal bleeding lasting an average of 12 days and the flow will gradually decrease in intensity.
- She must return to the center for a follow-up visit within 14-21 days of taking Mifegyne to verify that the expulsion is complete.
Contact your prescribing center immediately: if vaginal bleeding lasts longer than 12 days and / or is very intense (eg you need more than 2 tampons per hour for 2 hours); if you have severe abdominal pain; if you have fever or if you feel cold and have tremors.
- Another important point to remember: - Vaginal bleeding does not mean that the expulsion has been completed
Uterine bleeding usually begins 1-2 days after taking Mifegyne. In rare cases, expulsion may occur before prostaglandin is taken. It is essential that you have a check to confirm that a complete evacuation has occurred and therefore will have to return to the center.
If the pregnancy continues or the expulsion is incomplete your doctor will advise you of the options available to complete the termination of the pregnancy.
It is advisable not to go too far from the prescribing center until the follow-up visit has been carried out.
In an emergency, or if you have any questions, call or go to the prescribing center. You don't have to wait for the checkup appointment.
To soften and open the cervix before surgical termination of pregnancy:
Dosage in adults
- 1 tablet to be taken orally
Taking the tablet
- Swallow the tablet whole with a glass of water.
- If you vomit within 45 minutes after taking the mifepristone tablet, contact your doctor immediately. You will need to take another tablet.
For medical termination of pregnancy, the following program will be followed:
- Mifegyne will be delivered to you at the prescribing center and will need to be taken orally.
- 36-48 hours later, you will need to return to the prescribing center for surgery.
Your doctor will explain the procedure to you. You may have bleeding after taking Mifegyne, before surgery.In rare cases, expulsion can also occur before surgery. It is essential that you return to the center to confirm that the deportation has been complete.
He must then return to the chosen center to carry out the surgery.
In an emergency, or if you have any questions, call or go to the prescribing center. You don't have to wait for the checkup appointment.
For termination of pregnancy beyond the first three months of pregnancy:
Dosage in adults
- 3 tablets to be taken orally
Taking the tablets
- Swallow the tablets whole with a glass of water.
- 36-48 hours after this medicine take the prostaglandin analogue which can be repeated several times at regular intervals until the expulsion is complete.
- If you vomit within 45 minutes after taking the mifepristone tablets, contact your doctor immediately. You will need to take the tablets again.
For induction of labor when pregnancy has been terminated (intra-uterine fetal death).
Dosage in adults
- 3 tablets to be taken orally every day for two days
Taking the tablets
- Swallow the tablets whole with a glass of water.
- If you vomit within 45 minutes after taking the mifepristone tablets, contact your doctor immediately. You will need to take the tablets again.
Use in adolescents
Only limited data are available on the use of Mifegyne in adolescents.
IF YOU FORGET TO TAKE MIFEGYNE
If you forget to take any part of the treatment, it is likely that the method will not be fully effective. Talk to your doctor if you have forgotten to take Mifegyne or the prescribed portion of treatment.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist
Overdose What to do if you have taken too much Mifegyne
If you take too many tablets, contact your doctor immediately or go to the nearest emergency department.
Your doctor will give you the exact amount of Mifegyne, so it is unlikely that you will take too many tablets. Taking too many tablets can cause symptoms of adrenal insufficiency. Symptoms of acute intoxication may require specialist treatment, including administration of dexamethasone.
Side Effects What are the side effects of Mifegyne
Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly to the Italian Medicines Agency (www.agenziafarmaco.it/it/responsabili). By reporting side effects you can help provide more information on the safety of this medicine.
Serious side effects:
- Allergic reaction. Rash, localized swelling of the face and / or larynx also accompanied by hives.
Other serious side effects:
- Cases of severe or fatal toxic or septic shock. Fever with muscle pain, rapid heartbeat, dizziness, diarrhea, vomiting or a feeling of weakness. This side effect may occur if you do not take the second medicine, the misoprostol tablet, by mouth.
If you experience any of these side effects, contact your doctor IMMEDIATELY or go to the nearest emergency room.
Other side effects
Very common (may affect more than 1 in 10 people):
- contractions or cramps of the uterus
- diarrhea
- nausea or vomiting
Common (may affect up to 1 in 10 people):
- profuse bleeding
- mild or moderate gastrointestinal cramps
- infection of the uterus (endometritis and pelvic inflammatory disease)
Uncommon (may affect up to 1 in 100 people):
- lowering of blood pressure
Rare (may affect up to 1 in 1000 people):
- fever
- headache
- general malaise or feeling tired
- vagal symptoms (hot flashes, dizziness, chills)
- hives and skin reactions which can be severe
- rupture of the uterus following the administration of prostaglandin within the second and third trimesters of pregnancy, particularly in multiparous women or in women who had undergone a caesarean section
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton after "EXP". The expiry date refers to the last day of that month.
Do not use this medicine if you notice that the carton or blister shows signs of deterioration.
Do not throw any medicines down the drain. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other Information
What Mifegyne contains
The active ingredient is mifepristone.
One Mifegyne tablet contains 200 mg of mifepristone.
The other ingredients are anhydrous colloidal silica, corn starch, povidone, magnesium stearate, microcrystalline cellulose.
What Mifegyne looks like and contents of the pack
Mifegyne is available as yellow biconvex tablets with a diameter of 11 mm with "167 B" engraved on one side.
1 tablet in perforated unit dose blister (PVC / Aluminum).
3 x 1 tablets in perforated unit dose blister (PVC / Aluminum).
15 x 1 tablets in perforated unit dose blister (PVC / Aluminum).
30 x 1 tablets in perforated unit dose blister (PVC / Aluminum).
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
MIFEGYNE 200 MG TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 200 mg of mifepristone.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Tablets.
Light yellow, cylindrical, biconvex tablets of 11 mm diameter with "167 B" engraved on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
For the termination of pregnancy, the anti-progesterone mifepristone and the prostaglandin analogue can only be prescribed and administered in compliance with the national laws and regulations in the various countries.
1 - Medical termination of ongoing intrauterine pregnancy.
Used in sequential combination with a prostaglandin analog, up to day 63 of amenorrhea (see section 4.2).
2 - Softening and dilation of the uterine cervix before surgical termination of pregnancy during the first trimester.
3 - Preparation for the action of prostaglandin analogues in the therapeutic interruption of pregnancy (beyond the first quarter).
4 - Induction of labor in the event of fetal intrauterine death.
In patients in whom prostaglandins or oxytocin cannot be used.
04.2 Posology and method of administration
Dosage
1 - Medical termination of ongoing intrauterine pregnancy
The method of administration should be as follows:
• Up to the 49th day of amenorrhea:
Mifepristone is taken in a single oral dose of 600 mg (ie 3 tablets of 200 mg each) followed, 36-48 hours later, by the administration of the prostaglandin analogue: misoprostol 400 micrograms orally, or gemeprost, 1 mg vaginally.
• Between the 50th and 63rd day of amenorrhea:
Mifepristone is taken as a single oral dose of 600 mg (ie 3 tablets of 200 mg each) followed, 36 to 48 hours later, by vaginal administration of the prostaglandin analog gemeprost 1 mg.
Alternatively, mifepristone 200 mg (i.e. 1 tablet of 200 mg) can be administered in a single oral dose, followed 36-48 hours later by vaginal administration of the prostaglandin analog gemeprost 1 mg (see section 5.1 - Pharmacodynamic properties).
Information on the posology of misoprostol or gemeprost can be found in the respective package leaflets.
2 - Softening and dilation of the uterine cervix before surgical termination of pregnancy during the first trimester.
Mifepristone is taken as a single oral dose of 200 mg (1 tablet), followed 36-48 hours later (but not later) by surgical termination of pregnancy.
3 - Preparation for the action of prostaglandin analogues in the therapeutic interruption of pregnancy.
Mifepristone is taken in a single oral dose of 600 mg (ie 3 tablets of 200 mg each) 36-48 hours prior to the scheduled prostaglandin administration which will be repeated at the indicated frequency.
4 - Induction of labor in the case of intrauterine fetal death
Mifepristone is taken as a single daily oral dose of 600 mg (ie 3 tablets of 200 mg each), for two consecutive days.
Labor should be induced by the usual methods if it does not start 72 hours after the first administration of mifepristone.
Vomiting within 45 minutes of taking may cause a decrease in the efficacy of mifepristone: in this case it is recommended to take a new oral dose of 600 mg (eg 3 tablets of 200 mg each) of mifepristone.
Pediatric population
Only limited data are available on the use of mifepristone in adolescents.
Method of administration
Mifepristone tablets are for oral use only and should not be taken via any other route of administration.
04.3 Contraindications
This product MUST NEVER be prescribed in the following cases.
IN ALL INDICATIONS :
• chronic adrenal insufficiency,
• hypersensitivity to mifepristone or to any of the excipients listed in section 6.1,
• severe asthma not controlled by therapy,
• hereditary porphyria.
In the indication: medical termination of pregnancy in progress
• pregnancy not confirmed by ultrasound examination or laboratory tests,
• pregnancy beyond 63 days of amenorrhea,
• suspected ectopic pregnancy,
• contraindications to the selected prostaglandin analogue.
In the indication: softening and dilation of the uterine cervix before surgical termination of pregnancy :
• pregnancy not confirmed by ultrasound examination or laboratory tests,
• pregnancy beyond 84 days of amenorrhea,
• suspected ectopic pregnancy.
In the indication: preparation for the action of prostaglandin analogues in the therapeutic termination of pregnancy (beyond the first quarter) :
• contraindications to the selected prostaglandin analogue.
04.4 Special warnings and appropriate precautions for use
Warnings
Due to its abortive properties, mifepristone should never be used in women wishing to carry an ongoing pregnancy to term.
The time of pregnancy should be determined by interview and clinical examination of the patient. A uterine ultrasound is recommended.
In the absence of specific studies, mifepristone is not recommended in patients with:
- Malnutrition
- Hepatic insufficiency
- Kidney failure
1 - Medical termination of ongoing intrauterine pregnancy
This method requires the active involvement of the patient who must be informed about the requirements of the method:
• the need to combine treatment with a prostaglandin analogue to be administered at the second visit 36-48 hours after the administration of this medicine,
• the need for a follow-up visit (3rd visit) from 14 to 21 days after the administration of mifepristone to verify complete expulsion,
• the possible failure of the method, which involves the use of another method for terminating the pregnancy.
If pregnancy occurs with an intrauterine device in situ, the device must be removed prior to administration of mifepristone.
• Risks related to the method
• Bankruptcies
The non-negligible risk of bankruptcy occurs in 1.3-7.5% of cases, thus making the follow-up visit mandatory to verify that the expulsion is completed.
In the rare event of an incomplete expulsion, revision surgery may be required.
The effectiveness of the method decreases with the number of pregnancies, and consequently with the advancing age of the patient.
• Bleeding
The patient should be informed of the occurrence of prolonged vaginal bleeding (on average 12 days or more after taking mifepristone) which may be profuse. Bleeding occurs in almost all cases and is in no way evidence of a complete expulsion.
Bleeding can occur very quickly after taking misoprostol, but sometimes even later:
• In 60% of cases, expulsion occurs within 4 hours of taking misoprostol,
• In the remaining 40% of cases, expulsion occurs within 24-72 hours of taking misoprostol.
In rare cases, expulsion may occur prior to administration of the prostaglandin analogue (approximately 3% of cases). This does not preclude a follow-up visit in order to verify the complete expulsion and emptying of the uterus.
The patient must be informed of the impossibility of undertaking journeys that take her away from the prescribing center until complete expulsion has been verified. She will receive precise instructions on who to contact and where to go in case of problems, especially in case of bleeding. very heavy vaginal bleeding This is bleeding that lasts more than 12 days and / or more intense than normal menstrual bleeding.
A follow-up visit is required in a period between 14 and 21 days after taking mifepristone to verify with appropriate methods (clinical examination together with measurement of the beta-hCG level or ultrasound) that the expulsion has been completed and that vaginal bleeding has stopped. In case of persistent (even slight) bleeding after the follow-up visit, it must be checked for its disappearance within a few days.
If an ongoing pregnancy is suspected, an additional ultrasound examination may be required.
Persistent vaginal bleeding at this stage may indicate incomplete abortion or an undiagnosed ectopic pregnancy and appropriate treatment should therefore be considered.
Since profuse bleeding requiring hemostatic curettage occurs in 0-1.4% of cases of medical termination of pregnancy, special attention should be paid to patients with haemostatic disorders with hypocoagulability, or with anemia. the medical or surgical method must be established with a specialist consultation, depending on the type of haemostasis disorder and the degree of anemia.
In the event of an ongoing pregnancy, diagnosed after the follow-up visit, another method for terminating the pregnancy should be offered to the patient.
• Infection
Severe (sometimes fatal) cases of toxic shock syndrome and septic shock caused by infections with atypical pathogens (Clostridium sordellii or Escherichia coli), have been reported after medical termination of pregnancy with the use of 200 mg mifepristone followed by unauthorized vaginal or oral administration of misoprostol tablets. Doctors need to be aware of this potentially fatal complication.
2 - Softening and dilation of the uterine cervix before surgical termination of pregnancy
For the full efficacy of the therapy, the use of Mifegyne must be followed, 36-48 hours later and not beyond, by the surgical interruption.
• Risks related to the method
• Bleeding
The patient must be informed of the risk of vaginal bleeding, which may be profuse, following the intake of Mifegyne. She must be informed of the risk of miscarriage (although minimal) before surgery: she must be informed on where to go to check complete expulsion, or in the event of any emergency.
Since profuse bleeding requiring curettage occurs in approximately 1% of patients, special attention should be paid to patients with haemostatic disorders, hypocoagulability or severe anemia.
• Other risks
Risks associated with the surgical procedure.
Precautions for use
1 - In all cases
In case of suspected acute adrenal insufficiency, administration of dexamethasone is recommended. 1 mg dexamethasone antagonizes a 400 mg dose of mifepristone.
Due to the antiglucocorticoid activity of mifepristone, the efficacy of long-term corticosteroid therapy, including inhaled corticosteroids in asthmatic patients, may be reduced 3-4 days after taking Mifegyne. Adjustment of therapy is required.
Rh alloimmunization
The medical termination of pregnancy requires the determination of the Rh factor of the blood and, therefore, the prevention of Rh alloimmunization, as well as other general measures usually adopted in the termination of pregnancy.
Beginning of contraception after medical termination of pregnancy
During clinical trials, pregnancies occurred between the expulsion of the embryo and the resumption of menstruation. Therefore, when medically confirmed termination of pregnancy is medically confirmed, it is recommended that contraception be started immediately.
Other
Precautions related to prostaglandin analogues should also be observed.
2 - Medical termination of ongoing intrauterine pregnancy
Rare but serious cardiovascular events (myocardial infarction and / or spasm of the coronary arteries and severe hypotension) have been reported following intravaginal and intramuscular administration of a high dose of prostaglandin analogues. Misoprostol administered orally may also be a potential risk factor for acute cardiovascular events. For this reason, patients at risk for cardiovascular disease (e.g. over 35 years of age, chronic smokers with hyperlipidemia, diabetes) or established cardiovascular disease should be treated with caution.
3 - For the sequential use of Mifegyne - Prostaglandin, in any indication
If indicated, precautions relating to the prostaglandin used should be followed.
Method of administration of prostaglandin
The patient should be monitored in the treatment center during intake and for three hours thereafter to identify any acute effects due to prostaglandin administration. The treatment center must be equipped with adequate facilities.
At the time of discharge from the treatment center, if necessary, all women should be provided with the appropriate medications and they must be adequately informed of the possible signs and symptoms that may arise and must have direct access to the treatment center both by telephone and directly.
04.5 Interactions with other medicinal products and other forms of interaction
No interaction studies have been performed. Based on the metabolism of this drug, mediated by CYP3A4, it is possible that ketoconazole, itraconazole, erythromycin and grapefruit juice may inhibit its metabolism (increasing the serum levels of mifepristone). Furthermore, rifampicin, dexamethasone, St. John's wort and some anticonvulsants (phenytoin, phenobarbital, carbamazepine) can induce the metabolism of mifepristone (reducing the serum levels of mifepristone).
Based on inhibition information in vitro, co-administration of mifepristone may induce an increase in serum levels of drugs that are substrates of CYP3A4. Due to the slow elimination of mifepristone from the body, this interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is co-administered with drugs that are substrates of CYP3A4 and have a low therapeutic index. , including some agents used in general anesthesia.
The efficacy of the method may theoretically be reduced due to the antiprostaglandin properties of non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin (acetylsalicylic acid). There is some evidence to suggest that co-administration of NSAIDs on the day of administration of the prostaglandin dose does not adversely affect the effects of mifepristone or prostaglandin on cervical ripening or uterine contractility and does not reduce the clinical efficacy of medical discontinuation. of pregnancy.
04.6 Pregnancy and breastfeeding
Pregnancy
In animals (see section 5.3 Preclinical safety data), the abortive efficacy of mifepristone precludes the appropriate evaluation of any teratogenic effects of the molecule.
At lower doses than those used for abortion purposes, malformations were observed in rabbits, but not in rats, mice or monkeys.
In clinical practice, rare cases of malformation of the lower extremities (including clubfoot) have been reported when mifepristone was administered alone or in combination with prostaglandins. One of the possible mechanisms can be amniotic band syndrome. However, the data are too limited to determine whether the molecule is teratogenic even in humans.
Consequentially:
• Patients should be advised of the absolute necessity of the follow-up visit, due to the risk of failure of the medical method of termination of pregnancy and the risk to the fetus (see section 4.4 - Special warnings and precautions for use).
• In the event that failure of the method is detected at the follow-up visit (viable pregnancy in progress) and the patient still agrees, termination of the pregnancy should be completed by another method.
• In the event that the patient wishes to carry the pregnancy to term, careful ultrasound monitoring of the pregnancy, with particular attention to the limbs, must be initiated at a specialized center.
Feeding time
Mifepristone is secreted in breast milk in small quantities. Consequently, the use of mifepristone should be avoided during breastfeeding.
Fertility
Mifepristone does not affect fertility. It is possible that the woman has a new pregnancy immediately after the termination of pregnancy is completed. Therefore, it is important to inform the patient of the need to initiate contraception immediately after the termination of pregnancy is confirmed.
04.7 Effects on ability to drive and use machines
There are no known data showing effects on the ability to drive and use machines. Dizziness may occur as an undesirable effect related to the abortion procedure. Consider the possibility of this undesirable effect before driving or using machines.
04.8 Undesirable effects
The frequency of incidence of undesirable effects is classified as follows:
Very common (≥ 1/10)
Common (≥ 1/100 to
Uncommon (≥ 1 / 1,000 to
Rare (≥ 1 / 10,000 to
Very rare (
Not known (frequency cannot be estimated from the available data)
Infections and infestations
common:
• Post-abortion infection. Suspected or confirmed infections (endometritis, pelvic inflammatory disease) were reported in less than 5% of patients.
Very rare:
• Very rare cases of life-threatening toxic and septic shock (caused by Clostridium sordellii or Escherichia coli) with or without fever or other clear symptoms of infection, after medical termination of pregnancy by unauthorized vaginal or oral administration of misoprostol tablets for oral use. Physicians should be aware of this potentially fatal complication (see section 4.4. - Special warnings and precautions for use).
Nervous system disorders
Rare:
• Headache
Vascular pathologies
Uncommon:
• Hypotension (0.25%)
Gastrointestinal disorders
Very common
• Nausea, vomiting, diarrhea (gastrointestinal effects related to prostaglandins are reported frequently)
common
• Cramps, mild or moderate
Skin and subcutaneous tissue disorders
Uncommon
• Hypersensitivity: skin rash (0.2%).
Rare
• Isolated cases of urticaria, erythroderma, erythema nodosum, and toxic epidermal necrolysis have been reported.
Very rare
• Angioedema
Diseases of the reproductive system and breast
Very common
• Uterine contractions and cramps (10 - 45%) very common in the hours following prostaglandin intake.
common
• Severe bleeding occurs in approximately 5% of cases and may require hemostatic curettage in up to 1.4% of cases.
Rare
• Rupture of the uterus has been exceptionally reported following the intake of prostaglandin, during the induction of a termination of pregnancy in the second trimester or with the induction of labor for fetal death during the third trimester. they occurred, in particular, in multiparous women or in women who had undergone a caesarean section.
General disorders and administration site conditions
Rare
• Malaise, vagal symptoms (flushing, dizziness, chills), fever.
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency ( http://www.agenziafarmaco.gov.it/it/responsabili).
04.9 Overdose
No cases of overdose have been reported.
In the event of accidental ingestion of massive doses, signs of adrenal insufficiency may occur. Signs of acute intoxication may require specialist treatment including administration of dexamethasone.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: OTHER SEXUAL HORMONES AND FUNCTION MODULATORS
REPRODUCTIVE / ANTIPROGESTINICS
ATC code: G03XB01
Mifepristone is a synthetic steroid with an anti-progestin action, as a result of competition with progesterone at the progesterone receptor level.
At dosages between 3 and 10 mg / kg orally, it inhibits the action of endogenous or exogenous progesterone in various animal species (rat, mouse, rabbit and monkey). This action takes place in rodents in the form of termination of pregnancy.
In women, at doses greater than or equal to 1 mg / kg, mifepristone antagonizes the endometrial and myometrial effects of progesterone. During pregnancy it sensitizes the myometrium to the contraction-inducing action exerted by prostaglandins. During the first trimester, a pretreatment with mifepristone allows the cervix to dilate and open. While clinical data have shown that mifepristone facilitates dilation of the cervix, no data are available to indicate that this result may help reduce the rate of early or late complications of the dilation procedure.
In the event of 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 of approximately 95% of cases and accelerates the expulsion of the embryo.
In clinical studies, the results vary slightly depending on the prostaglandin used and the time of application.
The success rate is approximately 95% when 600 mg of mifepristone are combined with misoprostol 400 mcg orally up to the 49th day of amenorrhea, and reaches 98% up to the 49th day of amenorrhea and 95% up to the 63rd day of amenorrhea with vaginally applied gemeprost.
The failure rate varies depending on the clinical studies and the type of prostaglandin used. Failures occur in 1.3-7.5% of cases receiving Mifegyne sequentially, followed by a prostaglandin analogue, of which:
• 0 - 1.5% of ongoing pregnancies
• 1.3 - 4.6% partial abortion, with incomplete expulsion
• 0 - 1.4% hemostatic curettage
Comparative studies between 200 mg and 600 mg doses of mifepristone in combination with 400 micrograms of oral misoprostol in pregnancies up to the 49th day of amenorrhea failed to exclude a higher risk of continuing pregnancy with the 200 dose. mg.
Comparative studies between the 200 mg and 600 mg doses of mifepristone in combination with gemeprost 1 mg vaginally in pregnancies up to the 63rd day of amenorrhea indicate that a 200 mg dose of mifepristone is as effective as the 600 mg dose.
• The incidence of complete abortion with 200 mg and 600 mg was 93.8% and 94.3%, respectively, in patients with amenorrhea
• The ongoing pregnancy rate with 200 mg and 600 mg was 0.5% and 0.3%, respectively, in patients with amenorrhea
Combinations of mifepristone with other prostaglandin analogues other than misoprostol and gemeprost have not been studied.
During the therapeutic termination of pregnancy beyond the first quarter, mifepristone given at a dose of 600 mg, 36-48 hours before the first prostaglandin administration, shortens the induction interval of abortion and also reduces the prostaglandin doses needed for expulsion.
When used for the induction of labor in the event of fetal death in utero, mifepristone alone induces expulsion in approximately 60% of cases within 72 hours after the first intake. In such an event, the administration of prostaglandins or oxytocic drugs will not be necessary.
Mifepristone binds to the glucocorticoid receptor. In animals, at dosages from 10 to 25 mg / kg it inhibits the action of dexamethasone. In humans, the antiglucocorticoid action occurs at doses equal to or greater than 4.5 mg / kg through a compensatory increase in ACTH and cortisol. Glucocorticoid biological activity (GBA) may be depressed for several days after a single administration of 200 mg mifepristone for termination of pregnancy. The related clinical implications are unclear, however vomiting and nausea may be increased in susceptible women.
Mifepristone has a weak anti-androgenic action which is observed only in animals during prolonged administration of very high doses.
05.2 Pharmacokinetic properties
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 (mean of 10 subjects).
After oral administration of low doses of mifepristone (20 mg), the absolute bioavailability is 69%.
Distribution
In plasma, 98% of mifepristone is bound to plasma proteins: albumin and mainly alpha-1 acid glycoprotein (AAG); this bond is saturable. Due to this specific binding, the 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-propinyl chain are the main metabolic pathways in hepatic oxidative metabolism.
Elimination
The answer is not linear. After a distribution phase, elimination is initially slow, the concentration in fact is reduced by half between about 12 and 72 hours, and then it is faster, with an elimination half-life of 18 hours. With radio-receptor assay techniques , the terminal half-life is greater than 90 hours, including all metabolites of mifepristone capable of binding to progesterone receptors.
Mifepristone is essentially excreted in the faeces. After administration of a radiolabelled dose of 600 mg, 10% of the total radioactivity is eliminated in the urine and 90% in the faeces.
05.3 Preclinical safety data
In toxicological studies performed in rats and monkeys up to a duration of 6 months, mifepristone produced effects associated with its anti-hormonal (anti-progestin, anti-glycocorticoid and anti-androgenic) activity.
In reproductive toxicity studies, mifepristone acts as a potent abortion. No teratogenic effects of mifepristone were observed in rats and mice surviving fetal exposure. In rabbits surviving fetal exposure, however, fetal abnormalities (cranial vault, brain and spinal cord) were observed. The effect was dose-dependent. In monkeys, the number of fetuses that survived the abortive action of mifepristone was insufficient for a conclusive evaluation. No evidence of teratogenicity was observed in post-implantation rat and monkey embryos exposed to mifepristone in vitro.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Anhydrous colloidal silica (E551)
Cornstarch
Povidone (E1201)
Magnesium stearate (E572)
Microcrystalline cellulose (E460)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
4 years.
06.4 Special precautions for storage
06.5 Nature of the immediate packaging and contents of the package
1 tablet in perforated unit dose blister (PVC / Aluminum).
3 x 1 tablets in perforated unit dose blister (PVC / Aluminum).
15 x 1 tablets in perforated unit dose blister (PVC / Aluminum).
30 x 1 tablets in perforated unit dose blister (PVC / Aluminum).
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
EXELGYN
216, Boulevard Saint-Germain
75007 Paris
France
08.0 MARKETING AUTHORIZATION NUMBER
038704019 "200 mg tablets", 1 tablet in PVC / AL blister
038704021 "200 mg tablets", 3 tablets in PVC / AL blister
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
10.0 DATE OF REVISION OF THE TEXT
July 2015
