Consumer medicine information

Mifepristone Linepharma 200 mg Tablet

Mifepristone

BRAND INFORMATION

Brand name

Mifepristone Linepharma

Active ingredient

Mifepristone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Mifepristone Linepharma 200 mg Tablet.

What is in this leaflet

This leaflet answers some common questions about Mifepristone Linepharma 200 mg tablet. It does not contain all the available information. It does not take the place of talking to your doctor.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given Mifepristone Linepharma 200 mg tablet against the expected benefits it will have for you.

If you have any concerns about being given this medicine, ask your doctor.

Keep this leaflet. You may need to read it again.

What Mifepristone Linepharma 200 mg tablet is used for

Mifepristone Linepharma is an anti-hormone. It acts by blocking the effects of progesterone, a hormone which is needed for pregnancy to continue.

Mifepristone Linepharma can therefore be used to terminate a pregnancy.

Mifepristone Linepharma is recommended for:

The medical termination of a pregnancy beyond the first trimester (the first three months). Mifepristone Linepharma is used in combination with a second medication called a prostaglandin analogue.

Ask your doctor if you have any questions about why Mifepristone Linepharma 200 mg tablet has been prescribed for you.

This medicine is available only with a doctor’s prescription, and will be given to you under the care of an appropriately trained doctor. The required prostaglandin analogue will be administered in a hospital setting.

Before you are given Mifepristone Linepharma 200 mg tablet

When you must not be given it

You should not be given Mifepristone Linepharma 200 mg tablet if:

  • you are pregnant and wish to carry your pregnancy to term
  • you are unable to access emergency medical care after taking this medication until the medical termination is complete
  • your pregnancy and its duration have not been confirmed by an ultrasound or biological test such as urine or serum HCG.
  • you have any allergies to mifepristone or any of the other ingredients listed at the end of this leaflet
  • you suffer from chronic adrenal failure
  • you suffer from severe disease where it is necessary to take steroids (e.g. asthma uncontrolled by treatment)
  • you have known or suspected hypocoagulation diseases
  • you are on anticoagulant therapy
  • you are allergic to prostaglandins.
    This is because of the need to use a prostaglandin analogue in combination with Mifepristone Linepharma.

You should not use this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If this medicine is used after the expiry date it may not work as well.

If you are under 18 years of age, you should only take Mifepristone Linepharma if advised to do so by your doctor. There is limited information on the use of Mifepristone Linepharma in adolescents under 18 years of age.

If you are not sure whether you should be given this medicine, talk to your doctor.

Your doctor will give you more information about what to expect with medical abortion, the risks and side effects, when you need to seek advice or help, and contact numbers for 24 hour assistance.

Before you take Mifepristone Linepharma

Tell your doctor if you have allergies to any other medicines, foods preservatives or dyes.

Tell your doctor if you are a smoker.

Tell your doctor if you have or have had any of the following medical conditions:

  • kidney problems
  • liver problems
  • malnutrition
  • problems with your adrenal glands
  • heart or cardiovascular disease
  • anaemia
  • blood disorders which lead to difficulty in clotting
  • if you are taking anticoagulants
  • if you are taking corticosteroids including inhaled corticosteroids for the treatment of asthma
  • if you have an intra-uterine device (IUD) in place

If you have not told your doctor about any of the above, tell him/her before you take Mifepristone Linepharma 200 mg tablet.

Serious skin reactions including toxic epidermal necrolysis and acute generalized exanthematous pustulosis have been reported in association with mifepristone treatment. Stop using the Mifepristone Linepharma 200 mg tablet and seek medical attention immediately if you notice any of the symptoms described under the ‘Side Effects’ section. If you get a serious skin reaction you should not use mifepristone again in the future.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket, health food shop, naturopath, herbalist or internet.

Some medicines and Mifepristone Linepharma 200 mg tablet may interfere with each other. These include:

  • corticosteroids including inhaled corticosteroids for the treatment of asthma
  • ketoconazole or itraconazole, medicines used to treat fungal infections
  • erythromycin or rifampicin, antibiotics for treating infections
  • St John’s Wort, a natural remedy used to treat mild depression
  • phenytoin, phenobarbitone, carbamazepine, medicines used to treat epilepsy

These medicines may be affected by Mifepristone Linepharma 200 mg tablet, or may affect how well it works. You may need to be given different amounts of your medicines, or you may need to be given different medicines.

Your doctor and pharmacist may have more information on medicines to be careful with or avoid while being treated with Mifepristone Linepharma 200 mg tablet.

Grapefruit juice should not be taken when you are treated with Mifepristone Linepharma 200 mg tablet.

How Mifepristone Linepharma 200 mg tablet is given

How much to take

Your doctor will tell you how many tablets you need to take and when to take them.

The usual dose of Mifepristone Linepharma is 200 mg (one tablet). You will then receive a prostaglandin analogue to complete the termination of pregnancy.

It is recommended that Mifepristone Linepharma 200 mg tablet should be taken on an empty stomach - 2 hours before or 2 hours after a meal.

How to take Mifepristone Linepharma 200 mg tablet

Mifepristone Linepharma 200 mg tablet should be swallowed with water

It is very important that you follow any instructions your doctor has given you following administration of Mifepristone Linepharma.

The completion of your pregnancy termination will take place in a hospital environment. 36-48 hours after taking Mifepristone Linepharma you will be given the prostaglandin analogue. You may require several doses of the prostaglandin before completion of the termination occurs.

It is very important that you have follow up with your doctor after you take Mifepristone Linepharma to ensure that the termination was complete because incomplete termination will increase the risk of serious infection or bleeding.

It is recommended that you do not travel away from home during the time that you are bleeding so that you can visit your doctor, clinic or hospital if necessary.

In case of heavy and prolonged bleeding, you should contact your doctor, clinic or hospital immediately to get advice and care.

Very occasionally you may begin to bleed heavily or miscarry the pregnancy before the planned administration of the prostaglandin. If you are worried this may be occurring you must follow the instructions given to you by your doctor or seek urgent medical care.

If you are given too much (overdose)

Mifepristone Linepharma 200 mg is available as a single tablet pack and it is given to you by your doctor. An overdose is not likely to occur. Ask your doctor if you have any concerns.

While you are being given Mifepristone Linepharma 200 mg tablet

Things you must do

If you are pregnant

In some cases treatment with Mifepristone Linepharma may not result in a complete termination of pregnancy and you may require another method, such as surgery, to complete the termination.

If treatment with Mifepristone Linepharma does not work or you change your mind after taking it and wish to keep your pregnancy, it is not known if Mifepristone Linepharma can cause harm to your baby.

If you are Rhesus negative, the use of Mifepristone Linepharma requires that your doctor will take measures to prevent Rhesus factor sensitization, along with the general measures taken during any pregnancy termination.

If you are breastfeeding

Mifepristone Linepharma should not be taken if you are breast-feeding.

If you are taking other medicines

If you are about to be started on any new medicines, remind your doctor or pharmacist that you have recently been given Mifepristone Linepharma 200 mg tablet.

Ask your doctor or pharmacist for advice before taking any medicine.

Tell any other doctors, dentists, and pharmacists who treat you that you have recently been given this medicine, as it may interact with other medicines or anaesthetics they may use.

Side effects

Tell your doctor or nurse as soon as possible if you do not feel well while you are being given Mifepristone Linepharma 200 mg tablet.

Do not be alarmed by the following list of side effects, you may not experience any of them.

Tell your doctor if you notice any of the following and they worry you:

  • headache
  • vaginal bleeding which may be heavy or prolonged
  • spotting
  • cramps
  • breast tenderness
  • fainting
  • hot flushes, skin rashes or itching
  • side effects that may also be related to prostaglandin analogues such as nausea, vomiting, diarrhoea, dizziness, abdominal discomfort, abdominal pain, cramps, fatigue and chills and/or fever.

Tell your doctor if you notice anything that is making you feel generally unwell.

Skin Reaction
Serious skin reactions include reddish circular patches on the trunk, often with central blisters, skin peeling, ulcers of mouth, throat, nose, genitals and eyes. These serious skin rashes are rare and can be preceded by fever and flu-like symptoms. A red, scaly widespread rash with bumps under the skin and blisters accompanied by fever may appear at the initiation of treatment.

Bleeding
Contact your doctor if you are concerned about bleeding after taking Mifepristone Linepharma or following discharge from hospital. Contact your doctor immediately if you find you have very heavy bleeding and have soaked more than 2 pads over 2 hours.

Infection
Serious infections are very rare in a medical termination of pregnancy but can be potentially life threatening. If you have symptoms of ongoing abdominal pain, or feeling unwell, or feeling weak, with or without a fever, you should contact your doctor without delay.

Other side effects not listed above may also occur in some people.

After being given Mifepristone Linepharma 200 mg tablet

It is very important that you follow any instructions your doctor has given you and keep any follow up appointments following administration of Mifepristone Linepharma.

Storage

Mifepristone Linepharma will be stored by your doctor or pharmacist under the recommended conditions. It should be kept in a cool, dry place where the temperature stays below 30 degrees C. Store Mifepristone Linepharma in the original packaging.

Keep Mifepristone Linepharma where children cannot reach it.

Mifepristone Linepharma should not be used after the expiry date printed on the pack. If this medicine is used after the expiry date it may not work as well.

Disposal

Any Mifepristone Linepharma which is not used will be disposed of in a safe manner by your doctor or pharmacist.

Using contraceptives

It is possible for you to become pregnant again immediately after the pregnancy termination is completed. As some effects of Mifepristone Linepharma may still be present, it is recommended that you avoid getting pregnant again before your next menstrual period after taking Mifepristone Linepharma.

Product description

What it looks like

Mifepristone Linepharma 200 mg tablets are white to off-white, round tablets, with MF embossed on one side of the tablet. Each tablet contains 200 mg of mifepristone. Mifepristone Linepharma 200 mg is in a blister pack of one tablet.

Ingredients

Mifepristone Linepharma contains the active ingredient mifepristone plus maize starch, povidone, microcrystalline cellulose, colloidal anhydrous silica and magnesium stearate.

The tablets do not contain gluten, lactose, tartrazine or any azo dyes.

Supplier

Mifepristone Linepharma 200 mg tablet is supplied in Australia by:

MS Health Pty Ltd
Suite 60, 278 Church Street,
Richmond, VIC, Australia, 3121

MS Health After Care line:
1300 515 883 (24 hours)

Licensed from Linepharma International Limited (UK)

Australian registration number: AUST R 175671

This leaflet was updated in Sept 2022

Copyright. All rights reserved.

Published by MIMS October 2022

BRAND INFORMATION

Brand name

Mifepristone Linepharma

Active ingredient

Mifepristone

Schedule

S4

 

1 Name of Medicine

Mifepristone.

2 Qualitative and Quantitative Composition

Each tablet contains 200 mg of mifepristone.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablet, uncoated.
Mifepristone Linepharma, white to off-white, round biconvex tablets, diameter 11 mm, with MF debossed on one side of the tablet.

4 Clinical Particulars

4.1 Therapeutic Indications

Mifepristone Linepharma 200 mg tablet is indicated in females of childbearing age for:
Preparation for the action of registered prostaglandin analogues that are indicated for the termination of pregnancy for medical reasons beyond the first trimester.

4.2 Dose and Method of Administration

Preparation for the action of prostaglandin analogues during the termination of pregnancy for medical reasons beyond the first trimester.

The method of administration is as follows:
200 mg of mifepristone (1 tablet containing 200 mg) orally, followed 36 to 48 hours later by the scheduled prostaglandin analogue administration, which will be repeated as often as indicated.
No studies have been conducted on the effect of food intake on the absorption of mifepristone. It is recommended that Mifepristone Linepharma should not be taken within 2 hours of a meal.

4.3 Contraindications

This product should not be prescribed in the following situations:
Lack of access to emergency medical care until complete expulsion is recorded.
Suspected or confirmed ectopic pregnancy.
Uncertainty about gestational age.
Chronic adrenal failure.
Concurrent long-term corticosteroid therapy.
Suspected or known haemorrhagic disorders or treatment with anti-coagulants.
Hypersensitivity to mifepristone, the prostaglandin analogue to be used, or any of the excipients.
Contraindication to the prostaglandin analogue selected.
Pregnancy not confirmed by an ultrasound or biological test such as urine or serum HCG.

4.4 Special Warnings and Precautions for Use

The prescriber must ensure that consent and treatment of the patient is in accordance with the appropriate state or territory legislation.
This medication is for use in termination of pregnancy for medical reasons beyond the first trimester. Medical termination of pregnancy up to 63 days gestation requires the use of MS-2 Step (mifepristone, misoprostol).
Mifepristone Linepharma (or the prostaglandin analogue) should be used with caution if an intrauterine device is present. If it can be removed safely first, this should be done.
During clinical trials, pregnancies occurred between fetus expulsion and the resumption of menses. To avoid the 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 Linepharma administration.
Due to the antiglucocorticoid activity of mifepristone, take special care in case of suspected acute adrenal failure. In addition, 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. In case of suspected acute adrenal failure, dexamethasone administration is recommended (please refer to the dexamethasone Product Information).
The precautions related to the prostaglandin analogue used should be followed where relevant.
Rare serious cardiovascular accidents have been reported following administration of prostaglandins. For this reason women with risk factors for cardiovascular disease or established cardiovascular disease should be treated with caution.
Severe cutaneous adverse reactions, including toxic epidermal necrolysis and acute generalised exanthematous pustulosis, have been reported in association with mifepristone (see Section 4.8 Adverse Effects (Undesirable Effects)). In patients who experience severe cutaneous adverse reactions, treatment with mifepristone should be immediately discontinued. Re-treatment with mifepristone is not recommended.

Populations not studied.

In the absence of specific studies, Mifepristone Linepharma is not recommended in patients with:
Cardiovascular disease.
Hypertensive disease.
Respiratory disease.
Diabetes.
Severe anaemia.
Malnutrition.
Heavy smokers.
Women who are older than 35 years and who also smoke 15+ cigarettes per day should be treated with caution because such patients were generally excluded from clinical trials of mifepristone.

Precautions.

This medication should only be prescribed by medical practitioners with appropriate obstetric qualifications and training to provide termination of pregnancy beyond the first trimester.
Published guidelines should be consulted for appropriate prostaglandin regimens that should only be provided in appropriately equipped facilities.
Ectopic pregnancy. Ectopic pregnancy should be excluded and gestation confirmed prior to medical abortion.
Rhesus alloimmunisation. The use of Mifepristone Linepharma requires rhesus determination and hence the prevention of rhesus alloimmunisation.
Explanation of requirements for the method. This method requires the involvement of the woman who should be informed of the requirements of the medical method, which involves:
The necessity to combine treatment with a prostaglandin analogue;
The need to adhere to treatment protocols and for follow-up after intake of Mifepristone Linepharma;
On discharge from the treatment centre all women should 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.
The expulsion may take place before prostaglandin administration. Local protocols should be in place to manage this occurrence. This does not preclude the need for follow-up to confirm complete expulsion.
The following risks related to the medical method must be taken into account and explained to the woman.

Failures.

The non-negligible risk of failure, including retained placenta and incomplete abortion, which may require completion of the termination by another method.

Bleeding.

The patient must be informed of the potential for bleeding prior to the administration of the selected prostaglandin which in no way precludes the need to adhere to treatment protocols and follow-up. Bleeding post-expulsion in the second trimester may lead to a significant decrease in haemoglobin levels and can be large enough to necessitate a blood transfusion in around 0.5% of women.
The patient should be informed not to travel far away from the prescribing centre as long as complete expulsion has not been recorded. The patient must receive precise instructions as to whom she should contact and where to go, in the event of any problems emerging, particularly in the case of very heavy vaginal bleeding.
Follow-up as per local protocols must take place after administration of Mifepristone Linepharma and expulsion of the conceptus. Persistence of vaginal bleeding could signify incomplete abortion and appropriate treatment should be arranged.
Since heavy or prolonged bleeding requiring haemostatic curettage occurs in up to 5% of cases during the medical method of pregnancy termination, special care should be given to patients with haemostatic disorders with hypocoagulability, or with anaemia. The decision to use the medical method should be decided with specialised consultants according to the type of haemostatic disorder and the level of anaemia.

Infection.

As with other types of abortion, cases of serious bacterial infection, including very rare cases of fatal septic shock, have been reported following the use of mifepristone. Doctors evaluating a patient who is undergoing a medical abortion should be alert to the possibility of this rare event. In particular, a fever, severe abdominal pain, or pelvic tenderness in the days after a medical abortion may be an indication of infection.
A high index of suspicion is needed to rule out sepsis (from e.g. Clostridium sordellii or other species e.g. Streptococcus) if a patient reports abdominal pain or discomfort or general malaise (including weakness, nausea, vomiting or diarrhoea) more than 24 hours after taking mifepristone and a prostaglandin. Very rarely, deaths have been reported in patients who presented without fever, with or without abdominal pain, but with leukocytosis with a marked left shift, tachycardia, haemoconcentration, and generally feeling tired or unwell. Most of these deaths occurred in women who used vaginally administered misoprostol however other forms of administration have been reported. No causal relationship between mifepristone and prostaglandin use and an increased risk of infection or death has been established.
Clostridium sordellii and other infections such as Streptococcus and other bacteria have also been reported very rarely following childbirth (vaginal delivery and caesarian section), and in other gynaecologic and non-gynaecologic conditions. Reviews have estimated overall serious infection rates after medical abortion at less than 1%.
Following abortion, women must be given a written account of the symptoms they may experience and a list of those that would make an urgent medical consultation necessary. They should be given a 24 hour telephone helpline number to use if they feel worried about pain, bleeding or high temperature. Urgent clinical assessment and emergency gynaecology admission must be available when necessary. On discharge, each woman should be given a letter that gives sufficient information about the procedure to allow another practitioner elsewhere to deal with any complications.

Use in hepatic impairment.

Mifepristone Linepharma is not recommended for use in patients with hepatic disease, in the absence of specific studies.

Use in renal impairment.

Mifepristone Linepharma is not recommended for use in patients with renal disease, in the absence of specific studies.

Use in the elderly.

There is no relevant use of Mifepristone Linepharma in the elderly population in the indications.

Paediatric use.

Limited data are available for use of Mifepristone Linepharma in women under 18 years.
There is no relevant use of Mifepristone Linepharma in the prepubertal paediatric population in the indications.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interaction studies have been performed.
On the basis of mifepristone'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 information showing that mifepristone acts as a mechanism based inhibitor of CYP3A4, co-administration of mifepristone may lead to an increase in serum levels of drugs that are CYP3A4 substrates. Due to the irreversible nature of the CYP binding and 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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Mifepristone inhibited oestrus cycling in rats at oral doses of 0.3-1 mg/kg/day (less that the clinical dose adjusted for body surface area) in a 3 week study. This was reversed over the following 2-3 weeks and no subsequent effects on reproductive performance were found.
In animals, the abortifacient effect of mifepristone precludes the proper assessment of any teratogenic effect of the molecule.
Fetal skull/ brain malformations, presumed to be related to treatment, have been observed in rabbits and monkeys, but not mice or rats, treated with sub-abortive doses of mifepristone. These most likely occurred secondary to mifepristone's effect on the uterus due to antagonism of progesterone.
In humans, the few reported cases of malformations do not allow a causality assessment for mifepristone alone or associated with the prostaglandin analogue. Therefore, data are too limited to determine whether the molecule is a human teratogen.
Should the patient wish to continue with her pregnancy following the administration of Mifepristone Linepharma, the available data are too limited to justify a systematic termination of an exposed pregnancy. In that event, careful ultra-sonographic monitoring of the pregnancy should be carried out.
 Mifepristone is a lipophilic compound and may theoretically be excreted in the mother's breast milk. However, limited data is available. Consequently, Mifepristone Linepharma use should be avoided during breast-feeding.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

There are limited safety data from experience with use of mifepristone in medical terminations beyond the first trimester. The adverse events reported with mifepristone use in first trimester terminations with the prostaglandin analogues misoprostol or gemeprost, classified according to frequency and system organ class, are summarised as shown in Table 1.
Post-marketing experience for first trimester termination of pregnancy indicates that death can occur as a result of medical termination of pregnancy (although this is a very rare outcome, < 1 in 100,000). The reported deaths were due to sepsis (fatal toxic shock syndrome) associated with Clostridium sordellii, which also occurs in association with childbirth and spontaneous termination. The symptoms of Clostridium sordellii infection are sometimes not the usual symptoms of sepsis. Therefore, the possibility of sepsis should be considered in all women who present with nausea, vomiting, or diarrhoea and weakness, with or without abdominal pain following mifepristone/ prostaglandin use. These symptoms, even without a fever, may indicate Clostridium sordellii infection. Strong consideration should be given to obtaining a complete blood count in these patients. Significant leukocytosis with a marked left shift and haemo-concentration may be indicative of sepsis. Practitioners should consider immediately initiating treatment with antibiotics that includes coverage of anaerobic bacteria such as Clostridium sordellii. No causal relationship between mifepristone and prostaglandin use and an increased risk of infection or death has been established. Clostridium sordellii and other infections such as Streptococcus and other bacteria have also been reported very rarely following childbirth (vaginal delivery and caesarian section), and in other gynaecologic and non-gynaecologic conditions. Reviews have estimated overall serious infection rates after medical abortion at less than 1%.
Bleeding is an almost constant part of the procedure, whatever the prostaglandin analogue used. It can occur after mifepristone alone. When heavy, it usually reflects incomplete abortion: in clinical trials surgical evacuation was needed in 10-12% of women, with some studies reporting a rate as high as 20-30%. It can be prolonged for several days after prostaglandin analogue administration and sometimes leads to a decrease in haemoglobin levels. The degree of bleeding can necessitate a blood transfusion in around 0.5% of patients in the second trimester.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems and to MS Health at 1300 515 883.

4.9 Overdose

No case of overdose has been reported. 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.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pharmacotherapeutic group: Other Sex Hormone and Modulator 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.
Mifepristone binds to human progesterone receptors with nanomolar affinity. In animals, oral administration was shown to inhibit the action of endogenous or exogenous progesterone in multiple species (rat, mouse, rabbit, dog and monkey). This action is manifested in the form of pregnancy termination.
In women at doses of greater than or equal to 1 mg/kg, mifepristone antagonises the endometrial and myometrial effects of progesterone. During pregnancy it sensitises the myometrium to the contraction inducing action of prostaglandins. While clinical data have demonstrated that mifepristone facilitates dilatation of the cervix, no data are available to indicate that this results in a lowering of the rate of early or late complications to the dilatation procedure.
In termination of pregnancy, the combination of a prostaglandin analogue used in a sequential regimen after mifepristone leads to an increase in the success rate and accelerates the expulsion of the conceptus.
Mifepristone binds to the glucocorticoid receptor with affinity comparable to that for the progesterone receptor. Full inhibition of the action of dexamethasone was evident in rats at oral doses 0.5-1.1 times the human dose adjusted for body surface area. 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.
Mifepristone also has some antiandrogenic activity. 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.

Clinical trials.

In clinical trials the results vary slightly according to the prostaglandin analogue used and the time of application.
Evidence based guidelines and reviews should be consulted for prostaglandin regimens to be used for termination beyond the first trimester. Failures are due to retained placenta or incomplete abortion and may necessitate a surgical procedure to complete the abortion process. For termination of pregnancy beyond first trimester, pretreatment with 200 mg mifepristone facilitates the procedure: the induction to abortion interval is reduced, as well as the need for prostaglandin analogues (gemeprost or misoprostol). Several studies report prostaglandin regimens used in the gestation range of 12-24 weeks associated with median induction-abortion intervals in the range of 5-8 hours and over 90% of women aborting within 24 hours1,2,3,4,5. Surgical evacuation was needed in 10-12%, with some studies reporting as high as 20-30%6,7,8,9.

5.2 Pharmacokinetic Properties

Absorption.

After oral administration of a single dose of 200 mg, mifepristone is rapidly absorbed. The peak concentration of 2.3 to 2.7 mg/L is reached after 0.75 hours (mean of 49 subjects). The half-life of mifepristone is 36.5 to 38.3 hours.
Mifepristone shows non-linear pharmacokinetics. Following the distribution phase the elimination is at first slow, with a half-life of approximately 12 to 72 hours, and then the concentration is more rapidly reduced with a half-life of 18 hours. With radio receptor analysis, the final half-life is shown to be up to 90 hours, including all mifepristone metabolites that can bind to progesterone receptors.
After administration of low doses of mifepristone (20 mg orally or intravenously), 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, the volume of distribution and plasma clearance of mifepristone are inversely proportional to the plasma concentration of AAG.

Metabolism.

N-mono- and di-demethylation and terminal hydroxylation of the 17-propynyl chain are primary metabolic pathways of hepatic oxidative metabolism. Metabolites are detectable in plasma 1 hour after ingestion of mifepristone. Plasma AUC for the dominant metabolite, monodemethylated mifepristone, is approximately double that of the unchanged mifepristone at the clinical dose, and this metabolite retains significant affinity for the progesterone receptor. The other metabolites also display some progesterone receptor affinity (approximately 10 to 15% that of mifepristone). The metabolites may contribute to the pharmacological effects of mifepristone.
In vitro CYP3A4 appears as the isoenzyme primarily responsible for mifepristone demethylation and hydroxylation in human liver microsomes. CYP3A4 substrates progesterone and midazolam inhibited metabolite formation by up to 77%. Other isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1) had apparently no action on mifepristone metabolism.

Excretion.

After administration of 600 mg radiolabeled mifepristone, 10% of the total radioactivity was recovered in urine and 90% in faeces.

5.3 Preclinical Safety Data

Genotoxicity.

Mifepristone has been evaluated in tests for mutagenicity in bacterial, yeast and mammalian cells; gene conversion in yeast; unscheduled DNA synthesis in HeLa cells; and for clastogenicity in vitro (Chinese hamster ovary cells) and in vivo (mouse bone marrow micronucleus test). No evidence of genotoxicity was observed.

Carcinogenicity.

No long-term animal carcinogenicity studies have been conducted with mifepristone. Based on the negative genotoxicity results, findings in general repeat-dose toxicity studies and considering the pattern of clinical use, mifepristone is not predicted to pose a particular carcinogenic risk.

6 Pharmaceutical Particulars

6.1 List of Excipients

Mifepristone Linepharma 200 mg tablet contains the following excipients: maize starch, povidone, microcrystalline cellulose, colloidal anhydrous silica and magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.
Keep in the original carton in order to protect from light.
Keep out of reach of children.

6.5 Nature and Contents of Container

PVC/PVDC/Aluminium blister of 1 tablet.
Pack size of 1 tablet.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Mifepristone.

Chemical structure.


Molecular formula: C29H35NO2. Molecular weight: 429.6.

CAS number.

CAS Registry Number: 84371-65-3.

References

1. Thong KJ. Baird DT. A study of gemeprost alone, dilapan or mifepristone in combination with gemeprost for the termination of second trimester pregnancy. Contraception 1992, 46, 11-7.
2. Ho PC. Chan YF. Lau W. Misoprostol is as effective as gemeprost in termination of second trimester pregnancy when combined with mifepristone: a randomised comparative trial. Contraception 1996, 53, 281-3.
3. Ho PC. Ngai SW. Liu KL. Wong GC. Lee SW. Vaginal misoprostol compared with oral misoprostol in termination of second-trimester pregnancy. Obstetr Gynecol 1997, 90, 735-8.
4. Tang O.S. Thong K.J. Baird D.T. Second trimester medical abortion with mifepristone and gemeprost: A review of 956 cases. Contraception 2001, 64, 29-32.
5. Webster D. Penney GC. Templeton A. A comparison of 600 and 200 mg mifepristone prior to second trimester abortion with the prostaglandin misoprostol. Br J Obstetr Gynecol 1996, 103, 706-9.
6. Bartley J. Baird DT. A randomised study of misoprostol and gemeprost in combination with mifepristone for induction of abortion in the second trimester of pregnancy. Br J Obstetr Gynecol 2002, 109, 1290-4.
7. Ngai SW. Tang OS. Ho PC. Randomized comparison of vaginal (200 microg every 3 h) and oral (400 microg every 3 h) misoprostol when combined with mifepristone in termination of second trimester pregnancy. Human Reprod 2000, 15, 2205-8.
8. Tang OS. Chan CC. Kan AS. Ho PC. A prospective randomized comparison of sublingual and oral misoprostol when combined with mifepristone for medical abortion at 12-20 weeks gestation. Human Reprod 2005, 20, 3062-6.
9. Tang O.S. Thong K.J. Baird D.T. Second trimester medical abortion with mifepristone and gemeprost: A review of 956 cases. Contraception 2001, 64, 29-32.

7 Medicine Schedule (Poisons Standard)

Schedule 4.

Summary Table of Changes