Consumer medicine information

MS-2 Step Mifepristone Linepharma 200 mg Tablet Pack

Misoprostol; Mifepristone

BRAND INFORMATION

Brand name

MS-2 Step

Active ingredient

Misoprostol; Mifepristone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using MS-2 Step Mifepristone Linepharma 200 mg Tablet Pack.

What is in this leaflet

This leaflet answers some common questions about mifepristone, contained within the MS-2 Step pack. 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 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 the mifepristone tablet is used for

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

Mifepristone can therefore be used to terminate a pregnancy.

It is given in combination with another medicine called misoprostol a prostaglandin analogue.

Both medicines are contained within the MS-2 Step pack, and they are recommended for the termination of pregnancy up to 63 days after your last menstrual period.

Ask your doctor if you have any questions about why MS-2 Step has been prescribed for you.

The medicines in MS-2 Step are available only with a doctor's prescription.

Before you are given the mifepristone tablet

When you must not be given it

You should not be given the mifepristone tablet if:

  • you are unable to access to emergency medical care in the next 14 days
  • your doctor suspects an ectopic pregnancy (the egg is implanted outside the womb)
  • you are using an intrauterine contraceptive device. It should be removed first.
  • your pregnancy has not been confirmed by a pregnancy test or an ultrasound scan
  • the first day of your last period was more than 63 days ago, unless tests have been done to confirm the age of the pregnancy is no more than 63 days
  • you are pregnant and wish to carry your pregnancy to term
  • 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.

You should not use this medicine after the expiry date printed on the Mifepristone Linepharma 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 if advised to do so by your doctor. There is limited information on the use of mifepristone 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 the mifepristone tablet

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
  • asthma
  • epilepsy
  • porphyria
  • 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), as this needs to be removed.

If you have not told your doctor about any of the above, tell him/her before you take the mifepristone tablet contained in the MS-2 Step pack.

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 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, 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.

Grapefruit juice should not be taken when you are treated with mifepristone.

How the mifepristone 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 is 200 mg (one tablet) in the green box. Your doctor will advise you about taking misoprostol tablets, usually 36 to 48 hours later.

It is necessary to take the mifepristone tablet first and then, 36 to 48 hours later, take the misoprostol tablets. This must be done in this order for the medicines to work.

It is recommended that the mifepristone tablet should be taken on an empty stomach - 2 hours before or 2 hours after a meal.

How to take the mifepristone tablet

The mifepristone tablet should be swallowed with water.

Vaginal bleeding usually starts 1 to 2 days after taking the mifepristone tablet.

36 to 48 hours after taking the mifepristone tablet you need to take misoprostol tablets as directed by your doctor or given to you by medical staff. After you take misoprostol tablets, you should stay at home and rest for 3 hours. Some women may be at a clinic for this part of the treatment. Vaginal bleeding will usually occur and the pregnancy may be expelled within a few hours of taking misoprostol or during the next few days. The bleeding lasts on average for 10 to 16 days and may be heavy.

It is very important that you have follow up with your doctor 14 to 21 days after you take mifepristone, 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 or clinic if necessary.

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

In a few cases, a termination can occur after you take mifepristone but before you take misoprostol. It is essential that you are checked to confirm that a complete termination has occurred. If this occurs, you should contact your doctor immediately in order to schedule an appointment.

If you forget to take your dose of misoprostol

Contact your doctor immediately if you forget to take the dose of misoprostol tablets in the purple box, and it is greater than 48 hours after you have taken mifepristone tablet.

If you are given too much (overdose)

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

While you are being given MS-2 Step

Things you must do

If you are pregnant

In some cases treatment with MS-2 Step may not result in a termination of pregnancy. You must keep all of your clinic appointments so that your progress can be checked. This is very important.

If treatment with MS-2 Step does not work, a termination can be arranged using another method.

If treatment with MS-2 Step does not work and you wish to keep your pregnancy, it is not known if mifepristone can cause harm to your baby. It is believed, though, misoprostol can cause harm to your baby. You need to tell your doctor or nurse about MS-2 Step so that they can carefully monitor your pregnancy.

If you are Rhesus negative, the use of MS-2 Step 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 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 MS-2 Step.

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 the medicines in MS-2 Step.

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 misoprostol 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.

Bleeding
Vaginal bleeding usually starts a few hours after taking misoprostol tablets. Bleeding can occur for 10 to 16 days and it is usual for bleeding to be heavier than a normal period for 2 to 3 days. Contact your doctor immediately if you find you have very heavy bleeding and have soaked more than 2 pads per hour over 2 hours.

Infection
Serious infections are very rare in a medical termination of pregnancy and can be potentially life threatening. If you have symptoms more than 24 hours after taking misoprostol or 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 the mifepristone tablet

Follow up with your doctor

It is very important for you to receive follow-up with a doctor in the 14-21 days after taking the Mifepristone Linepharma tablet, even if you feel well.

Storage

Mifepristone will be stored within the MS-2 Step pack by your doctor or pharmacist under the recommended conditions. It should be kept in a cool, dry place where the temperature stays below 25 degrees C. Store mifepristone in the original packaging.

Keep MS-2 Step where children cannot reach it.

MS-2 Step should not be used after the expiry date printed on the MS-2 Step pack. If this medicine is used after the expiry date it may not work as well.

Disposal

Any MS-2 Step which is not used must 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 and misoprostol may still be present after taking MS-2 Step, it is recommended that you avoid getting pregnant again before your next menstrual period.

Product description

What it looks like

The mifepristone tablet is a white to off-white, round tablet, with MF embossed on one side of the tablet. Each tablet contains 200 mg of mifepristone. Mifepristone is in a blister pack of one tablet. There is one Mifepristone Linepharma pack in each MS-2 Step pack.

Ingredients

The mifepristone tablet 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

MS-2 Step is supplied in Australia by:

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

MS Health Nurse After-care Telephone Service: 1300 515 883 (24 hours)

Mifepristone Linepharma is licensed from Linepharma International Limited (UK).

MS-2 Step and Mifepristone Linepharma are trademarks and GyMiso® is a registered trademark of Linepharma International Limited (UK).

Australian registration number: AUST R 210574.

This leaflet was updated in March 2017.

Copyright. All rights reserved.

Published by MIMS September 2020

BRAND INFORMATION

Brand name

MS-2 Step

Active ingredient

Misoprostol; Mifepristone

Schedule

S4

 

1 Name of Medicine

Mifepristone and misoprostol.

Note.

This document refers to the use of MS-2 Step, which consists of Mifepristone Linepharma 200 mg tablet and GyMiso misoprostol 200 microgram tablets in combination. These medicines are indicated in females of childbearing age for the medical termination of a developing intrauterine pregnancy, up to 63 days of gestation. The Mifepristone Linepharma 200 mg tablet component of this therapy is also used to treat another condition. For information about the treatment of the other condition, refer to the full product information for Mifepristone Linepharma 200 mg tablet individual product (AUST R 175671).

2 Qualitative and Quantitative Composition

MS-2 Step is a composite pack containing:

Mifepristone Linepharma.

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

GyMiso.

Each tablet contains 200 micrograms of misoprostol as a 1% dispersion of misoprostol-hypromellose. Misoprostol is a clear, colourless or yellowish oily liquid.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Mifepristone Linepharma.

White to off-white, round biconvex tablets, diameter 11 mm, with "MF" debossed on one side of the tablet.

GyMiso.

White, flat round tablet with "ML" debossed on one side and "200" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

MS-2 Step is indicated in females of childbearing age for the medical termination of a developing intrauterine pregnancy, up to 63 days of gestation.
It is recommended that the duration of pregnancy (i.e. up to 63 days gestation) be confirmed by ultrasound. In the event that an ultrasound is not possible, extra caution should be exercised.
Ultrasound is also useful to exclude ectopic pregnancy.

4.2 Dose and Method of Administration

MS-2 Step is indicated for medical termination of developing intrauterine pregnancy, up to 63 days of gestation.
The method of administration is as follows.

Mifepristone.

200 mg of mifepristone (1 tablet containing 200 mg) orally, followed 36 to 48 hours later by the administration of GyMiso.

GyMiso.

800 micrograms of misoprostol (4 tablets, each tablet containing 200 micrograms) buccally, i.e. kept between the cheek and the gum for 30 minutes before any fragments being swallowed with water.
When MS-2 Step fails to cause termination of intrauterine pregnancy, the patient should return to the treating doctor for assessment and discussion of treatment options, which may include pregnancy termination by surgery.
No dosage adjustment of misoprostol or mifepristone is necessary with renal or hepatic insufficiency when administered at the recommended doses.
There are no data available on the effect of food intake on the absorption of mifepristone or misoprostol. MS-2 Step should be taken 2 hours before or 2 hours after a meal.
Also see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use.
MS-2 Step should only be prescribed by doctors with the appropriate qualifications and certified training. Ectopic pregnancy should be excluded, an IUD (if present) must be removed, consent must be obtained and patients must have the ability to access 24 hour emergency care if and when required for incomplete abortion or bleeding.

4.3 Contraindications

MS-2 Step should not be prescribed in the following situations:
Lack of access to emergency medical care in the 14 days following start of the treatment (i.e. administration of mifepristone).
Suspected or confirmed ectopic pregnancy.
IUD in place.
Uncertainty about gestational age.
Chronic adrenal failure.
Concurrent long-term corticosteroid therapy.
Suspected or known haemorrhagic disorders or treatment with anticoagulants.
Hypersensitivity to mifepristone, misoprostol (or any prostaglandin), or any of the excipients used in MS-2 Step.

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.
Take special care in case of suspected acute adrenal failure.
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.
Rare serious cardiovascular accidents have been reported following administration of prostaglandins including misoprostol. For this reason women with risk factors for cardiovascular disease or established cardiovascular disease should be treated with caution.
Although no epileptic seizures have been reported with misoprostol, some have been reported with prostaglandins and other prostaglandin analogues, and therefore this possibility should be borne in mind in patients with a history of epilepsy.
Bronchospasm may occur with some prostaglandins and prostaglandin analogues. The possibility should be borne in mind in patients with a history of asthma.
No data are available in patients with inherited porphyria.

Populations not studied.

In the absence of specific studies, MS-2 Step is not recommended in patients with: cardiovascular disease, hypertensive disease, hepatic disease, respiratory disease, renal 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.

Specific precautions relating to medical termination of a developing intrauterine pregnancy.

Ectopic pregnancy.

Ectopic pregnancy should be excluded and gestation confirmed prior to medical abortion.

Rhesus alloimmunisation.

The use of MS-2 Step 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 take both Mifepristone Linepharma and GyMiso in sequence according to instructions.
The need for follow-up within 14 to 21 days after intake of Mifepristone Linepharma in order to confirm that the abortion is complete.
The non-negligible risk of failure (see Section 5.1 Pharmacodynamic Properties, Clinical trials) of the medical method which may require termination by another method.
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.
The expulsion may take place before GyMiso administration (in about 3% of cases). 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, which occurs in up to 7% of cases prior to 63 days gestation, makes follow-up mandatory in order to check that the expulsion is completed. Up to 63 days about 1% women will have continuing pregnancies, the rest needing curettage for other reasons.

Bleeding.

The patient must be informed of the occurrence of prolonged vaginal bleeding (an average of 10 to 16 days after Mifepristone Linepharma and GyMiso intake) which may be heavy. Bleeding occurs in almost all cases and is not in any way proof of complete expulsion. Persistent bleeding can be the consequence of incomplete expulsion. Bleeding can be large enough to necessitate a blood transfusion, in up to 0.2% of cases up to 63 days gestation and to lead to a significant decrease in haemoglobin levels.
The patient should be informed not to travel far away from the prescribing centre as long as complete expulsion has not been recorded. She will 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.
As per the Royal College of Obstetricians and Gynaecologists guideline (The Care of Women Requesting Induced Abortion, September 2004), the following is recommended:
"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."
Follow-up must take place within a period of 14 to 21 days after administration of Mifepristone Linepharma to verify by the appropriate means (clinical examination, ultrasound scan, or beta-hCG measurement) that expulsion has been completed and that vaginal bleeding has stopped. In case of persistent bleeding (even light) beyond this follow-up, the disappearance of bleeding should be checked within a few days.
If an ongoing 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 extrauterine pregnancy, and appropriate treatment should be considered. In the event of an ongoing pregnancy diagnosed after follow-up, termination by another method will be offered to the woman.
Since heavy 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 or the surgical 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 and misoprostol. No causal relationship between these events and the use of mifepristone and misoprostol has been established. Treating doctors evaluating a patient who is undergoing a medical abortion should be alert to the possibility of this rare event. In particular, a sustained fever of 38°C or higher, 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 misoprostol. However, the symptoms of Clostridium sordellii infection are sometimes not the usual symptoms of sepsis and 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 general malaise. Therefore, the possibility of sepsis should be considered in all women who are undergoing medical termination and who present with nausea, vomiting, or diarrhoea and weakness with or without abdominal pain. 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 haemoconcentration may be indicative of sepsis. Doctors should consider immediately initiating treatment with antibiotics that includes coverage of anaerobic bacteria such as Clostridium sordellii. Most of the reported deaths occurred in women who used vaginally administered misoprostol however deaths following other forms of administration have been reported. No causal relationship between mifepristone and misoprostol 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 nongynaecologic conditions. Reviews have estimated overall serious infection rates after medical abortion at less than 1%.

Use in the elderly.

There is no relevant use of MS-2 Step in the elderly population in the indication.

Paediatric use.

Limited data are available for use of MS-2 Step in women under 18 years of age.
There is no relevant use of MS-2 Step in the prepubertal paediatric population in the indication. Administration to adolescents less than 18 years of age should be undertaken with caution.

Effects on laboratory tests.

There are no known effects of mifepristone or misoprostol on laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Mifepristone Linepharma.

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, coadministration 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 anaesthesia.

GyMiso.

Misoprostol has no known drug interactions. No induction of the hepatic cytochrome P-450 enzyme system has been observed. The serum protein binding of misoprostol acid was not affected by indomethacin, ranitidine, digoxin, phenylbutazone, warfarin, diazepam, methyldopa, propranolol, triamterene, cimetidine, paracetamol, ibuprofen, chlorpropamide and hydrochlorothiazide. With salicylic acid (300 microgram/mL), the protein binding of misoprostol was lowered from 84 to 52% which is not considered clinically significant since the binding of misoprostol acid is not extensive and its elimination half-life is very short.
In laboratory studies, misoprostol has no significant effect on the cytochrome P450 linked hepatic mixed function oxidase system, and therefore should not affect the metabolism of theophylline, warfarin, benzodiazepines or other drugs normally metabolised by this system. No drug interactions have been attributed to misoprostol in extensive clinical trials. As such, other drugs would be unlikely to interfere with misoprostol's metabolism in either normal or hepatically impaired patients.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

During clinical trials, pregnancies occurred between embryo expulsion and the resumption of menses. To avoid the potential exposure of a subsequent pregnancy to MS-2 Step it is recommended that conception be avoided during the next menstrual cycle. Reliable contraceptive precautions should therefore commence as early as possible after administration of MS-2 Step.

Mifepristone Linepharma.

Mifepristone inhibited oestrus cycling in rats at oral doses of 0.3-1 mg/kg/day (less than 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.

GyMiso.

In fertility studies in rats in which treated females were mated with treated males, increased preimplantation losses were observed with misoprostol at oral doses greater than 1 mg/kg/day (11 times the recommended human dose, on a mg/m2 basis). Postimplantation loss was also increased at 10 mg/kg/day (114 times the recommended human dose, on a mg/m2 basis).

Mifepristone Linepharma.

In animals, the abortifacient effect of mifepristone precludes the proper assessment of any teratogenic effect of the molecule.
Foetal skull/brain malformations, presumed to be related to treatment, have been observed in rabbits and monkeys, but not mice or rats, treated with subabortive doses of mifepristone. These most likely occurred secondary to mifepristone's effect on the uterus due to antagonism of progesterone.
Delayed development of the righting reflex and slight inhibition of locomotor development were observed in rats when administered mifepristone at the high dose level (1 mg/kg/day) from day 15 of gestation to the end of the lactation period (postnatal day 21).
A review of births from 105 pregnancies exposed during first trimester of pregnancy to mifepristone alone (46 cases) or to both mifepristone and misoprostol (59 cases) has recently been published. There were 94 live births (90.4%) and 10 (9.6%) miscarriages (including one with major malformation). Elective termination of pregnancy was performed after the subsequent diagnosis of trisomy 21 in one case. The overall rate of major congenital malformations was 4.2% (95% CI: 1.2-10.4%), with two cases among 38 patients exposed to mifepristone alone and two cases among 57 patients exposed to both mifepristone and misoprostol. In conclusion, this unique prospective study found that the rate of major malformations after exposure to mifepristone during the first trimester of pregnancy is only slightly higher than the expected 2-3% rate in the general population. Nevertheless, data in humans are still too limited to determine whether the molecule is a human teratogen.

GyMiso.

Use of misoprostol has been associated with birth defects. In a few cases where misoprostol was self administered (orally or vaginally) in order to induce an abortion, the following deleterious effects of misoprostol have been suggested: malformations of limbs, of foetal movements and of cranial nerves (hypomimia, abnormalities in suckling, deglutition, and eye movements). To date, a risk of malformation cannot be excluded.
Reproductive toxicity studies in animals showed embryotoxicity (increased resorptions) with oral doses of 1 mg/kg/day in rabbits, 10 mg/kg/day in rats, and 20 mg/kg in mice when treatment occurred during the period of organogenesis. An increased incidence of skeletal abnormalities was observed with an oral dose of 1 mg/kg/day in rabbits (possibly due to maternal toxicity) while an increased incidence of cleft palate was seen at a single oral dose of 30 mg/kg in mice (28 and 170 times the recommended human dose, on a mg/m2 body surface area basis, respectively).

MS-2 Step.

As a consequence of the above information on mifepristone and misoprostol:
women should be informed that due to the risk of failure of the medical method of pregnancy termination and to the unknown risk to the foetus, follow-up is very important (see Section 4.4 Special Warnings and Precautions for Use);
should a failure of the medical method be diagnosed at follow-up (viable ongoing pregnancy), and should the patient still agree, pregnancy termination should be completed by another method.
Should the patient wish to continue with her pregnancy, she should be appropriately counselled as to the risk of birth defects. In that event of continuation of the pregnancy, careful ultrasonographic 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 are available. Misoprostol is rapidly metabolised in the mother to misoprostol acid, which is biologically active and is excreted in breast milk. This could cause undesirable effects such as diarrhoea in breastfeeding infants. MS-2 Step use should be avoided during breastfeeding.

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)

The most frequent undesirable effects which are observed during treatment with MS-2 Step are the following:

Gastrointestinal disorders.

Nausea (transient and mild), vomiting, diarrhoea, abdominal pain.

Reproductive system disorders.

Very frequent uterine contractions observed in the hours following the intake of the misoprostol component of the MS-2 Step pack; vaginal bleeding, sometimes heavy and prolonged (see Section 4.4 Special Warnings and Precautions for Use).

General disorders.

Headache, dizziness, and chills and fever. (Because castor oil is an excipient of the misoprostol component of the MS-2 Step pack, digestive symptoms (nausea, vomiting, abdominal pain) can be observed).
The adverse events reported with mifepristone and a prostaglandin analogue such as GyMiso, classified according to frequency and system organ class, are summarised as shown in Table 1.
Postmarketing experience 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 are undergoing medical termination and who present with nausea, vomiting, or diarrhoea and weakness, with or without abdominal pain. 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 haemoconcentration may be indicative of sepsis. Doctors should consider immediately initiating treatment with antibiotics that includes coverage of anaerobic bacteria such as Clostridium sordellii. See Section 4.4 Special Warnings and Precautions for Use.
Bleeding is an almost constant part of the procedure, whatever the prostaglandin analogue used, and at any pregnancy term, although it is usually more abundant when pregnancy age increases. It can occur after mifepristone alone. When heavy, it usually reflects incomplete abortion and is observed in approximately 3 to 12% of cases, depending on the pregnancy age and the prostaglandin analogue used, and needs specific treatment. It can necessitate a blood transfusion in up to 0.2% of cases. It can be prolonged for several days after prostaglandin analogue administration and sometimes leads to a decrease in haemoglobin levels. This potentially severe complication justifies that after intake (i) follow-up takes place approximately 14 to 21 days after Mifepristone Linepharma administration to ensure that expulsion is complete with no persisting bleeding and (ii) until follow-up has taken place, the woman remains close to a facility where she can be treated at any moment in case of severe or prolonged bleeding. See Section 4.4 Special Warnings and Precautions for Use.
The issue of the outcome of persisting pregnancy in the case of failure of the medical method remains incompletely solved; a risk of malformation attributable to mifepristone or to prostaglandin analogues such as misoprostol cannot be excluded, and women should be adequately counselled in such a situation. Another fact to take into consideration is the possibility of a pregnancy persisting in the form of an ectopic pregnancy, since evidence suggests that the method does not appear able to terminate an ectopic pregnancy.

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

Mifepristone Linepharma.

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.

GyMiso.

The toxic dose of misoprostol in humans has not been determined. Cumulative total daily doses of 1600 micrograms have been tolerated, with only symptoms of gastrointestinal discomfort reported.
Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnoea, abdominal pain, diarrhoea, fever, palpitations, hypotension or bradycardia. Hypertension and tachycardia have also been reported following overdoses. Overdose in pregnancy has resulted in uterine contractions with foetal death.
There is no specific antidote. Treatment should be symptomatic and supportive. Consider administration of activated charcoal in the event of a potentially toxic ingestion. Activated charcoal may reduce absorption of misoprostol if given within one or two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Mifepristone Linepharma.

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 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 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.

GyMiso.

Pharmacotherapeutic group: Other gynecological medicines, prostaglandins. ATC code: G02AD06.
Misoprostol is a synthetic analogue of prostaglandin E1. At the recommended dosages, misoprostol induces contractions of the smooth muscle fibers in the myometrium and relaxation of the uterine cervix. The uterotonic properties of misoprostol should facilitate cervical opening and evacuation of intrauterine debris.
In the event of an early termination of pregnancy, the combination of GyMiso used in a sequential regimen after mifepristone leads to an increase in the success rate and accelerates the expulsion of the conceptus.
Pharmacodynamic studies in early pregnancy have found an increase in uterine tone around 8 minutes after oral and 40 minutes after buccal misoprostol, with sustained contractions achieved by a mean of around 90 minutes and uterine activity peaking prior to 5 hours.
Following oral administration uterine activity rises earlier than other routes, but is lower overall. Pretreatment with mifepristone has previously been shown to increase uterine contractility in response to misoprostol.

Clinical trials.

Clinical efficacy of early medical abortion is defined as complete abortion without surgical intervention, regardless of the reason for the intervention, which may include continuing pregnancy, missed or incomplete abortion, prolonged or heavy vaginal bleeding or a woman's request.
An open label single group prospective trial performed in Mexico by Gynuity Healthcare, USA, involving 971 women available for efficacy treated with 200 mg mifepristone followed by 800 micrograms misoprostol administered buccally indicated that efficacy was 98.0, 96.8 and 95.9% for women with gestational age 49 days and below, 50-56 days and 57-63 days, respectively. In these 3 gestational age groups, the rate of surgical evacuation was 2.0, 3.2 and 4.1% respectively. In this study 25 women received a second dose of misoprostol, in each case, a dose of 800 micrograms by the buccal route. Of those 25, 20 had a successful outcome with medication alone, 4 had a surgical intervention and 1 woman did not return for follow-up. In this study, bleeding occurred in all women independent of outcome, and was judged as more than expected in 27.1% of the women.
In an Authorised Prescribers Program in Australia in 2012 that included 7,166 women, efficacy was 97.4% for women with gestational age < 49 days, and 95.2% for women with gestational age of 49-63 days. The rate of incomplete termination requiring aspiration was: < 49 days: 2.3%; 49-63 days: 4.8%. The rate of ongoing pregnancies was: < 49 days: 0.3%; 49-63 days: 0.6%. Bleeding was considered as an adverse event in 0.24% of women, independent of pregnancy age.
Studies published in the literature have reported mifepristone and oral or buccal misoprostol regimens. In one study of 966 patients1 with pregnancies up to gestational age of 63 days, randomised to 200 mg mifepristone followed 24-36 hours later by 800 micrograms of misoprostol orally or buccally, reported efficacy rates were 91.3% for the oral and 96.2% for the buccal group (RR 0.95, 95% CI 0.92-0.98, p = 0.003).
Studies published on the combination of mifepristone 200 mg and misoprostol 800 micrograms buccally, and reporting outcomes by gestational age, encompass 399 women with gestational ages 50-56 days and 344 women with gestational ages 57-632,3,4,5,6,7 days. Efficacy ranged from 86.5 to 98.5% in women with gestational age 50-56 days and from 93.0 to 100% in those with gestational age 57-63 days. In these studies, the rate of ongoing pregnancies ranged from 0 to 7.1% in women with gestational age 50-56 days and from 0 to 2.3% in those with gestational age 57-63 days.
Literature data provides information on the bleeding and expulsion pattern after termination of pregnancy with mifepristone and misoprostol: approximately half of women start to bleed before prostaglandin administration. Median bleeding time is 10 to 16 days. Bleeding is judged more or much more abundant than usual menses for 2 to 3 days after prostaglandin. In studies where it was measured, there was a slight but significant decrease in haemoglobin level after compared to baseline. In one study blood loss was quantified: the median blood loss was 83 mL and 5.4% of women had a blood loss above 200 mL. Expulsion usually takes place within 3 hours after misoprostol in approximately half of the women, and within 4 hours after misoprostol in approximately 50 to 90% of women.
1 Winikoff B et al. Obstetr Gynecol 2008, 1303-10.
2 Chong et al 2012 Contraception 86, 251-256.
3 Fjerstad et al 2009 Contraception 80, 282-286.
4 Boersma et al 2011 Eur J of Contraception and Reproductive Health Care 16, 61-66.
5 Ngoc et al 2011 Contraception 83, 410-417.
6 Blum et al 2012 Int J Gynecol Obstetr 118, 166-171.
7 WHO 2000 Br J Obstetr Gynecol 107, 524-30.

5.2 Pharmacokinetic Properties

Absorption.

Mifepristone Linepharma.

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 nonlinear 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 radioreceptor 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%.

GyMiso.

When administered orally, misoprostol is rapidly absorbed and metabolised. Peak concentrations around 1.1 nanogram/mL were reached about 15 minutes after a 400 micrograms dose in the fasting state. Plasma concentrations of its main degradation metabolite, misoprostol acid, reach their peak of 2-2.5 nanogram/mL after a 2 micrograms/kg oral dose within approximately 30 minutes and rapidly decline thereafter. As a result, uterine contractility increases and then plateaus after about one hour. Absorption is almost complete, measured at levels between 64-73% from urinary data.
For a single oral administration of 800 micrograms misoprostol (4 tablets of 200 microgram GyMiso), AUC0-t was 1.9709 ± 0.8130 hr.nanogram/mL, AUC0-∞ was 2.0192 ± 0.8032 hr.nanogram/mL and Cmax was 2.6830 ± 1.2161 nanogram/mL. For a single buccal administration of 800 micrograms misoprostol (4 tablets of 200 microgram GyMiso), AUC0-t was 1.9095 ± 0.2909 hr.nanogram/mL, AUC0-∞ was 2.0726 ± 0.3578 hr.nanogram/mL and Cmax was 1.3611 ± 0.3436 nanogram/mL. For a single sublingual administration of 800 micrograms misoprostol (4 tablets of 200 microgram GyMiso), AUC0-t was 3.0574 ± 0.9872 hr.nanogram/mL, AUC0-∞ was 3.2094 ± 1.0417 hr.nanogram/mL and Cmax was 2.4391 ± 1.1567 nanogram/mL. For log transformed AUC0-t, AUC0-∞ and Cmax, there were statistically significant differences between 3 treatment groups (p = 0.0159, 0.0162 and 0.0083, respectively). Sublingual administration of misoprostol had a higher AUC0-∞ compared with buccal and oral administration which indicated bioavailability was higher by the sublingual route. Misoprostol sublingual and oral administration resulted in higher Cmax compared with buccal. The Cmax of buccal administration was achieved later compared with other routes of administration. No difference was found when comparing oral, sublingual and buccal half-lives (p = 0.4495).

Distribution.

Mifepristone Linepharma.

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.

GyMiso.

Serum protein binding of labeled misoprostol acid was studied in man and was similar in young (81-88%) and elderly (81-89%) subjects. Accumulation in erythrocytes was not seen.

Metabolism.

Mifepristone Linepharma.

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.

GyMiso.

Metabolism of misoprostol to misoprostol acid is rapid with no intact misoprostol found in plasma consistent with an in vitro half-life of 6.4 minutes for de-esterification of misoprostol in human plasma at 37°C. Elimination of misoprostol and its metabolites is also rapid with a plasma elimination half-life of 35 minutes.

Excretion.

Mifepristone Linepharma.

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

GyMiso.

The liver is the primary site of metabolism and between 1-4% of misoprostol acid is excreted in the urine.

5.3 Preclinical Safety Data

Genotoxicity.

Mifepristone Linepharma.

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.

GyMiso.

Misoprostol has been evaluated in tests for mutagenicity in bacterial, yeast and mammalian 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.

Mifepristone Linepharma.

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.

GyMiso.

The potential carcinogenicity of misoprostol has been evaluated in both mice and rats. There was no evidence of an effect of misoprostol on tumour occurrence or incidence in rats receiving oral doses up to 2.4 mg/kg/day for 24 months. Similarly, there was no effect of misoprostol on tumour occurrence or incidence in mice receiving oral doses up to 16 mg/kg/day for 21 months. These doses are at least 27 times the recommended human dose, on a mg/m2 body surface area basis.

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.
GyMiso contains the following excipients: hypromellose, microcrystalline cellulose, sodium starch glycollate type A and hydrogenated castor oil.

6.2 Incompatibilities

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

6.3 Shelf Life

Do not use after the expiry date printed on the carton labels of the composite pack and the individual components.
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 25°C, keep in the original container to protect from light.
Keep out of reach of children.

Mifepristone Linepharma.

Keep in the original green carton in order to protect from light.

GyMiso.

Keep in the original purple carton.

6.5 Nature and Contents of Container

Each MS-2 Step composite pack consists of:
1 green carton containing Mifepristone Linepharma 200 mg tablet packaged in a PVC/PVDC/Aluminium blister. Pack size of 1 tablet.
1 purple carton containing GyMiso misoprostol 200 microgram tablet packaged in a dual-faced Aluminium blister. Pack size of 4 tablets (2 tablets per blister).

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

Chemical structure.

Mifepristone.


Molecular formula: C29H35NO2. Molecular weight: 429.6.

CAS number.

CAS Registry Number: 84371-65-3.

Chemical structure.

GyMiso.


Molecular formula: C22H38O5. Molecular weight: 382.5.

CAS number.

CAS Registry Number: 59122-46-2.

7 Medicine Schedule (Poisons Standard)

Schedule 4.

Summary Table of Changes