Consumer medicine information

MS-2 Step GyMiso 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 GyMiso Tablet Pack.

SUMMARY CMI

MS-2 Step® Mifepristone Linepharma

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your healthcare practitioner (doctor, nurse or pharmacist).

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I using MS-2 Step Mifepristone Linepharma?

MS-2 Step® is a composite pack product containing Mifepristone Linepharma 200 mg tablet and GyMiso® misoprostol 200 microgram tablets. MS-2 Step Mifepristone Linepharma contains the active ingredient mifepristone. MS-2 Step Mifepristone Linepharma is used to terminate a pregnancy up to 63 days after your last menstrual period when given in combination with MS-2 Step GyMiso®.

For more information, see Section 1. Why am I using MS-2 Step Mifepristone Linepharma? in the full CMI.

2. What should I know before I use MS-2 Step Mifepristone Linepharma?

Do not use if you have ever had an allergic reaction to mifepristone or any of the ingredients listed at the end of the CMI.

Talk to your healthcare practitioner if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use MS-2 Step Mifepristone Linepharma? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with MS-2 Step Mifepristone Linepharma and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use MS-2 Step Mifepristone Linepharma?

MS-2 Step Mifepristone Linepharma tablet should be taken first and then, 36 to 48 hours later, take the MS-2 Step GyMiso® tablets. The MS-2 Step Mifepristone Linepharma tablet should be swallowed with water. It is recommended that the MS-2 Step Mifepristone Linepharma tablet should be taken on an empty stomach 2 hours before or 2 hours after a meal.

More instructions can be found in Section 4. How do I use MS-2 Step Mifepristone Linepharma? in the full CMI.

5. What should I know while using MS-2 Step Mifepristone Linepharma?

Things you should do
  • Remind any doctor, nurse, dentist or pharmacist you visit that you are using MS-2 Step Mifepristone Linepharma.
  • Contact your healthcare practitioner immediately if you forget to take the dose of MS-2 Step GyMiso® tablets in the purple box, and it is greater than 48 hours after you have taken MS-2 Step Mifepristone Linepharma tablet.
  • It is important to have a follow up with your doctor 14-21 days after you take MS-2 Step Mifepristone Linepharma
Things you should not do
  • Do not take grapefruit juice when you are treated with MS-2 Step Mifepristone Linepharma.
  • Do not travel away from home during the time that you are bleeding so that you can visit your doctor if necessary.
Driving or using machinesBe careful before you drive or use any machines or tools until you know how MS-2 Step Mifepristone Linepharma affects you.
Drinking alcoholTell your healthcare practitioner (doctor, nurse or pharmacist) if you drink alcohol.
Looking after your medicine
  • MS-2 Step Mifepristone Linepharma should be stored within the MS-2 Step composite pack and be kept in a cool and dry place where the temperature stays below 25 degrees C
  • Keep MS-2 Step where children cannot reach it

For more information, see Section 5. What should I know while using MS-2 Step Mifepristone Linepharma? in the full CMI.

6. Are there any side effects?

The common side effects include headache, spotting, cramps, breast tenderness, fainting. Serious side effects include serious skin reactions, prolonged heavy vaginal bleeding, infections that can be potentially life threatening, ongoing abdominal pain.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

WARNING: It is very important that all patients receiving this medication are followed up by a healthcare practitioner, preferably the prescriber, to ensure that the medication has been effective. Even if no adverse events have occurred all patients must receive follow-up 14 to 21 days after taking MS-2 Step Mifepristone Linepharma.



FULL CMI

MS-2 Step® Mifepristone Linepharma

Active ingredient: mifepristone


Consumer Medicine Information (CMI)

MS-2 Step is a composite pack product containing Mifepristone Linepharma 200 mg tablet and GyMiso® misoprostol 200 microgram tablets (this medicine in the purple box).

Mifepristone Linepharma = mifepristone

GyMiso® = misoprostol

This leaflet provides important information about using MS-2 Step Mifepristone Linepharma contained within the MS-2 Step pack. You should also speak to your doctor, nurse or pharmacist if you would like further information or if you have any concerns or questions about using MS-2 Step Mifepristone Linepharma.

Where to find information in this leaflet:

1. Why am I using MS-2 Step Mifepristone Linepharma?
2. What should I know before I use MS-2 Step Mifepristone Linepharma?
3. What if I am taking other medicines?
4. How do I use MS-2 Step Mifepristone Linepharma?
5. What should I know while using MS-2 Step Mifepristone Linepharma?
6. Are there any side effects?
7. Product details

1. Why am I using MS-2 Step Mifepristone Linepharma?

MS-2 Step Mifepristone Linepharma contains the active ingredient mifepristone. Mifepristone is an anti-hormone. It acts by blocking the effects of progesterone, a hormone which is needed for pregnancy to continue.

MS-2 Step Mifepristone Linepharma 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 healthcare practitioner (doctor, nurse or pharmacist) if you have any questions about why MS-2 Step has been prescribed for you.

2. What should I know before I use MS-2 Step Mifepristone Linepharma?

Warnings

Do not use MS-2 Step Mifepristone Linepharma if:

  • you are allergic to mifepristone, or any of the ingredients listed at the end of this leaflet. Some of the symptoms of an allergic reaction may include:
    - Reddish circular patches on the trunk
    - Skin peeling
    - Ulcers of mouth, throat, nose, genitals, and eyes.
  • Always check the ingredients to make sure you can use this medicine.
  • 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)
  • if you have an intra-uterine device (IUD), as this needs to be removed.
  • your pregnancy has not been confirmed by an ultrasound scan or biological test such as urine or serum HCG
  • 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 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.

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.

Check with your healthcare practitioner if you:

  • have any other medical conditions such as:
    - 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
    - are taking anticoagulants
    - are taking long term corticosteroids including inhaled corticosteroids for the treatment of asthma

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.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your healthcare practitioner if you are pregnant or intend to become pregnant.

Do not use MS-2 Step Mifepristone Linepharma if:

  • your healthcare practitioner suspects an ectopic pregnancy (the egg is implanted outside the womb)
  • 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

Talk to your healthcare practitioner if you are breastfeeding or intend to breastfeed. MS-2 Step Mifepristone Linepharma should not be taken if you are breast-feeding.

3. What if I am taking other medicines?

Tell your healthcare practitioner if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with MS-2 Step Mifepristone Linepharma and affect how it works. 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 MS-2 Step Mifepristone Linepharma 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.

Grapefruit juice should not be taken when you are treated with MS-2 Step Mifepristone Linepharma.

4. How do I use MS-2 Step Mifepristone Linepharma?

How much to take

  • Your healthcare practitioner will tell you how many tablets you need to take and when to take them.
  • The usual dose of MS-2 Step Mifepristone Linepharma is 200 mg (one tablet) in the green box.

When to take

  • It is necessary to take the MS-2 Step Mifepristone Linepharma tablet first and then, 36 to 48 hours later, take the MS-2 Step GyMiso® tablets. This must be done in this order for the medicines to work.
  • It is recommended that the MS-2 Step Mifepristone Linepharma tablet should be taken on an empty stomach - 2 hours before or 2 hours after a meal.

How to take

  • The MS-2 Step Mifepristone Linepharma 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 your healthcare practitioner.

If you forget to take your dose of MS-2 Step GyMiso®

Contact your healthcare practitioner immediately if you forget to take the dose of MS-2 Step GyMiso® tablets in the purple box, and it is greater than 48 hours after you have taken MS-2 Step Mifepristone Linepharma tablet.

If you use too much MS-2 Step Mifepristone Linepharma

MS-2 Step Mifepristone Linepharma is available as a single tablet pack, and it is prescribed for you by your healthcare practitioner. An overdose is not likely to occur. Ask your doctor or healthcare practitioner if you have any concerns. If you think that you have used too much MS-2 Step Mifepristone Linepharma, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using MS-2 Step Mifepristone Linepharma?

Things you must do

  • After you take MS-2 Step GyMiso® 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 MS-2 Step GyMiso® or during the next few days. The bleeding lasts on average for 10 to 16 days and may be heavy.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 MS-2 Step Mifepristone Linepharma can cause harm to your baby. It is believed, though, MS-2 Step GyMiso® 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.

It is very important that you have follow up with your doctor or healthcare practitioner 14 to 21 days after you take MS-2 Step Mifepristone Linepharma, to ensure that the termination was complete because incomplete termination will increase the risk of serious infection or bleeding.

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

Using contraceptives: It is possible for you to become pregnant again immediately after the pregnancy termination is completed. As some effects of misoprostol and mifepristone may still be present after taking MS-2 Step, it is recommended that you avoid getting pregnant again before your next menstrual period.

Tell your doctor if you are a smoker.

Call your healthcare practitioner straight away:

  • In case of heavy and prolonged bleeding, you should contact your healthcare practitioner or clinic immediately to get advice and care.
    In a few cases, a termination can occur after you take MS-2 Step Mifepristone Linepharma but before you take MS-2 Step GyMiso®. 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.

Remind any doctor, nurse, dentist or pharmacist you visit that you are using MS-2 Step as it may interact with other medicines or anaesthetics they may use.

Things you should not do

  • 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

Driving or using machines

Be careful before you drive or use any machines or tools until you know how MS-2 Step Mifepristone Linepharma affects you.

Drinking alcohol

Tell your healthcare practitioner if you drink alcohol.

Looking after your medicine

  • MS-2 Step Mifepristone Linepharma should be stored within the MS-2 Step pack
  • Store below 25 degrees C.
  • Store in the original packaging.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your healthcare practitioner if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Gastrointestinal upset
  • Nausea
  • Vomiting
  • Diarrhoea
Tiredness related
  • Fainting
  • Dizziness
  • Fatigue
  • Headache
Vagina related
  • Vaginal bleeding which may be heavy or prolonged
  • Spotting
Pain related
  • Abdominal discomfort
  • Abdominal pain
  • Cramps
  • Breast tenderness
Skin related
  • Hot flushes
  • Skin rashes or itching
Infection related
  • Chills and /or fever
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Skin related
  • 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 related
  • Vaginal bleeding usually starts a few hours after taking MS-2 Step GyMiso® 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 related
  • 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 MS-2 Step GyMiso® or ongoing abdominal pain, or feeling unwell or feeling weak, with or without a fever, you should contact your doctor without delay.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your healthcare practitioner if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your healthcare practitioner before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a prescription.

What MS-2 Step Mifepristone Linepharma contains

Active ingredient
(main ingredient)
mifepristone
Other ingredients
(inactive ingredients)
colloidal anhydrous silica
magnesium stearate
maize starch
microcrystalline cellulose
povidone
Potential allergensNo

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

Do not take this medicine if you are allergic to any of these ingredients.

What MS-2 Step Mifepristone Linepharma looks like

The MS-2 Step Mifepristone Linepharma 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. MS-2 Step Mifepristone Linepharma is in a blister pack of one tablet. There is one Mifepristone Linepharma pack in each MS-2 Step pack.

Australian registration number: AUST R 210574

Who distributes MS-2 Step Mifepristone Linepharma

MS-2 Step is supplied in Australia by:

MS Health Pty Ltd
Suite 60, 278 Church Street,
Richmond, VIC, Australia, 3121.
Ph: 1300 515 883

MS-2 Step® is a registered trademark of MSI Reproductive Choices (UK).

Mifepristone Linepharma and GyMiso® are licensed from Linepharma International Limited (UK).

This leaflet was prepared in June 2023.

Published by MIMS September 2023


SUMMARY CMI

MS-2 Step® GyMiso®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your healthcare practitioner (doctor, nurse or pharmacist).

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I using MS-2 Step GyMiso®?

MS-2 Step GyMiso® contains the active ingredient misoprsotol. MS-2 Step GyMiso® is used to terminate pregnancy when given in combination with another medicine called Mifepristone Linepharma.

For more information, see Section 1. Why am I using MS-2 Step GyMiso®? in the full CMI.

2. What should I know before I use MS-2 Step GyMiso®?

Do not use if you have ever had an allergic reaction to misoprostol or any of the ingredients listed at the end of the CMI.

Talk to your healthcare practitioner if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use MS-2 Step GyMiso®? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with MS-2 Step GyMiso® and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use MS-2 Step GyMiso®?

  • MS-2 Step GyMiso® is usually taken 36-48 hours after you have taken MS-2 Step Mifepristone Linepharma tablet. You will need to take the four MS-2 Step GyMiso® tablets in one dose.
  • MS-2 Step GyMiso® should be taken by holding the tablets in your mouth, between the cheek and gum (buccal method), for 30 minutes before swallowing any fragments with water. It is recommended to that MS-2 Step GyMiso® should be taken on an empty stomach before or after a meal.

More instructions can be found in Section 4. How do I use MS-2 Step GyMiso®? in the full CMI.

5. What should I know while using MS-2 Step GyMiso®?

Things you should do
  • Remind any doctor, nurse, dentist or pharmacist you visit that you are using MS-2 Step GyMiso®
  • MS-2 Step GyMiso® tablets must be taken only after taking the MS-2 Step Mifepristone Linepharma tablet provided in the MS-2 Step pack.
  • It is important to keep all healthcare practitioner appointments so that your progress can be checked
Things you should not do
  • Do not travel away from home during the time that you are bleeding so that you can visit your doctor or clinic if necessary.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how MS-2 Step GyMiso® affects you.
Drinking alcohol
  • Tell your healthcare practitioner if you drink alcohol.
Looking after your medicine
  • MS-2 Step GyMiso® should be stored within the MS-2 Step composite pack and be kept in a cool and dry place where the temperature stays below 25 degrees C
  • Keep MS-2 Step where children cannot reach it

For more information, see Section 5. What should I know while using while using MS-2 Step GyMiso®? in the full CMI.

6. Are there any side effects?

The common side effects include headache, spotting, cramps, breast tenderness, fainting, abdominal discomfort, vomiting, diarrhea, fever. Serious side effects include prolonged heavy vaginal bleeding, infections that can be potentially life threatening, ongoing abdominal pain, or feeling unwell or feeling weak, with or without a fever.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

WARNING: It is very important that all patients receiving this medication are followed up by a healthcare practitioner, preferably the prescriber, to ensure that the medication has been effective. Even if no adverse events have occurred all patients must receive follow-up 14 to 21 days after taking mifepristone.



FULL CMI

MS-2 Step® GyMiso®

Active ingredient: misoprostol


Consumer Medicine Information (CMI)

MS-2 Step is a composite pack product containing Mifepristone Linepharma 200 mg tablet and GyMiso® misoprostol 200 microgram tablets (this medicine in the purple box).

Mifepristone Linepharma = mifepristone

GyMiso® = misoprostol

GyMiso® misoprostol 200 microgram tablets must be taken only after having taken the mifepristone tablet.

This leaflet provides important information about using MS-2 Step GyMiso®. You should also speak to your doctor, nurse or pharmacist if you would like further information or if you have any concerns or questions about using MS-2 Step GyMiso®.

Where to find information in this leaflet:

1. Why am I using MS-2 Step GyMiso®?
2. What should I know before I use MS-2 Step GyMiso®?
3. What if I am taking other medicines?
4. How do I use MS-2 Step GyMiso®?
5. What should I know while using MS-2 Step GyMiso®?
6. Are there any side effects?
7. Product details

1. Why am I using MS-2 Step GyMiso®

MS-2 Step GyMiso® contains the active ingredient misoprostol. MS-2 Step GyMiso® belongs to a group of medicines called prostaglandins. It acts like prostaglandin E1. MS-2 Step GyMiso® induces contractions of the smooth muscle and relaxation of the cervix. These properties help open the cervix and push out the contents of the uterus.

MS-2 Step GyMiso® can therefore be used to terminate a pregnancy. It is given in combination with another medicine called Mifepristone Linepharma (in the green box), which blocks progesterone, a hormone that is needed for pregnancy to continue. Both medicines are contained within the MS-2 Step pack, and they are recommended for termination of pregnancy up to 63 days after the first day of your last menstrual period.

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

2. What should I know before I use MS-2 Step® GyMiso®

Warnings

Do not use MS-2 Step GyMiso® if:

  • you are allergic to misoprostol, mifepristone (or any prostaglandin) or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.
  • 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 an ultrasound scan or biological test such as urine or serum HCG
  • 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 not taken, first, the mifepristone tablet
  • 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

If you are under 18 years of age, you should only take MS-2 Step GyMiso® if advised to do so by your doctor. There is limited information on the use of MS-2 Step GyMiso® in adolescents less than 18 years of age.

Check with your healthcare practitioner if you:

  • have any other medical conditions:
    - heart or cardiovascular disease
    - epilepsy
    - asthma
    - porphyria
    - kidney problems
    - liver problems
    - malnutrition
    - problems with your adrenal glands
    - 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), as this needs to be removed
  • take any medicines for any other condition

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

Your healthcare practitioner 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 hours assistance.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your healthcare practitioner if you are pregnant or intend to become pregnant.

You should not be given MS-2 Step GyMiso® if:

  • your healthcare practitioner suspects an ectopic pregnancy (the egg is implanted outside the womb)
  • your pregnancy has not been confirmed by a pregnancy test or an ultrasound scan
  • you are pregnant and wish to carry your pregnancy to term

Talk to your healthcare practitioner if you are breastfeeding or intend to breastfeed.

MS-2 Step GyMiso® should not be taken if you are breastfeeding.

3. What if I am taking other medicines?

Tell your healthcare practitioner if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with MS-2 Step GyMiso® and affect how it works.

Different medicines may be affected by MS-2 Step GyMiso® 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 healthcare practitioner may have more information on medicines to be careful with or avoid while being treated with MS-2 Step GyMiso®.

Check with your healthcare practitioner if you are not sure about what medicines, vitamins or supplements you are taking and if these affect MS-2 Step GyMiso®.

4. How do I use MS-2 Step GyMiso®?

How much to take

  • Your healthcare practitioner will tell you how many tablets you need to take and when to take them.
    MS-2 Step GyMiso® is usually taken 36 to 48 hours after you have taken the MS-2 Step Mifepristone Linepharma tablet. You will need to take the four MS-2 Step GyMiso® tablets (misoprostol 800 micrograms) which are in the purple box. These are taken as four tablets in one dose.

When to take

  • It is necessary to take the MS-2 Step Mifepristone Linepharma tablet first and then, 36 to 48 hours later, take the MS-2 Step GyMiso® tablets. This must be done in this order for the medicines to work.
  • It is recommended that MS-2 Step GyMiso® should be taken on an empty stomach 2 hours before or after a meal.

How to take

  • MS-2 Step GyMiso® should be taken by holding the tablets in your mouth, between the cheek and gum (buccal method), for 30 minutes before swallowing any fragments with water.

If you forget to use MS-2 Step GyMiso®

Contact your healthcare practitioner immediately if you forget to take MS-2 Step GyMiso® tablets and it has been more than 48 hours after you have taken a MS-2 Step Mifepristone Linepharma tablet.

If you use too much MS-2 Step GyMiso®

MS-2 Step GyMiso® is prescribed for you by your healthcare practitioner. An overdose is not likely to occur. Ask your healthcare practitioner if you have any concerns. If you think that you have used too much MS-2 Step GyMiso®, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using MS-2 Step GyMiso®?

Things you should do

  • After you taken MS-2 Step GyMiso® tablets, you should stay at home and rest for 3 hours. Vaginal bleeding will occur and the pregnancy may be expelled within a few hours of taking MS-2 Step GyMiso® 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 healthcare practitioner 14 to 21 days after you take MS-2 Step Mifepristone Linepharma, to ensure that the termination was complete, because incomplete termination will increase the risk of serious infection or bleeding.
  • In some cases treatment with MS-2 Step may not result in a termination of pregnancy. You must keep all of your doctor's 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, that MS-2 Step GyMiso® 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.
  • Using contraceptives: It is possible for you to become pregnant again immediately after the pregnancy termination is completed. As some effects of misoprostol and mifepristone may still be present after taking MS-2 Step, it is recommended that you avoid getting pregnant again before your next menstrual period.

Call your healthcare practitioner straight away:

  • If bleeding does not occur, it is very important that you contact your doctor immediately. For some patients, the healthcare practitioner may prescribe a repeat dose of MS-2 Step GyMiso®or a termination can be arranged using another method.
  • In case of heavy and prolonged bleeding, you should contact your doctor immediately in order to schedule an appointment.
  • In rare cases, a termination can occur after you take the MS-2 Step Mifepristone Linepharma tablet but before you take MS-2 Step GyMiso®. 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.

Remind any doctor, nurse, dentist or pharmacist you visit that you are using MS–2 Step GyMiso®.

Things you should not do

  • 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

Driving or using machines

Be careful before you drive or use any machines or tools until you know how MS-2 Step GyMiso® affects you.

Drinking alcohol

Tell your healthcare practitioner if you drink alcohol.

Looking after your medicine

  • MS-2 Step GyMiso® should be stored within the MS-2 Step pack
  • Store below 25 degrees C.
  • Store in the original packaging.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your healthcare practitioner if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Gastrointestinal upset
  • Nausea
  • Vomiting
  • Diarrhoea
Tiredness related
  • Fainting
  • Dizziness
  • Fatigue
  • Headache
Vagina related
  • Vaginal bleeding
  • Spotting
Pain related
  • Abdominal discomfort
  • Abdominal pain
  • Cramps
  • Breast tenderness
Skin related
  • Hot flushes
  • Skin rashes or itching
Infection related
  • Chills and /or fever
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Bleeding related
  • 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 related
  • Serious infections are very rare in a medical termination of pregnancy and can be potentially life threatening. If you have symptoms occurring 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.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your healthcare practitioner if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your healthcare practitioner before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a prescription.

What MS-2 Step GyMiso® contains

Active ingredient
(main ingredient)
misoprostol
Other ingredients
(inactive ingredients)
Hydrogenated castor oil
Hypermellose
Microcrystalline cellulose
Sodium starch glycollate type A
Potential allergensNo

Do not take this medicine if you are allergic to any of these ingredients.

What MS-2 Step GyMiso® looks like

MS-2 Step GyMiso® is presented in a box containing a blister pack of 4 white, round, flat tablets with ML on one side and 200 on the other.

Each tablet contains 200 micrograms of misoprostol. There is one GyMiso® pack in each MS-2 Step pack.

Australian registration number: AUST R 210574.

Who distributes MS-2 Step GyMiso®

MS-2 Step is supplied in Australia by:

MS Health Pty Ltd
Suite 60, 278 Church Street,
Richmond, VIC, Australia, 3121.
Ph: 1300 515 883

GyMiso® is licensed from Linepharma International Ltd, UK

MS-2 Step® is a registered trademark of MSI Reproductive Choices (UK). Mifepristone Linepharma and GyMiso® are licensed from Linepharma International Limited (UK).

This leaflet was updated in June 2023.

Published by MIMS September 2023

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 an 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 microgram 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 an 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 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 microgram of misoprostol (4 tablets, each tablet containing 200 microgram) 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 healthcare practitioner 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 healthcare practitioners with the appropriate qualifications and certified training. Ectopic pregnancy should be excluded, an intrauterine device (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.
Asthma uncontrolled by therapy.
Intrauterine device (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.
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.
If applicable, medical practitioner's advice should be sought in the event that further management of patients with medical comorbidities or adverse events is required.
Take special care in case of suspected acute adrenal failure. In case of suspected acute adrenal failure, dexamethasone administration is recommended (please refer to the dexamethasone Product Information).
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.
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.
Cases of skin rash following misoprostol administration were reported by patients in clinical trials. Angioedema of the face, lips, tongue, and/or larynx, including cases of anaphylaxis have been reported in post-market surveillance with the use of mifepristone and misoprostol, including angioedema occurring within an hour of misoprostol intake. Angioedema associated with upper airway swelling may be life threatening. If the tongue, hypopharynx, or larynx has been involved, appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided.
No data is available in patients with inherited porphyria.
In the case of a pregnancy occurring with an intrauterine device in situ, this device must be removed before administration of Mifepristone Linepharma.

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 an intrauterine pregnancy.

Ectopic pregnancy.

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

Rhesus alloimmunisation.

The need for rhesus determination and prevention of rhesus alloimmunisation should be assessed in line with the current clinical guidelines for induced abortions.

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 (including continuing pregnancy and incomplete abortion), 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.
Exposure of the fetus to misoprostol or mifepristone increases the risk of developing Moebius syndrome and/or an amniotic band syndrome and/or central nervous system anomalies (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy). A second termination of pregnancy procedure shall be considered. In case of continuation of the pregnancy close monitoring by ultrasound scan must be performed in specialised centres.
In cases of non-complete expulsion, a surgical intervention may be necessary.

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, November 2011), the following is recommended:
"Following abortion, women should be provided with verbal and written information about:
symptoms they may experience emphasising those which would necessitate an urgent medical consultation.
symptoms suggestive of continuing pregnancy.
Independent providers of abortion services should have arrangements in place for referring women to a public hospital emergency department for assessment and admission."
"On discharge, all women should be given a letter providing sufficient information about the procedure to allow another practitioner elsewhere to manage 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 healthcare practitioners evaluating a patient who is undergoing a medical abortion should be alert to the possibility of this rare event and immediately seek a medical practitioner's (doctors) advice. 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 (phenobarbitone), 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 indometacin, 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.

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.
Fetal 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 fetal 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).

Failure of pregnancy termination (continuing pregnancy).

Use in pregnancy has been associated with an increased risk of birth defects/malformations for ongoing pregnancies exposed to mifepristone and misoprostol or misoprostol alone, compared to control group. In particular, prenatal exposure to misoprostol has been associated with Moebius syndrome (congenital facial paralysis leading to hypomimia, troubles of sucking and deglutition and eye movements, with or without limb defects) and with amniotic band syndrome (limb deformities/ amputations, especially clubfoot, acheiria, oligodactyly, cleft palate inter alia), and central nervous system anomalies (cerebral and cranial anomalies such as anencephaly, hydrocephaly, cerebellar hypoplasia, neural tube defects).
Women considering medical termination of pregnancy should be precisely counselled on the risks to their fetus if an abortion failure occurs and a second termination of pregnancy procedure is not desirable.

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 fetus, 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.
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 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 microgram 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 fetal 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 Poisons 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 microgram 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 microgram 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 microgram 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 microgram 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 microgram 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 microgram/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 microgram 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 microgram 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 microgram 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