Registration of medicines for the medical termination of early pregnancy
The Therapeutic Goods Administration (TGA) has included Mifepristone (RU 486) on the Australian Register of Therapeutic Goods (ARTG) as of 29 August 2012. Marie Stopes International Australia applied for its registration to the TGA and is the sponsor of the medicine. The decision to include Mifepristone on the ARTG followed the TGA process with respect to any application for registration for a prescription medicine - assessment for efficacy, safety and quality for its intended indications. Assessment took into account advice received from the TGA's Advisory Committee on Prescription Medicines and the Advisory Committee on the Safety of Medicines.
Although new to the ARTG, mifepristone has been available in Australia since 2006 through the TGA Authorised Prescriber Scheme. With ARTG inclusion, Marie Stopes International Australia is introducing it in a controlled way including a tailored educational package which they have developed and will be made available for medical practitioners who wish to prescribe mifepristone.
Mifepristone (RU 486) is a synthetic steroid with an anti-progestational action. Misoprostol is a synthetic analogue of prostaglandin E1 and induces contractions of the smooth muscle fibres in the myometrium and relaxation of the uterine cervix. The combination of misoprostol, used in a sequential regimen after mifepristone, has been used in a number of countries for medical termination of pregnancy. The TGA has registered these prescription medicines on the ARTG for the following approved indications:
- Mifepristone Linepharma 200 mg tablet is indicated in females of childbearing age for:
- Medical termination of a developing intra-uterine pregnancy in sequential combination with a prostaglandin analogue up to 49 days of gestation
- Preparation for the action of registered prostaglandin analogues that are indicated for the termination of pregnancy for medical reasons beyond the first trimester.
- GyMiso® (misoprostol) is indicated in females of childbearing age for medical termination of a developing intrauterine pregnancy in sequential combination with a mifepristone 200 mg tablet, up to 49 days of gestation.
The registration decision allows these medicines to be prescribed in Australia by registered medical practitioners. As with all market authorisation approvals, availability of the products will be managed by the sponsor/commercial partner, in this case, Marie Stopes International Australia.
What has registration of the medicines involved?
In order to register a medicine in Australia, a sponsor must submit an application, together with supporting data, to the TGA for evaluation. This ensures that the decision is made considering all the benefits and risks, and the medicine is approved with appropriate controls for its safe use. Assessment for efficacy, safety and quality for its intended indications took into account advice received from the TGA's Advisory Committee on Prescription Medicines and the Advisory Committee on the Safety of Medicines.
Marie Stopes International Australia, as part of its Risk Management Plan (RMP), has set out a strategy for the safe use of the medicines for the proposed population. In keeping with all new registrations, an Australian Product Assessment Report (AusPAR) which summarises the issues considered by TGA and the Committees in registering the two medicines will be made available to the public on the TGA website within 30 days.
Isn't misoprostol already on the ARTG?
Prior to this approval, misoprostol was only approved in Australia for the treatment of acute duodenal and gastric ulcers.
Is this the first time these medicines have been available for medical terminations in Australia?
The medicines have been available in Australia for the last 6 years to a number of prescribers under the Authorised Prescriber scheme (under subsection 19(5) of the Therapeutic Goods Act 1989). Under this scheme, particular authorised medical practitioners can prescribe the product/s to specific patients (or classes of recipients) with a particular medical condition. In addition, authorisation to prescribe mifepristone has conditions and must be approved and monitored by relevant human research ethics committees. As of August 2012, 187 medical practitioners have a special authorisation to prescribe mifepristone for the termination of pregnancy under this scheme.
What do the medicines look like?
Mifepristone Linepharma 200 mg tablets are white to off-white, round tablets, with MF embossed on one side of the tablet. Each tablet contains 200 mg of mifepristone. Mifepristone Linepharma 200 mg is in a blister pack of one tablet.
When will the medicines be available?
Market availability and launch of the medicines are decisions of the sponsor. There can be some lag time between registration of new medicines and commercial supply as the sponsor has to organise supply, packaging and labelling of the medicines as approved for marketing in Australia. In the meantime, access to the medicines through the Authorised Prescriber scheme will continue.
What will be different from their earlier availability under the Authorised Prescriber Scheme?
Prior to ARTG registration, mifepristone had not been evaluated by the TGA for quality, safety and efficacy and, as an unapproved medicine it had different controls on its availability under the Authorised Prescriber scheme. This evaluation has now been completed. The sponsor has indicated that the product will only be made available in circumstances set out in their RMP including practitioner education on the appropriate selection of women, the counselling of women, the need for patient consent, information on the risks and adverse events, and the need to follow up women who have been prescribed the medicine.
How will the medicines be available given that Marie Stopes International Australia is not a pharmaceutical company?
The supply chain and distribution arrangements are for the sponsor to organise; however there are a number of well-established distribution mechanisms available that the sponsor is planning to utilise.
How will it be available?
The decision to use a particular medicine should be made in consultation between the prescribing medical practitioner and the patient. The availability will be limited to sponsor recognised prescribers and the sponsor will enter into arrangements with pharmacies prepared to stock mifepristone for the recognised prescribers.
How much will it cost?
This is a commercial decision of the sponsor and is not presently known to the Department of Health and Ageing.
Where are the medicines available now under the current scheme?
As at August 2012 there were 187 authorised prescribers in Sydney, NSW Central Coast, Hunter Valley, Brisbane, Cairns, Melbourne, Adelaide and Perth.
How will be medicines be accessed by medical practitioners and patients?
It is the sponsor's intention that access and distribution will be controlled via successful completion of the training and medical practitioner registration with the sponsor. The sponsor is planning a comprehensive education program. This is a component of the RMP, implementation of which is a condition of registration on the ARTG of the products.
Will the medicines be available in community pharmacies?
Based on the sponsors' proposed distribution plan, where a pharmacy is nominated by a medical practitioner recognised by the sponsor as having completed appropriate training to prescribe the medicines, and the pharmacy agrees to supply the product, it will be available. The availability is therefore dependent on the location of the medical practitioner in the first instance.
Could other companies apply to register these medicines?
As these medicines are no longer patented, any other applications to register these medicines for the same indications will be evaluated as per any other generic medicines. These are still assessed by TGA to the same standards and the conditions of registration in force for these medicines will apply to any subsequent medicine registration.
Do the doctors do a pregnancy test before prescribing the medicines?
As for surgical termination, the pregnancy should be confirmed before considering any termination and the medical practitioner should confirm gestational age and where possible to exclude ectopic pregnancy. Dependent on the gestation, ultrasound may not be useful in excluding an ectopic pregnancy and therefore, as for surgical termination, follow up is essential. The Product Information (PI) includes a section under 'Precaution' that states "Ectopic pregnancy should be excluded and gestation confirmed prior to medical abortion."
What sort of training will be available to doctors who prescribe the medicines?
A tailored educational package, developed by the sponsor as part of the Risk Management Plan, will be made available for medical practitioners who wish to prescribe mifepristone. This package includes information on the appropriate selection of women, the counselling of women, the need for patient consent, information on the risks and adverse events, and the need to follow up women who have been prescribed the medicine.
In addition the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG), who are responsible for the training and accreditation of specialists in these areas, produce a number of clinical guidelines for health professionals, including:
- Termination of Pregnancy (C-Gyn 17)
- The use of Misoprostol in obstetrics and gynaecology (C-Obs 12), and
- The use of mifepristone for medical termination of pregnancy (C-Gyn 21).
These documents can be downloaded from www.ranzcog.edu.au/the-ranzcog/policies-and-guidelines/college-statements.html.
The RANZCOG website also provides access to a number of more detailed publications on the termination of pregnancy including:
- Termination of Pregnancy: A health resource for health professionals, RANZCOG, Nov 2005
- The Care of Women requesting Induced Abortion, Evidence-based Clinical Guideline Number 7, Royal College of Obstetricians and Gynaecologists, Sept 2004.
How will doctors access the training developed by the sponsor?
The sponsor is proposing to provide education online or directly to health care professionals by suitably qualified and experienced users. Practitioners with a Fellowship of the RANZCOG (FRANZCOG) or a Diploma of the RANZCOG (DRANZCOG) will not have to complete the training.
How will Marie Stopes International Australia know who has completed the training?
The sponsor plans to make the training a requirement for prescribing practitioners to have access to the medicines. Except as described above, practitioners will need to complete and pass the course evaluation. Once this has occurred they will be on a register kept by the sponsor. Practitioners who have FRANZCOG or DRANZCOG can be registered by the sponsor without undertaking the training.
What sort of counselling or other advice will be available at GP clinic or on the phone? How does this compare with counselling associated with surgical abortions?
It is anticipated that counselling and advice provided by practitioners who prescribe the medicines will be similar to that provided for women seeking information about surgical termination, as it will be an alternative option. The associated types of risks and complications are similar for both medical and surgical termination of pregnancy.
What sources of information will there be for patients?
Product Information (PI) documents and Consumer Medicines Information (CMI) leaflets ensure that consumers (as well as health care professionals) are informed on the safe and effective use of registered medicines. In the case of mifepristone, the TGA has required that the CMI leaflet is included in the pack with the medicine.
The Product Information for the medicine provides the following advice:
- The need for follow-up within 14 to 21 days after intake of Mifepristone in order to confirm the abortion is complete - this is included as a "black box" warning in both the PI and CMI
- The necessity to combine treatment with a prostaglandin analogue (i.e. Misoprostol)
- The non-negligible risk of failure of the medical method, and the potential requirement for termination by another method, and
- That 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 in person.
What are the adverse events from mifepristone?
Mifepristone is generally well-tolerated. Adverse effects that are commonly reported include nausea, vomiting, diarrhoea, dizziness, gastric discomfort, abdominal pain, headache, vaginal bleeding, uterine spasm, fatigue, chills / fever, effects related to the abortion itself include prolonged post-abortion bleeding, spotting, severe haemorrhage, endometritis, breast tenderness, heavy bleeding and fainting.
Since its approval under the Authorised Provider scheme, 792 reports of adverse events have been provided to the TGA. The most common are retained products of conception (579) followed by ongoing pregnancy (126) requiring D&E (dilation and evacuation) or D&C (dilation and curettage). Other, rare adverse events include significant haemorrhage, cervical tear noted following initial dilatation, uterine perforation or rupture; nausea and vomiting; infection or suspected infection; endometritis; abdominal pain, fainting, dizziness; dehiscence of caesarean section scar. There has been one recorded case of death in Australia due to sepsis.
How do medical and surgical termination compare?
Women may prefer medical termination to surgical termination of their pregnancy as it occurs in the privacy of home and is less invasive. Both methods have risks and adverse effects associated with them. Surgical termination involves the risk of anaesthesia and post-operative infection and complications such as uterine injury and excessive bleeding can occur. On the other hand, bleeding and pain is more significant with a medical termination and there is the risk of failure to achieve complete abortion which occurs at a rate of 2-7 % and which will consequently involve a woman requiring surgical treatment.
How do surgical and medical abortions compare for efficacy and safety?
As mentioned above, the failure rate is slightly higher (2-7 % of cases) with mifepristone and misoprostol in first trimester termination than a surgical termination. Based on South Australian experience, Mulligan and Messenger (Australian Family Physician, 40 (2011) 342-345) stated "The complication rates of early medical abortion with mifepristone compared favourably to early surgical abortion. There are implications in service delivery of early medical abortion compared to early surgical abortion. ... Both surgical and medical abortion are safe and effective, however, retained products of conception treated with [dilatation and curettage] are more likely after early medical abortion." Wider experience has shown that bleeding and pain are more significant with a medical termination, but medical termination does not involve an anaesthetic and its attendant risk.
What are the responsibilities of the sponsor?
All sponsors of registered prescription medicines must notify all serious adverse events associated with the use of the medicine that they become aware of to the TGA. They are required to provide regular safety updates that include international safety data and assessment of that data for three years following registration of the medicine. This report will also include distribution figures. The sponsor's RMP also requires the sponsor to undertake a post-market study that looks specifically at serious adverse events that require patient follow up to detect and minimise such as retained products, infection and bleeding. The study will determine whether there is any difference in adverse events following cessation of the authorised prescriber scheme and a move to wider availability.
What is TGA's role now the medicines have been approved?
The TGA monitors all products on the ARTG. The TGA will monitor adverse event reports related to the use of the medicines it receives from all sources such as consumers and health care professionals, as well as the sponsor. The TGA will monitor the safety updates provided by the sponsor and ensure that the post-market study is completed and provided as agreed at the time of registration. Any new safety issue that emerges will be investigated and action taken.
What actually is the process? How long will patients be off work? What pain relief is offered?
The CMI has information for patients about expected events: "Mifepristone Linepharma 200 mg tablet should be swallowed with water in the presence of your doctor or a member of his or her medical staff. You can then return home. Vaginal bleeding usually starts 1 to 2 days after taking Mifepristone Linepharma 200 mg tablet. 36 to 48 hours after taking Mifepristone Linepharma, 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 12 to 16 days and may be heavy." Provision of pain relief is a clinical decision for the medical practitioner to discuss with the patient during the consultation prior to prescribing the medicines. The patient may develop cramping and this can usually be managed in a similar manner to period pain.
What check up will be required to see that all of the placenta is removed?
All women should be followed up. The PI and CMI documents include a "black box" warning that clearly states the need for follow up to both medical practitioners and consumers. This check up must take place 14 to 21 days after taking the medicines.
Can it be used after 49 days of pregnancy?
The first trimester indication includes that "Mifepristone Linepharma 200 mg tablet is indicated in females of childbearing age for: 1- Medical termination of a developing intra-uterine pregnancy in sequential combination with a prostaglandin analogue up to 49 days of gestation." There is an indication for later pregnancy "2- Preparation for the action of registered prostaglandin analogues that are indicated for the termination of pregnancy for medical reasons beyond the first trimester."
Medical terminations and the MBS
It is not usual practice for a separate Medicare item to be introduced for the prescribing of medication. The prescribing of medications for terminations (including mifepristone) would usually be covered by MBS item 3, 23, 36 or 44 from Group A1, for general practitioner attendances, items 52, 53, 54 or 57 from Group A2, for non-referred specialist attendances or items 104 and 105 from Group A3 for referred specialist consultations. Any surgical procedures required as follow-up treatment to medical terminations (a minority of women will require surgical evacuation of the uterus to complete the termination) would be claimed under the appropriate Medicare item (35643 or 16525).
What will the Risk Management Plan involve?
Registration is conditional upon agreement between TGA and the sponsor about the nature and period of pharmacovigilance and risk minimisation activities as set out in the Risk Management Plan (RMP). The RMP includes a post market study that specifically looks at serious adverse events associated with the use of mifepristone such as retained products, bleeding and infection. The study will be required to focus on follow-up and adverse event rates including any differences seen between data collected in the Authorised Prescriber setting and the general registration setting.
The Risk Management Plan also includes the requirement for the black box warning related to the need for follow up at 14 to 21 days following use of mifepristone in the PI and CMI and the requirement that the CMI to be included in the pack. The sponsor has developed an educational package that includes information on the appropriate selection of women, the counselling of women, the need for patient consent, information on the risks and adverse events, and the need to follow up women who have been prescribed the medicine. The sponsor will also implement a scheme for restricted access to the medicine requiring that medical practitioners complete the education module or have the DRANZCOG or FRANZCOG to become registered.
Is the education package for medical practitioners mandatory?
For the product to be supplied to patients, the sponsor, as part of the RMP, will require prescribers to undertake specific training. Those prescribers who demonstrate appropriate experience in the management of terminations through holding gynaecological specialist qualifications through a DRANZCOG or a FRANZCOG will not be required by the sponsor to undertake further training. The sponsor has indicated that it intends to maintain a list of those practitioners who meet these criteria and would then supply directly to the clinic or to a pharmacy selected by the doctor. The sponsor has indicated that the product can be supplied to any pharmacy in Australia where the doctor has completed the training and the pharmacy has agreed to receive the product.
Any health practitioner wishing to prescribe mifepristone will be able to undergo training as the sponsor intends to provide it on line as well as face to face for larger centres. In some circumstances, other sponsors have also undertaken additional risk minimisation activities associated with their products where follow up and monitoring are required. For example, clozapine requires intensive monitoring of patients as the long term use of the medicine is associated with major potential adverse effects.
Does legislation in some jurisdictions require abortion to be provided in hospitals? Would GPs be prevented from providing early medical abortion using mifepristone in these jurisdictions?
Any practitioner deciding to prescribe mifepristone should ensure they are familiar with the relevant legislation about the termination of pregnancy in the jurisdiction in which they are practising.