Consumer medicine information

Mirena

Levonorgestrel

BRAND INFORMATION

Brand name

Mirena

Active ingredient

Levonorgestrel

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Mirena.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Mirena. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using Mirena against the benefits they expect it will have for you.

If you have any concerns about using this medicine, ask your doctor or pharmacist.

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

WHAT MIRENA IS USED FOR

Mirena consists of a small T-shaped frame made from a plastic called polyethylene. This carries 52 mg levonorgestrel, a hormone used in many contraceptive pills. The hormone is contained within a substance called dimethylsiloxane/methylvinylsiloxane cross linked elastomer and is surrounded by a membrane (skin) also made of the same elastomer.

This structure provides a system for releasing the hormone gradually into the womb (uterus).

There are two fine threads, made of iron oxide and polyethylene, attached to the bottom of the frame. These allow easy removal and allow you or your doctor to check that the system is in place.

Mirena may be used as a long term and reversible method of contraception, for the treatment of excessive menstrual bleeding (menorrhagia) or for protection from endometrial hyperplasia (excessive growth of the lining of the womb) during hormone replacement therapy. It is placed inside the womb where it slowly releases the hormone (at an initial rate of 20 micrograms per 24 hours) over a period of five years or until it is removed.

Mirena works in the treatment of excessive monthly bleeding and as protection in estrogen replacement therapy by slowly releasing the progestogen hormone levonorgestrel, within the womb. Levonorgestrel suppresses the response of the cells in the lining of the womb to estrogen making the lining of the womb insensitive to circulating oestradiol. This stops the growth of the lining of the womb, which results in a reduction in the volume and duration of menstrual bleeding. This is the mechanism of action in the treatment of excessive bleeding (menorrhagia) and for protection against over stimulation of the lining of the womb in estrogen replacement therapy.

The hormone in Mirena prevents pregnancy by:

  • controlling the monthly development of the womb lining so that it is not thick enough for you to become pregnant
  • making the normal mucus in the cervical canal (opening to the womb) thicker, so that the sperm cannot get through to fertilise the egg
  • preventing ovulation (the release of eggs) in some women
  • there are also local effects on the lining of the womb caused by the presence of the T-shaped frame - since Mirena is an intrauterine system (IUS)
  • affecting the movement of sperm inside the womb, preventing fertilisation.

Mirena is not an emergency contraceptive.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

BEFORE YOU USE MIRENA

Not all women can use Mirena. All products have benefits and risks. If you are unsure if Mirena is suitable for you, discuss this with your doctor.

Mirena should not be the first choice of contraception in young women who have not had a baby.

When you must not use it

Do not use Mirena if you have an allergy to:

  • levonorgestrel, the active ingredient in Mirena
  • any of the inactive ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty in breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not use this medicine if you are pregnant or suspect you may be pregnant.

Do not give it to a child.

Do not use Mirena if you have, or have had any of the following medical conditions:

  • undiagnosed vaginal bleeding from the womb
  • abnormal cervix or womb, or fibroids which distort the cavity of the womb
  • progestogen dependent tumours
  • tumours in the cervix or womb
  • liver disease or liver tumour
  • if you have pelvic inflammatory disease or have had recurrent pelvic inflammatory disease in the past (infection of the female reproductive organs)
  • if you have conditions associated with increased risk of developing pelvic infections
  • lower genital tract infections
  • infections of the womb after childbirth or after an abortion in the last three months
  • infection or cell abnormalities in the cervix (opening to the womb)

Do not use this medicine after the expiry date printed on the pack. If it has expired or is damaged, return it to your pharmacist for disposal. The expiry date is printed on the carton and on the sachet after “To be inserted before” (e.g. 11 18 refers to November 2018). The expiry date refers to the last day of that month by which it should be inserted.

Do not use this medicine if the packaging is torn or shows signs of tampering.

If you are not sure whether you should start using this medicine, talk to your doctor.

Before you start to use it

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

Before insertion, your doctor will inform you of the benefits and risks of Mirena. Your doctor will perform physical examination including pelvic examination and examination of the breasts. Your doctor will advise if you also need a Cervical Screening Test.

Your doctor should also rule out pregnancy. Any sexually transmitted infections (STIs) and genital infections should be treated successfully before insertion.

Your doctor will also need to do a gynaecological examination to determine the position and the size of your womb.

Your doctor may consider removal of the system if any of the following conditions exist or arise for the first time. Mirena should be used with caution after specialist consultation.

  • migraine with visual disturbances or other symptoms which may be signs of a temporary blockage of blood supply to the brain
  • severe headaches
  • jaundice (yellowing of the skin and eyes)
  • increase in blood pressure
  • stroke or heart attack
  • blood clots in the legs (deep vein thrombosis), the lungs (pulmonary embolism) or other parts of the body.

Tell your doctor if you have any of the following conditions, Mirena may be used with caution:

  • if you were born with heart disease (congenital) or valvular heart disease
  • diabetes, there is generally no need to alter your diabetic medication while using Mirena but this may need to be checked by your doctor

Pelvic infections have been reported with the use of intrauterine delivery systems such as Mirena. You have an increased risk of pelvic infections if you have multiple sexual partners, STIs or a history of pelvic inflammatory disease. Pelvic infections may impair fertility and increase the risk of ectopic pregnancy.

Pain, bleeding or dizziness may occur when Mirena is placed or removed. If you have epilepsy, tell your doctor because seizures can occur during placement or removal.

If you have not told your doctor about any of the above, tell them before you start using Mirena.

Taking other medicines

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

Some medicines and Mirena may interfere with each other. These include:

  • medicines to treat high blood pressure, chest pain and/or irregular heartbeats such as verapamil, diltiazem
  • medicines used to treat epilepsy such as phenytoin, barbituates, primidone, carbamazepine, felbamate, topiramate, oxcarbazepine
  • rifampicin or rifabutin for the treatment of tuberculosis
  • macrolide antibiotics (e.g. clarithromycin, erythromycin)
  • herbal medicines containing St John’s Wort
  • medicines used to treat HIV/AIDS such as efavirenz or nevirapine
  • some medicines used to treat Hepatitis C Virus (HCV) such as boceprevir, telaprevir
  • medicines used to treat fungal infections such as ketoconazole, itraconazole, voriconazole, fluconazole, griseofulvin
  • grapefruit juice

These medicines may be affected by Mirena or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

HOW TO USE MIRENA

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions given, ask your doctor or pharmacist for help.

How to use it

Mirena is inserted and removed by a professional, experienced in the use of IUSs.

When to use it

The system should be inserted within seven days from the beginning of your period. If you already have the system and it is time to replace it with a new one, you do not need to wait for your period.

Mirena can be inserted immediately after a first trimester abortion. It should not be used until the womb has returned to normal size after giving birth and no earlier than six weeks after delivery.

When Mirena is used to protect the lining of the womb during estrogen replacement therapy, it can be inserted at any time if you do not have monthly bleeding or else during the last days of menstruation or withdrawal bleeding. You may feel faint after the system is inserted. This is normal and your doctor will tell you to rest for a while.

WHILE USING MIRENA

The current recommendation is to wait about 48 hours after having Mirena inserted before having sexual intercourse.

You may feel faint after Mirena is placed. This is normal and your doctor will tell you to rest for a while. Infrequently, part or all of the system could penetrate the wall of the womb. If this happens, Mirena needs to be removed.

You should have Mirena checked usually 4-12 weeks after it is placed and then once a year until it is removed. It can stay in place for five years.

Your doctor can remove the system at any time and removal is usually easy. Mirena should be removed before the seventh day of the menstrual cycle unless another form of contraception is used in the week leading up to the removal. Intercourse during this week could lead to pregnancy after Mirena is removed.

Mirena does not protect against HIV infection (AIDS) and other STIs. Additional methods should be used (i.e. condoms) to prevent transmission of STIs.

The removal threads may be felt by the partner during sexual intercourse.

Expulsion

If the system comes out either partially or completely you may not be protected against pregnancy. It is rare but possible for this to happen without you noticing during your menstrual period. The muscular contractions of the womb during menstruation may sometimes push the IUS out of place or expel it. This is more likely to occur if you are overweight or have heavy periods.

Possible symptoms of an expulsion are pain and increased amount of bleeding. If you have signs indicative of an expulsion or you cannot feel the threads you should either avoid intercourse or use another contraceptive (e.g. condoms) and consult your doctor.

After each menstrual period, you can feel for the two thin threads attached to the lower end of the system. Your doctor will show you how to do this. Do not pull on the threads because you may accidentally pull it out. If you cannot feel the threads, consult your doctor.

You should see your doctor if you can feel the lower end of the system itself or you or your partner feel pain or discomfort during sexual intercourse.

Bleeding patterns

Many women have frequent spotting or light bleeding in addition to their periods for the first 3-6 months after they have had Mirena inserted. Overall, you are likely to have a gradual reduction in the number of bleeding days and in the amount of blood loss. Some women eventually find that their periods stop altogether.

If you are using Mirena with estrogen replacement therapy, a non-bleeding pattern is likely to develop during the first year of use.

Tell your doctor if bleeding remains heavy or irregular.

Perforation

Perforation or penetration of the wall of the womb may occur, most often during placement of Mirena, although it may not be detected until sometime later. The risk of perforation increases in breastfeeding women and in postpartum (after giving birth) insertions. The risk may also be increased in women with a fixed retroverted uterus (tilted womb). If this happens, the IUS must be removed as soon as possible. You may need surgery to have Mirena removed. If you experience excessive pain or bleeding after insertion, tell your doctor immediately.

Ectopic pregnancy

It is very rare to become pregnant while using Mirena. However, if you become pregnant while using Mirena, the risk of an ectopic pregnancy (where the foetus is carried outside of your womb) is increased

The risk of an ectopic pregnancy happening is lower than for women using no contraception.

Although the rate of pregnancy is low, if you suspect you are pregnant, you should see your doctor straight away.

Ectopic pregnancy can cause internal bleeding, infertility, and death. It is a serious condition that requires immediate medical attention.

The following symptoms could mean that you may have an ectopic pregnancy and you should see your doctor immediately:

  • your menstrual periods cease and then you start having persistent bleeding or pain
  • you have vague or very bad pain in your lower abdomen
  • you have normal signs of pregnancy but you also have bleeding and feel dizzy

There are also risks if you get pregnant while using Mirena and the pregnancy is in the womb. Miscarriage and premature delivery can occur with pregnancies that continue with an intrauterine device or system (IUD/IUS). Because of this, your doctor may try to remove Mirena, even though removing it may cause a miscarriage. If Mirena cannot be removed, talk with your healthcare provider about the benefits and risks of continuing the pregnancy, and possible effects of the hormone on the developing baby.

If you continue your pregnancy, see your doctor regularly. Call your doctor right away if you get flu-like symptoms, fever, chills, cramping, pain, bleeding, vaginal discharge, or fluid leaking from your vagina. These may be signs of infection. It is not known if Mirena can cause long-term effects on the foetus if it stays in place during a pregnancy.

Pelvic infections

The Mirena system and insertion technique have been designed to minimise the risk of infections. Despite this, there is an increased risk of pelvic infection immediately and during the first month after insertion. You have an increased risk of pelvic infections if you have multiple sexual partners, STIs or a history of pelvic inflammatory disease. When having sex with anybody who is not a long-term partner, a condom should be used to minimise the risk of infection with HIV, hepatitis B and other STIs.

Pelvic infections must be treated promptly. Pelvic infection may impair fertility and increase the risk of ectopic pregnancy.

Mirena must be removed if there are recurrent pelvic infections or if an infection does not respond to treatment within a few days. Tell your doctor immediately if you have persistent lower abdominal pain, fever, pain during sexual intercourse or abnormal bleeding.

As with other gynaecological or surgical procedures, severe infections or sepsis can occur following IUD insertions.

Ovarian Cysts

Ovarian cysts or enlarged group of cells (follicles) have been reported with the use of Mirena and may cause pelvic pain or pain during intercourse. You may not experience any symptoms with ovarian cysts or follicles. In most cases, the follicles resolved spontaneously. Your doctor will monitor you while you are using Mirena. Keep all of your doctor’s appointments.

Breast cancer

Breast cancer has been detected slightly more often in women who use combined oral contraceptives (the Pill) compared to women of the same age who do not use the Pill. It is not known whether the difference is caused by the Pill or whether cancers were detected earlier in Pill users. The evidence is not conclusive for progestogen-only presentations such as Mirena. Available data is not conclusive for whether Mirena increases your risk for breast cancer when using Mirena during estrogen replacement therapy. The patient information leaflet of the estrogen replacement therapy should also be consulted for additional information. Should breast cancer be diagnosed, your doctor may consider removal of Mirena.

If you are breastfeeding

There is a small amount of the progestogen hormone levonorgestrel, which will be absorbed by babies who are breastfeeding when Mirena is used. This is lower than that received by babies when the mother is using the minipill (a progestogen only contraceptive). There has been extensive experience with the minipill during breastfeeding, indicating no harmful effects to breastfed babies.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using Mirena.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

During placement or removal of Mirena, the following side effects have been reported: pain, bleeding, dizziness and fainting.

Side effects are most common during the first months after the system is placed and decrease as time goes on. It is normal to experience changes in menstrual patterns during the use of Mirena. The changes may include spotting, shorter or longer menstrual periods, irregular bleeding, prolonged periods of no bleeding at all, heavy flow and menstrual pain.

Tell your doctor or pharmacist if you notice any of the following, particularly if they worry you:

  • genital tract infection
  • ovarian cyst
  • nervousness
  • depressed mood, mood swings
  • lower abdominal/pelvic pain or back pain
  • bleeding changes including increased or decreased menstrual bleeding, spotting, infrequent or light periods, absence of bleeding
  • headache, migraine
  • nausea
  • acne
  • excessive hairiness
  • tender or painful breasts
  • period pain
  • itching, redness and/or swelling of the vagina
  • vaginal discharge
  • weight gain
  • decreased libido
  • expulsion of Mirena

The above list includes the common side effects of your medicine.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • signs of allergy such as rash, swelling of the face, lips, mouth, throat or other parts of the body, shortness of breath, wheezing or trouble breathing
  • excessive abdominal pain or vaginal bleeding
  • fever, chills or generally feeling unwell

You may need urgent medical attention or hospitalisation if you experience the above side effects.

Cases of allergic reactions such as rash, hives and swelling have been reported with the use of Mirena.

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

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

STORAGE

Keep it where children cannot reach it. A locked cupboard at least one-and-a half metres above the ground is a good place to store medicines.

Store Mirena in a cool dry place where the temperature stays below 30°C.

Do not store it or any other medicine in the bathroom, near a sink, or on a window-sill.

Do not leave it in the car. Heat and dampness can destroy some medicines.

PRODUCT DESCRIPTION

What it looks like

Mirena is a small, white coloured T-shaped plastic system. Two brown removal threads are attached to the lower end of the vertical arm.

The T-shaped frame also contains barium sulfate so that it can be seen on X-rays.

Mirena is contained within an insertion device and is provided in a sterile pouch for insertion by a doctor experienced in the insertion of IUSs.

Ingredients

Active ingredient:

  • Mirena – 52 mg of levonorgestrel per IUS

Inactive ingredients:

  • dimethylsiloxane/methylvinylsiloxane (cross-linked) elastomer
  • silica - colloidal anhydrous
  • polyethylene
  • barium sulfate
  • iron oxide black CI77499

Supplier

Bayer Australia Ltd
ABN 22 000 138 714
875 Pacific Highway
Pymble NSW 2073

Bayer New Zealand Limited
P O Box 2825
Shortland Street
Auckland 1140
New Zealand
Free phone 0800 229 376

Australian Registration Number

Mirena - AUST R 73027

Date of preparation

September 2021

See TGA website (www.ebs.tga.gov.au) for latest Australian Consumer Medicine Information.

See MEDSAFE website (www.medsafe.govt.nz) for latest New Zealand Consumer Medicine Information.

® Registered trademark of the Bayer Group, Germany

© Bayer Australia Ltd

All rights reserved.

Published by MIMS November 2021

BRAND INFORMATION

Brand name

Mirena

Active ingredient

Levonorgestrel

Schedule

S4

 

1 Name of Medicine

Levonorgestrel.

2 Qualitative and Quantitative Composition

Mirena 20 microgram per 24 hours intrauterine delivery system contains 52 mg levonorgestrel, a progestogen, as the active ingredient.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Intrauterine drug delivery system.

Mirena intrauterine delivery system (IUS) consists of a white or almost white drug core covered with an opaque membrane, which is mounted on the vertical stem of a T-body. The white T-body has a loop at one end of the vertical stem and two horizontal arms at the other end. Brown removal threads are attached to the loop. The T-body of Mirena contains barium sulfate, which makes it visible in X-ray examination. The vertical stem of the IUS is loaded in the insertion tube at the tip of the inserter. The IUS and inserter are essentially free of visible impurities. See Figure 1.

4 Clinical Particulars

4.1 Therapeutic Indications

Mirena is indicated for:
Contraception.
Treatment of idiopathic menorrhagia.
Prevention of endometrial hyperplasia during estrogen replacement therapy.

4.2 Dose and Method of Administration

Dosage.

The in vivo dissolution rate is approximately 20 microgram/24 h and is gradually reduced to approximately 10 microgram/24 h after five years. The mean dissolution rate of levonorgestrel is about 14 microgram/24 h over the time up to five years.
Special instructions for insertion are in the package. The insertion technique differs to that for other intrauterine devices. Care must, therefore, be given to adequate training in the correct insertion technique and the availability of appropriate instruments for the insertion of Mirena.

Method of administration.

Medical examination.

Before insertion, the woman must be informed of the efficacy, risks and side effects of Mirena. A physical examination including pelvic examination and examination of the breasts should be conducted. A cervical smear should be performed as needed, according to healthcare professional's evaluation. Standard testing procedures should be used to exclude pregnancy and sexually transmitted diseases, and genital infections must have been successfully treated. The position of the uterus and the size of the uterine cavity should be determined. Fundal positioning of Mirena is particularly important in order to ensure uniform exposure of the endometrium to the progestogen, prevent expulsion and maximise efficacy. Therefore, the instructions for insertion should be followed carefully. Insertion and removal may be associated with some pain and bleeding. The procedure may precipitate fainting as a vasovagal reaction or a seizure in an epileptic patient. The woman should be re-examined 4 to 12 weeks after insertion and once a year thereafter, or more frequently if clinically indicated.

Insertion and removal of Mirena.

In women of fertile age, Mirena is to be inserted into the uterine cavity within seven days of the onset of menstruation. Mirena can be replaced by a new system at any time in the cycle. The system can also be inserted immediately after first trimester abortion.
Postpartum insertions should be postponed until the uterus is fully involuted, however, not earlier than six weeks after delivery. If involution is substantially delayed, consider waiting until 12 weeks postpartum. In case of a difficult insertion and/or exceptional pain or bleeding during or after insertion, or any time during the use of Mirena, the possibility of perforation should be considered and appropriate steps should be taken, such as physical examination and ultrasound. Mirena is not suitable for use as a post-coital contraceptive.
When used for endometrial protection during estrogen replacement therapy, Mirena can be inserted at any time in an amenorrhoeic woman, or during the last days of menstruation or withdrawal bleeding.
It is recommended that Mirena should only be inserted by physicians/ health care professionals who are experienced in Mirena insertions and/or have undergone sufficient training for Mirena insertion.
Because irregular bleeding/ spotting is common during the first months of therapy, endometrial pathology should be excluded before insertion of Mirena. If the woman continues the use of Mirena inserted earlier for contraception, endometrial pathology has to be excluded in the case of bleeding disturbances that appear after commencing estrogen replacement therapy. If bleeding irregularities develop during prolonged treatment, appropriate diagnostic measures should also be taken.
Mirena is removed by gently pulling on the threads with forceps. If the threads are not visible and the system is in the uterine cavity, it may be removed using either ovum forceps or an IUD hook. This may require dilatation of the cervical canal or other surgical intervention.
The system should be removed after five years. If the user wishes to continue using the same method, a new system can be inserted at the same time.
If pregnancy is not desired, the removal should be carried out within seven days of the onset of menstruation in women of reproductive age, provided the woman is experiencing regular menses. If the system is removed at some other time during the cycle or the woman does not experience regular menses and the woman has had intercourse within a week, she is at risk of pregnancy. To ensure continuous contraception, a new system should be immediately inserted or an alternative contraceptive method should have been initiated.
After removal of Mirena, the system should be checked to see if it is intact. During difficult removals, single cases have been reported of the hormone cylinder sliding over the horizontal arms hiding them inside the cylinder. Further intervention is not required once completeness of the IUS has been ascertained. The knobs of the horizontal arms usually prevent complete detachment of the cylinder from the T-body.

Concomitant dosage instructions for use in HRT.

The concomitant estrogens used in the HRT studies were oral continuous estradiol valerate 2 mg/day, continuous transdermal estradiol 50 microgram/24 h, oral conjugated equine estrogen 0.625, 1.25 mg/day, estradiol implants 36 microgram/24 h and estradiol gel 1.5 mg/day. Mirena was effective in preventing endometrial hyperplasia in association with these regimens.

Instructions for use and handling.

Mirena is supplied in a sterile pack, which should not be opened until required for insertion by a professional experienced in the insertion of intrauterine systems. The exposed product should be handled with aseptic precautions. If the seam of the sterile package is broken, the product should be discarded. A discarded or removed IUS should be treated as medicinal waste, since it may contain hormone remnants. Each pack contains one intrauterine system.
Special instructions for insertion are in the package.

4.3 Contraindications

Known or suspected pregnancy.
Current or recurrent pelvic inflammatory disease.
Lower genital tract infection.
Postpartum endometritis.
Infected abortion during the past three months.
Cervicitis.
Cervical dysplasia.
Uterine or cervical malignancy.
Confirmed or suspected hormone dependent tumours including breast cancer.
Undiagnosed abnormal uterine bleeding.
Congenital or acquired uterine anomaly including fibroids if they distort the uterine cavity.
Conditions associated with increased susceptibility to infections.
Acute liver disease or liver tumour.
Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings and Precautions for Use

General.

Mirena may be used with caution after specialist consultation, or removal of the system should be considered if any of the following conditions exist or arise for the first time:
migraine, focal migraine with asymmetrical visual loss or other symptoms indicating transient cerebral ischaemia;
exceptionally severe headache;
jaundice;
marked increase in blood pressure;
severe arterial disease such as stroke or myocardial infarction;
acute venous thromboembolism.
Mirena is not the method of first choice for young nulligravid women. Previous studies indicate that an increased number of sexual partners may increase susceptibility to sexually transmitted infections (see Section 4.4 Special Warnings and Precautions for Use, Pelvic infection). Mirena is not the first choice for postmenopausal women with advanced uterine atrophy as the cervical canal is likely to be narrow, making the insertion more difficult.

Tumours.

A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using combined oral contraceptives (COCs), mainly using estrogen progestogen preparations. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. The risk of having breast cancer diagnosed in progestogen only pill users is possibly of similar magnitude to that associated with COC. However, for progestogen only preparations, the evidence is based on much smaller populations of users and so is less conclusive than that for COCs.
Due to the limited exposure in Mirena trials in the indication "prevention of endometrial hyperplasia during estrogen replacement therapy", the available data is not sufficient to confirm or refute a risk for breast cancer when Mirena is used in this indication. The product information of the estrogen replacement therapy should also be consulted for additional information.
Since a biological effect cannot be excluded, an individual benefit-risk assessment should be made in women in whom breast cancer is diagnosed while using Mirena. Removal of Mirena should be considered.
Irregular bleedings may mask some symptoms and signs of endometrial polyps or cancer. Endometrial pathology should, therefore, be excluded before using Mirena. Irregular bleeding/ spotting is common during the first few months of treatment, however, if irregular bleeding develops during prolonged treatment, appropriate diagnostic measures should be taken.

Heart disease.

Mirena may be used with caution in women who have congenital heart disease or valvular heart disease, at risk of infective endocarditis. It is recommended that physicians consult local guidelines with regards to antibiotic prophylaxis during insertion and removal.

Diabetes.

Low dose levonorgestrel may affect glucose tolerance, and the blood glucose concentration should be monitored in diabetic users of Mirena. However, there is generally no need to alter the therapeutic regimen in type 1 diabetics using Mirena.

Oligo/amenorrhoea.

In a study with women of fertile age using Mirena, oligomenorrhoea and amenorrhoea developed gradually in about 57% and 16% of women during the first year of use, respectively. The possibility of pregnancy should be considered if menstruation does not occur within six weeks of the onset of the previous menstruation. A repeated pregnancy test is not necessary in amenorrhoeic subjects unless indicated by other signs of pregnancy.
When Mirena is used in combination with continuous estrogen replacement therapy, a non-bleeding pattern gradually develops in most women during the first year. The rate of total amenorrhoea for at least 90 days is about 30% when Mirena is used in perimenopausal women, and 50% in postmenopausal women after 1 year. During prolonged use of Mirena the amount of amenorrhoea increases.

Pelvic infection.

The insertion tube helps to prevent Mirena from contamination with microorganisms during the insertion and the Mirena inserter has been designed to minimise the risk of infections. In users of copper intrauterine devices, the highest rate of pelvic infections occurs during the first month after insertion and decreases later. Some studies suggest that the rate of pelvic infection in users of Mirena is lower than with the copper releasing intrauterine devices. Known risk factors for pelvic inflammatory disease are multiple sexual partners. Pelvic infection may have serious consequences and it may impair fertility and increase the risk of ectopic pregnancy.
As with other gynaecological or surgical procedures, severe infection or sepsis (including group A streptococcal sepsis) can occur following IUD insertion.
If the woman experiences recurrent endometritis or pelvic infections or if an acute infection is severe or does not respond to treatment (antibiotics) within a few days, Mirena must be removed.
Even when clinical symptoms indicate an infection, bacteriological examinations (to test for organisms such as chlamydia) are indicated and further gynaecological monitoring over the subsequent days is recommended in order to ensure proper diagnosis of the underlying infection.

Expulsion.

From the clinical studies with Mirena, the 5 year gross cumulative expulsion rate was 2.2 to 5.8 per 100. Expulsion is reported as "common" or ≥ 1% and < 10% in the table which lists adverse drug reactions. Symptoms of the partial or complete expulsion of any intrauterine device may include bleeding or pain. Other indications of a partial expulsion include an increase in the length of the removal threads or if the stem of the intrauterine system is visible in the cervix. An ultrasonographic examination may be needed to ensure the proper fundal position of Mirena. However, the system can be expelled from the uterine cavity without the woman noticing it, leading to a loss of contraceptive protection. As Mirena decreases menstrual flow, increase of menstrual flow may be indicative of an expulsion.
Risk of expulsion is increase in:
Women with history of heavy menstrual bleeding.
Women with greater than normal BMI at the time of insertion; this risk increases gradually with increasing BMI.
Counsel the woman on possible signs of expulsion and instruct her on how to check the threads of Mirena. Advise her to contact her doctor if the threads cannot be felt and avoid intercourse or use a barrier contraceptive (such as condoms) until the location of Mirena has been confirmed.
Partial expulsion may decrease the effectiveness of Mirena.
A partially expelled Mirena should be removed. A new system can be inserted at the time of removal, provided pregnancy has been excluded.

Perforation.

Perforation or penetration of the uterine corpus or cervix by an intrauterine device may occur, most often during insertion, although it may not be detected until sometime later, and may decrease the effectiveness of Mirena. Excessive pain or bleeding during insertion or while Mirena is in situ may be indicative of a perforation. Such occurrences and/or lost threads should be further investigated. The frequency of perforations is similar to that with a copper intrauterine device (≥ 0.01% to < 0.1%). Should a perforation occur, the system must be removed as soon as possible; surgery may be required.
In a large, prospective, comparative, non-interventional cohort study in IUD users (n = 61,448 women) with a 1-year observational period, the incidence of perforation was 1.3 (95% CI: 1.1-1.6) per 1000 insertions in the entire study cohort; 1.4 (95% CI: 1.1-1.8) per 1000 insertions in the Mirena cohort and 1.1 (95% CI: 0.7-1.6) per 1000 insertions in the copper IUD cohort. Extending the observational period to 5 years in a subgroup of this study (n = 39,009 women using Mirena or copper IUD), the incidence of perforation detected at any time during the entire 5-year period was 2.0 (95% CI: 1.6 - 2.5) per 1000 insertions; 2.1 (95% CI: 1.6 - 2.8) per 1,000 insertions in the Mirena cohort and 1.6 (95% CI: 0.9 - 2.5) per 1,000 insertions in the copper IUD cohort.
The study showed that both breastfeeding at the time of insertion and insertion up to 36 weeks after giving birth were associated with an increased risk of perforation (see Table 1). These risk factors were confirmed in the subgroup followed up for 5 years. Both risk factors were independent of the type of IUD inserted.
The risk of perforations may be increased in women with fixed retroverted uterus.
Re-examination after insertion should follow the guidance given under the heading "Medical examination" (see Section 4.2 Dose and Method of Administration), which may be adapted as clinically indicated in women with risk factors for perforation.

Ectopic pregnancy.

Women with a previous history of ectopic pregnancy, tubal surgery or pelvic infection carry a higher risk of ectopic pregnancy. The possibility of an ectopic pregnancy should be considered in the case of lower abdomen pain, especially in connection with missed periods or if an amenorrhoeic woman starts bleeding. In clinical trials, the ectopic pregnancy rate with Mirena was approximately 0.1% per year. In a large, prospective, comparative, non-interventional cohort study with an observation period of one year, the ectopic pregnancy rate with Mirena was 0.02%. This rate is lower than in women not using any contraception (0.3-0.5% per year). The absolute risk of ectopic pregnancy in Mirena users is low. However, when a woman becomes pregnant with Mirena in situ, the relative likelihood of this pregnancy being ectopic is increased and urgent assessment is required (see Section 4.8 Adverse Effects (Undesirable Effects)).

Sexually transmitted infections.

Mirena does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs). The woman should be advised that additional measures, e.g. condoms, are needed to prevent the transmission of STIs.

Lost threads.

If the retrieval threads are not visible at the cervix on follow-up examinations, pregnancy must be excluded. The threads may have been drawn up into the uterus or cervical canal and may appear during the next menstrual period. If pregnancy has been excluded, the threads may usually be located by gently probing with a suitable instrument. If they cannot be found, the possibility of expulsion or perforation should be considered.
Ultrasound diagnosis may be used to ascertain the correct position of the system. If ultrasound is not available or successful, X-ray may be used to locate Mirena.

Ovarian cysts.

Since the contraceptive effect of Mirena is mainly due to its local effect, ovulatory cycles with follicular rupture occur in women of fertile age. Sometimes atresia of the follicle is delayed and folliculogenesis may continue. These enlarged follicles cannot be distinguished clinically from ovarian cysts. Ovarian cysts have been reported as adverse drug reactions in approximately 7% of women using Mirena. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia. In most cases, the ovarian cysts disappear spontaneously during two to three months observation. Should this not happen, continued ultrasound monitoring and other diagnostic/ therapeutic measures are recommended. Rarely, surgical intervention may be required.

Use in hepatic impairment.

Mirena is contraindicated in women with acute liver disease or liver tumour.

Use in renal impairment.

Mirena has not been studied in women with renal impairment.

Use in the elderly.

Mirena has not been studied in women over the age of 65 years.

Paediatric use.

Safety and efficacy have been established in women of reproductive age. There is no relevant indication for the use of Mirena before menarche.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interactions can occur with drugs that induce or inhibit microsomal enzymes, which can result in increased or decreased clearance of sex hormones.

Substances increasing the clearance of levonorgestrel e.g.

Phenytoin, barbiturates, primidone, carbamazepine, rifampicin, rifabutin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, and products containing St. John's wort.
The influence of these drugs on the contraceptive efficacy of Mirena is not known, but it is not believed to be of major importance due to the local mechanism of action.

Substances with variable effects on the clearance of levonorgestrel.

When co-administered with sex hormones, many HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of the progestogen.

Substances decreasing the clearance of levonorgestrel (enzyme inhibitors) e.g.

Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice can increase plasma concentrations of the progestin.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Studies have suggested that in women who discontinue Mirena for planned pregnancy, the pregnancy rate at one year is similar to those who do not use contraception.
(Category B3)
Mirena is not to be used during an existing or suspected pregnancy. If the woman becomes pregnant when using Mirena, removal of the system is recommended, since any intrauterine contraceptive device left in situ may increase the risk of abortion and preterm labour. Removal of Mirena or probing of the uterus may result in spontaneous abortion. Ectopic pregnancy should be excluded. If the intrauterine contraceptive device cannot be gently removed, termination of the pregnancy may be considered. If the woman wishes to continue the pregnancy and the system cannot be withdrawn, she should be informed about the risks and the possible consequences of premature birth to the infant. The course of such a pregnancy should be monitored closely. The woman should be instructed to report all symptoms that suggest complications of the pregnancy, like cramping abdominal pain with fever.
There have been isolated cases of masculinisation of the external genitalia of the female foetus following the local exposure to levonorgestrel during pregnancy with an LNG-IUS in place.
When levonorgestrel impregnated silastic devices were introduced into the uteri of pregnant rabbits, the incidence of late foetal resorption was increased when compared to sham operated controls. There were no other effects on the foetuses that could be attributed specifically to the device or to levonorgestrel.
 About 0.1% of the levonorgestrel dose is transferred to the infant during breastfeeding. However, it is not likely that there will be a risk for the infant with the dose released from Mirena when it is inserted in the uterine cavity. Uterine bleeding has rarely been reported in women using Mirena during lactation. There appears to be no deleterious effects on infant growth or development when using Mirena after six weeks postpartum. Progestogen only methods do not appear to affect the quantity or quality of breast milk (see Section 4.4 Special Warnings and Precautions for Use, Perforation).

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)

Adverse events are more common during the first months after the insertion, and subside during prolonged use. In addition to the adverse effects listed (see Section 4.4 Special Warnings and Precautions for Use), the following undesirable effects have been reported in users of Mirena.
Menstrual problems are the most often reported adverse events as described below. The most common adverse effect of Mirena is a change in menstrual bleeding patterns. The changes may include spotting, shorter or longer menstrual periods, irregular bleeding, oligomenorrhoea, amenorrhoea, heavy flow, back pain and period pain/ dysmenorrhoea (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The majority of women experience changes in menstrual bleeding pattern after insertion of Mirena. In a study with women of fertile age using Mirena, prolonged bleeding was experienced by 22% and irregular bleeding by 67% of women during the first 90 days after postmenstrual insertion of Mirena, decreasing to 3% and 19% at the end of the first year of use, respectively. Concomitantly, amenorrhoea is experienced by 0% and infrequent bleeding by 11% during the first 90 days, increasing to 16% and 57% at the end of the first year of use, respectively.
When Mirena is used in combination with continuous estrogen replacement therapy, a non-bleeding pattern gradually develops in most women during the first year.
Table 2 reports adverse reactions by MedDRA system organ classes with the frequencies based on clinical trial data. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100) and rare (≥ 1/10,000 to < 1/1000).
The frequencies are crude incidences of the events observed in clinical trials for the indications "contraception" and "idiopathic menorrhagia" (with 5091 women and 12,101 woman years).
Adverse reactions in clinical trials in the indication "prevention of endometrial hyperplasia during estrogen replacement therapy" (with 514 women and 1218.9 woman years) were observed at a similar frequency unless specified by footnotes.

Description of postmarket adverse reactions.

Pregnancy, puerperium and perinatal conditions.

When a woman becomes pregnant with Mirena in situ, the relative risk of ectopic pregnancy is increased. The ectopic pregnancy rate with Mirena is approximately 0.1% per year (see Section 4.4 Special Warnings and Precautions for Use).

Reproductive system and breast disorders.

The system or parts of it may perforate the uterine wall (see Section 4.4 Special Warnings and Precautions for Use).
Functional ovarian cysts may develop, and have been diagnosed in about 7% of women using Mirena. Most of these cysts are asymptomatic (see Section 4.4 Special Warnings and Precautions for Use).

Breast disorders.

Cases of breast cancer have been reported (frequency unknown) (see Section 4.4 Special Warnings and Precautions for Use). The risk of breast cancer is unknown when Mirena is used in the indication "prevention of endometrial hyperplasia during estrogen replacement therapy".

Immune system disorders.

Hypersensitivity including rash, urticaria and angioedema.

Reproductive system disorders.

The removal threads may be felt by the partner during intercourse.

Injury, poisoning and procedural complications.

The following ADRs have been reported in connection with the insertion or removal procedure of Mirena: procedural pain, procedural bleeding, insertion related vasovagal reaction with dizziness or syncope. The procedure may precipitate a seizure in an epileptic patient.

Infections and infestations.

Cases of sepsis (including group A streptococcal sepsis) have been reported following IUD insertion (see Section 4.4 Special Warnings and Precautions for Use).

Investigations.

Blood pressure increased.

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.

4.9 Overdose

Not applicable for this product.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Levonorgestrel is a potent progestin of the 19-nortestosterone class which possesses characteristic gestagenic properties such as endometrial transformation (development of a secretory endometrium), antigonadotropic action and antiestrogenic effects. The antiestrogenic activity of levonorgestrel is not the result of direct estrogen antagonism, since levonorgestrel does not bind to the estrogen receptor in vitro, but the result of modification of peripheral estrogenic effects. Levonorgestrel does not possess antiandrogenic or glucocorticoid properties, but does have marked partial androgenic activity.
Levonorgestrel is used in gynaecology as the progestogenic component in combined oral contraceptives and for contraception in progestogen only pills. Levonorgestrel can also be administered into the uterine cavity with an intrauterine delivery system such as Mirena. This allows a very low daily dosage, as the hormone is released directly into the uterine cavity.
Mirena, when inserted according to the instructions, has a failure rate of approximately 0.2% at 1 year and a cumulative failure rate of approximately 0.7% at 5 years.
Mirena has mainly local progestogenic effects in the uterine cavity. The high levonorgestrel concentrations in the endometrium inhibits the endometrial synthesis of estrogen receptors, making the endometrium insensitive to the circulating estradiol, and a strong antiproliferative effect is seen. Thickening of the cervical mucus prevents passage of sperm through the cervical canal. The local milieu of the uterus and of the ovarian tubes inhibits sperm motility and function, preventing fertilisation. Ovulation is inhibited in some women. Morphological changes of the endometrium and a weak foreign body reaction, due to the presence of an intrauterine contraceptive device, are also observed during use of Mirena.

Clinical trials.

Contraception.

The contraceptive efficacy of Mirena has been studied in 5 major clinical studies with 3330 women using Mirena. Two of the 5 studies were 5 year studies and 3 were 1 year studies. The failure rate (Pearl Index) was 0.21% at 1 year (based on data from 3330 women) and 0.14% at 5 years (based on data from 2245 women). This Pearl Index also includes pregnancies due to undetected expulsions and perforations. The cumulative failure rate was 0.2% at 1 years and 0.71% at 5 years.
In a large, prospective, comparative, non-interventional cohort study with an observation period of one year including more than 43,000 Mirena users, the Pearl Index of Mirena was 0.06 (95% CI: 0.04-0.09).
The use of Mirena does not alter the course of future fertility. About 80% of the women wishing to become pregnant conceived within 12 months following the removal of Mirena.
Menstrual blood loss is generally reduced during use of Mirena. Scanty blood flow frequently develops into oligomenorrhoea or amenorrhoea. Amenorrhoea is due to the local effect of levonorgestrel on the endometrium which, under strong local suppression, does not proliferate in response to estrogen. The menstrual pattern does not reflect the ovarian cycle. In the process of inactivation of the proliferation of the endometrium there can be an initial increase of spotting during the first months of use. Thereafter, the strong suppression of the endometrium results in the reduction of the duration and volume of menstrual bleeding during use of Mirena. The production of the ovarian hormones progesterone and estradiol remain within normal limits, even when the users of Mirena are amenorrhoeic.
In clinical studies during the first year of use, 17% of women experienced amenorrhoea of at least three months' duration, but the cumulative gross discontinuation rate for amenorrhoea was very low. The most common adverse event with the use of Mirena is the change in menstrual bleeding pattern. These changes may include spotting, shorter or longer menstrual periods, or oligo/ amenorrhoea.
However, spotting decreases gradually and the number of days spotting after six months was less than four, which was comparable to the experience with copper IUDs. During the first month of use, 20% of users experienced prolonged bleeding (more than eight days). For many women, periods became shorter and during the third month of use, only 3% of users had prolonged bleeding.
Although bleeding patterns may vary from regular scanty menstruation in some women to oligo/ amenorrhoea in others, there is no clear difference in follicle development, ovulation or estradiol and progesterone production in women with different bleeding patterns.

Menorrhagia.

Mirena can be successfully used in the treatment of idiopathic menorrhagia, where no organic reasons for excessive bleeding can be found (see Section 4.3 Contraindications). Menorrhagia caused by submucosal fibroids may respond less favourably to treatment with Mirena. Results from three comparative studies indicate that in menorrhagic women, menstrual blood loss decreased by 62-94% at the end of three months and by 71-95% at the end of six months of use. Mirena appears to have similar effects to endometrial ablation/ resection in reducing the menstrual blood loss up to two years. Reduced bleeding may increase ferritin and haemoglobin levels. Mirena may also alleviate dysmenorrhoea.
The following table (see Table 3) indicates the effectiveness of Mirena in the treatment of idiopathic menorrhagia from the clinical trials. The results indicate that menstrual blood loss was reduced by approximately 93% in women using Mirena while the reduction in blood loss in the reference treatments was 63-100% depending upon the treatment. Another clinical trial (study no. 102-90528) compared the use of Mirena with various standard oral treatments prior to a planned hysterectomy. More patients in the Mirena group (67% compared with 15% in the reference group) decided to continue with Mirena rather than proceed with the hysterectomy.

Hormone replacement therapy (HRT).

Mirena provides the progestogenic component of continuous HRT. Due to the local administration, the systemic levonorgestrel concentration is very low. The efficacy of Mirena in preventing endometrial hyperplasia during continuous estrogen treatment has been equally efficacious when administering estrogen either orally or transdermally. The observed hyperplasia rate under estrogen therapy alone is as high as 20% after one year of continuous treatment. In clinical studies with a total of 634 perimenopausal and postmenopausal users of Mirena, no endometrial hyperplasias were reported during the observation period varying from one up to five years. To date, clinical data presented on the use of Mirena for the prevention of endometrial hyperplasia has been in study trials of 24 months duration or less. In clinical studies with Mirena and copper IUDs used in contraception, no significant differences were found between the groups in serum levels of triglycerides, HDL cholesterol and total cholesterol after two and five years of treatment. The effect of Mirena on lipid levels has been shown to be neutral.
The concomitant estrogens used in the HRT studies were oral continuous estradiol valerate 2 mg/24 h, continuous transdermal estradiol 50 microgram/24 h, oral conjugated equine estrogen 0.625, 1.25 mg/day, estradiol implants 36 microgram/24 h and estradiol gel 1.5 mg/24 h. Mirena was effective in preventing endometrial hyperplasia in association with these regimens.

5.2 Pharmacokinetic Properties

Absorption.

Following insertion, levonorgestrel is released from the IUS into the uterine cavity without delay based on serum concentration measurements.
After insertion of Mirena, levonorgestrel is detectable in serum after 1 hour. The maximum concentration is reached within 2 weeks after insertion. In correspondence with the declining release rate, the median serum concentration of levonorgestrel declines from 206 picogram/mL (25th to 75th percentiles: 151 picogram/mL to 264 picogram/mL) at 6 months to 194 picogram/mL (146 mg/mL to 266 picogram/mL) at 12 months, and to 131 picogram/mL (113 picogram/mL to 161 picogram/mL) at 60 months in women of reproductive age weighing above 55 kg.
In postmenopausal women using Mirena together with non-oral estrogen treatment, the median serum concentration of levonorgestrel declines from 257 picogram/mL (25th to 75th percentiles: 186 picogram/mL to 326 picogram/mL) at 12 months, to 149 picogram/mL (122 picogram/mL to 180 picogram/mL at 60 months. When Mirena is used together with oral estrogen treatment, the serum levonorgestrel concentration at 12 months is increased to approximately 478 picogram/mL (25th to 75th percentiles: 341 picogram/mL to 655 picogram/mL) due to the induction of SHBG by oral estrogen treatment.

Distribution.

Levonorgestrel is bound non-specifically to serum albumin and specifically to sex hormone-binding globulin (SHBG). About 1-2% of the circulating levonorgestrel is present as free steroid and 42-62% is specifically bound to SHBG. During the use of Mirena, the concentration of SHBG declines. Accordingly, the fraction bound to SHBG decreases during the treatment and the free fraction increases. The mean apparent volume of distribution of levonorgestrel is about 106 L.
Body weight and serum SHBG concentration have been shown to affect systemic levonorgestrel concentration i.e. low body weight and/or a high SHBG level increase levonorgestrel concentration. In women of reproductive age with a low body weight (37 to 55 kg) the median serum concentration of levonorgestrel is about 1.5 fold higher.

Metabolism.

Levonorgestrel is extensively metabolised. The major metabolites in the plasma are the unconjugated and conjugated forms of 3α, 5β-tetrahydrolevonorgestrel. Based on in vitro and in vivo studies, CYP3A4 is the main enzyme involved in the metabolism of levonorgestrel. CYP2E1, CYP2C19 and CYP2C9 may also be involved, but to a smaller extent.

Excretion.

The total clearance of levonorgestrel from plasma is approximately 1.0 mL/min/kg. Only trace amounts of levonorgestrel are excreted in unchanged form. The metabolites are excreted with the faeces and urine at an excretion ratio of about 1. The excretion half-life which is mainly represented by metabolites is about 1 day.

5.3 Preclinical Safety Data

Genotoxicity.

Saline, ethanol and DMSO extracts of Mirena were without mutagenic activity when tested in histidine dependent auxotrophs of Salmonella typhimurium and tryptophan dependent auxotrophs of Escherichia coli. Saline and DMSO extracts of the drug releasing core of Mirena were not mutagenic in mouse lymphoma cells or clastogenic in Chinese hamster ovary cells in vitro and they did not induce bone marrow micronuclei in mice in vivo. Saline and DMSO extracts of the polyethylene T-body of Mirena were not mutagenic in bacteria or mouse lymphoma cells or clastogenic in human lymphocytes in vitro and neither saline or sesame oil extracts induced bone marrow nuclei in mice in vivo.

Carcinogenicity.

No studies of the carcinogenic potential of Mirena have been performed. Some studies suggest that combination oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women but there continues to be controversy about the extent to which this finding is attributable to the confounding effects of sexual behaviour and other factors such as human papilloma virus (HPV). Irregular bleeding patterns associated with the use of Mirena could mask symptoms of cervical or endometrial cancer. Close clinical surveillance is essential in all women using Mirena and in all cases of persistent or recurrent abnormal vaginal bleeding, appropriate diagnostic measures should be taken to eliminate the possibility of malignancy. Benign hepatic adenomas have been found to be associated with the use of oral contraceptives containing levonorgestrel. Although benign, hepatic adenomas may rupture and cause death through intra-abdominal haemorrhage. The contribution of the progestin component of oral contraceptives to the development of hepatic adenomas is not known.

6 Pharmaceutical Particulars

6.1 List of Excipients

Dimethylsiloxane/methylvinylsiloxane cross-linked elastomer, colloidal anhydrous silica, polyethylene, barium sulfate, iron oxide black CI77499.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 30°C.
Protect from direct sunlight and moisture (for product in APET packaging (not marketed) only).

6.5 Nature and Contents of Container

Mirena is packaged in a polyethylene terephthalate glycol (PETG) or APET (not marketed) sachet sealed with a peelable polyethylene film. Each pack contains one intrauterine system.

6.6 Special Precautions for Disposal

A discarded or removed IUS should be treated as medicinal waste, since it may contain hormone remnants.
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Levonorgestrel is a white or almost white, odourless or almost odourless, crystalline powder. It is insoluble in water or hexane, slightly soluble in ethanol or acetone, and sparingly soluble in methylene chloride.
The chemical name for levonorgestrel is 13β-ethyl-17β-hydroxy -18,19-dinor-17α-pregn-4-en-20-yn-3-one.
Chemical Formula: C21H28O2.
Molecular Weight: 312.45.
Melting Point: 232-239°C.

CAS number.

797-63-7.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes