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.

SUMMARY CMI

MIRENA®

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 doctor or pharmacist.

1. Why am I using MIRENA?

MIRENA is an intrauterine device which is inserted into the uterus. It contains the active ingredient levonorgestrel. MIRENA is used as a long term and reversible method of contraception, treatment of excessive menstrual bleeding and excessive growth of the lining of the womb during hormone replacement therapy.

For more information, see Section 1. Why am I using MIRENA? in the full CMI.

2. What should I know before I use MIRENA?

Do not use if you have ever had an allergic reaction to levonorgestrel or any of the ingredients listed at the end of the CMI, if you are pregnant or plan to become pregnant, if you have medical conditions that affect the female reproductive organs in particular the womb or the pelvis or certain tumours.

Talk to your doctor if you have any other medical conditions or take any other medicines.

For more information, see Section 2. What should I know before I use MIRENA? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with MIRENA and affect how it works. The main types of medicines that interfere with how MIRENA works include HIV treatments, Hepatitis C virus treatments, antifungals, certain antibiotics, medicines to treat epilepsy and medicines to treat high blood pressure, chest pain and or irregular heartbeats.

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 MIRENA?

MIRENA is inserted and removed by a professional, experienced in the use of intrauterine devices

More information can be found in Section 4. How do I use MIRENA? in the full CMI.

5. What should I know while using MIRENA?

Things you should do
  • Wait about 48 hours after having MIRENA inserted before having sexual intercourse.
  • Remind any doctor, dentist or pharmacist you visit that you are using MIRENA.
  • Have regular checkups with the doctor to ensure MIRENA is in place
  • After each menstrual period check that the device is in place by feeling for the thin threads attached to the lower end of the system
Things you should not doDo not pull on the removal threads because you may accidentally pull the MIRENA system out
Driving or using machinesBe careful before you drive or use any machines or tools until you know how MIRENA affects you.
Looking after your medicineStore it in a cool dry place away from moisture, heat or sunlight where the temperature stays below 30°C

For more information, see Section 5. What should I know while using MIRENA? in the full CMI.

6. Are there any side effects?

Less serious side effects may include period changes, tender or painful breasts, itching, redness or swelling of the vagina, mood changes, headache, acne.

Serious side effects that require immediate medical attention include: signs of allergy, excessive abdominal pain or vaginal bleeding, fever, chills or generally feeling unwell.

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.



FULL CMI

MIRENA® (Mi·RAY·na)

Active ingredient(s): [levonorgestrel intrauterine delivery system]

Consumer Medicine Information (CMI)

This leaflet provides important information about using MIRENA. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using MIRENA.

Where to find information in this leaflet:

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

1. Why am I using MIRENA?

MIRENA is an intrauterine device (IUD) which contains the active ingredient levonorgestrel a hormone used in many contraceptive pills.

The hormone is carried in a small T-shaped frame made from plastic. There are two fine threads (removal strings) attached to the bottom of the frame.

The purpose of the T-body is to adjust the system to the shape of the womb (uterus). The vertical arm of the white T-body carries a drug reservoir containing levonorgestrel which is gradually released into the womb. MIRENA may be used for

  • long acting reversible contraception
  • treatment of heavy menstrual bleeding (menorrhagia)
  • protection from endometrial hyperplasia (excessive growth of the lining of the womb) during hormone replacement therapy.

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 estradiol. 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.

Levonorgestrel 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

2. What should I know before I use MIRENA?

  • Before you can begin using MIRENA, your doctor will ask you some questions about your personal health history and that of your close relatives.
  • About 2 in a 1000 women correctly using MIRENA become pregnant in the first year.
  • About 7 in a 1000 women correctly using MIRENA become pregnant in five years.
  • About 7 in a 1000 women correctly using MIRENA become pregnant during a 3 year period of use beyond 5 years (Years 6-8)

Warnings

Do not use MIRENA if:

  • you are allergic to levonorgestrel, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.
  • you are pregnant or suspect you may be pregnant
  • you have, or 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 tumours
    - 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)
    - cancer or suspected cancer of the cervix or womb
    - tumours which depend on progestogen hormones to grow
    - unexplained abnormal uterine bleeding
    - increase susceptibility to infections

Check with your doctor if you:

  • were born with heart disease (congenital) or valvular heart disease
  • have diabetes, there is generally no need to alter your diabetic medication while using MIRENA but this may need to be checked by your doctor. In diabetic users of MIRENA, the blood glucose concentration should be monitored
  • have epilepsy, seizures can occur during placement or removal

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:

  • migraines with visual disturbances or other symptoms this might be a sign 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.

MIRENA and physical examinations

  • Before your doctor inserts MIRENA intrauterine system, they may perform physical examinations including cervical smear test (Pap smear), pelvic examination and examination of the breasts.
  • 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.

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

Do not use this product if you intend to get pregnant, think you may be pregnant or are pregnant. If you become pregnant when using MIRENA contact your doctor immediately. It is recommended to remove the MIRENA as it may increase the risk of miscarriage and preterm labor if it is left in. However the removal procedure 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.

It is not known if MIRENA can cause long-term effects on the foetus if it stays in place during a pregnancy.

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.”

Talk to your doctor if you are breastfeeding or intend to breastfeed. There is a small amount of levonorgestrel that will be absorbed by your baby if you breastfeed whilst using MIREANA. This is a smaller amount absorbed by babies in comparison to when the mother is using the minipill. There has been extensive experience with the minipill during breastfeeding, indicating no harmful effects to breastfed babies.

3. What if I am taking other medicines?

Tell your doctor or pharmacist 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 and MIRENA may interfere with each other. These include:

Medicines to treat high blood pressure, chest pain and/or irregular heart beatsVerapamil
Diltiazem
Medicines to treat epilepsyCarbamazepine, topiramate, oxcarbazepine, phenytoin, barbituates, primidone, felbamate
AntibioticsRifampicin, rifabutin Macrolide antibiotics (e.g. clarithromycin, erythromycin)
HIV treatmentsEfavirenz, nevirapine
Hepatitis C Virus treatmentsBoceprevir, telaprevir
AntifungalsKetoconazole, itraconazole, voriconazole, fluconazole, griseofluvin
OtherSt John's Wort
Grapefruit juice

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect MIRENA.

4. How do I use MIRENA?

Mirena is inserted into the uterus and removed by a healthcare professional, experienced in the use of intrauterine devices.

You may feel faint after the system is inserted. This is normal and your doctor will tell you to rest for a while afterwards.

When to insert MIRENA

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 provided that there are no genital infections. 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.

For how long can MIRENA be used?

Mirena is effective for 8 years for prevention of pregnancy (contraception). Are you using Mirena for this reason? If so, your Mirena should be removed or replaced after 8 years at the latest.

Mirena is effective for 5 years for heavy menstrual bleeding (idiopathic menorrhagia). Are you using Mirena for one of these reasons? If so, your Mirena should be removed or replaced when the heavy menstrual bleeding or painful menses return or after 8 years at the latest.

Mirena is effective for protection from excessive growth of the lining of the womb (endometrial hyperplasia) during estrogen replacement therapy for 5 years. Are you using Mirena for this reason? If so, your Mirena should be removed after 5 years.

If you like, you may have a new Mirena inserted at the same appointment when the old one is removed.

5. What should I know while using MIRENA

Things you should do

  • 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 at least once a year until it is removed.
  • If you received a patient reminder card from your doctor, bring this with you to every scheduled appointment.
  • In addition, you should contact your doctor if any of the following occurs
    - You no longer feel the threads in your vagina
    - You can feel the lower end of the system
    - You think you may be pregnant
    - You have persistent abdominal pain, fever or unusual discharge from the vagina
    - You or your partner feel pain or discomfort during sexual intercourse
    - There are sudden changes in your menstrual periods (for example if you have little or no menstrual bleeding and then you start having persistent bleeding or pain, or you start bleeding heavily
    - You have other medical problems such as migraine headaches or intense headaches that recur, sudden problems with vision, jaundice or high blood pressure
    - You experience any of the conditions mentioned in section “before you use MIRENA”
  • 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. MIRENA does not protect against HIV infection (AIDS) and other STIs.
  • After each menstrual period, you should feel for the two thin threads attached to the lower end of the system. Your doctor will show you how to do this. If you cannot feel the threads, consult your doctor.

Things you should not do

  • Do not pull on the removal threads because you may accidentally pull the MIRENA system out. If tampons or menstrual cups are used, you should change them with care so as not to pull the threads of Mirena.

Removal

  • 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.

Expulsion

  • 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.
  • If the IUS is out of place, it may not work as intended.
    If the IUS is expelled you are not protected against pregnancy anymore.
  • Possible symptoms of an expulsion are pain and increased amount of bleeding but MIRENA may also come out without you noticing. As MIRENA decreases menstrual flow, increase of menstrual flow may be indicative of an expulsion. 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.

Bleeding patterns

  • You may have frequent spotting or light bleeding in addition to your periods for the first 3-6 months after you have MIRENA inserted.
  • You will likely 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 do not have your period and have other symptoms of pregnancy (for example nausea, tiredness, breast tenderness) you should see your doctor for an examination and have a pregnancy test.
  • 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 if MIRENA is inserted while you are breastfeeding and up to 36 weeks after giving birth). The risk may also be increased if you have a fixed retroverted uterus (tilted womb).
  • If you experience excessive pain or bleeding after insertion, tell your doctor immediately.
  • If this perforation occurs MIRENA must be removed as soon as possible. You may need surgery to have MIRENA removed.

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.
  • About 1 in a 1000 women correctly using MIRENA have an ectopic pregnancy per year.
  • Woman who already had an extrauterine pregnancy, surgery of the tubes from the ovaries to the womb or a pelvic infection carry a higher risk.
  • 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

Pelvic infections

  • As with other gynaecological or surgical procedures, severe infections or sepsis can occur following MIRENA insertion.
  • 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.
  • 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.

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.
  • Available data is not conclusive for whether MIRENA increases your risk for breast cancer when it is being used for 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

Driving or using machines

Be careful before you drive or use any machines or tools until you know how MIRENA affects you.

MIRENA may cause dizziness in some people especially immediately after insertion.

Looking after your medicine

Follow the instructions in the carton on how to take care of your medicine properly before it is inserted by your healthcare professional.

Store it in a cool dry place away from moisture, heat or sunlight where the temperature stays below 30°C

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 doctor or pharmacist if you have any further questions about side effects.

Side effects are most common during the first months after the system is placed and decrease as time goes on.

Less serious side effects

Less serious side effectsWhat to do
Reproductive System related
  • decreased libido
  • bleeding changes including increased or decreased menstrual bleeding, spotting, infrequent or light periods, absence of bleeding
  • genital tract infection
  • ovarian cyst
  • tender or painful breasts
  • period pain
  • itching, redness and/or swelling of the vagina
  • vaginal discharge
  • lower abdominal/pelvic pain or back pain
Mood related
  • nervousness
  • depressed mood, mood swings
Other
  • headache, migraine
  • nausea
  • acne
  • excessive hairiness
  • hair loss
  • expulsion of MIRENA
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
  • 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
  • seizure in an epileptic patient
  • excessive abdominal pain or vaginal bleeding
  • fever, chills or generally feeling unwell
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 doctor or pharmacist 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 doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What MIRENA contains

Active ingredient
(main ingredient)		52 mg of levonorgestrel
Other ingredients
(inactive ingredients)
  • dimethylsiloxane/methylvinylsiloxane (cross-linked) elastomer
  • silica - colloidal anhydrous
  • polyethylene
  • barium sulfate
  • iron oxide black CI77499

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.

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

What MIRENA 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.

(AUST R 73027)

Who distributes MIRENA

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

® Registered trademark of the Bayer Group, Germany

© Bayer Australia Ltd

All rights reserved.

This leaflet was prepared in June 2024.

Published by MIMS August 2024

BRAND INFORMATION

Brand name

Mirena

Active ingredient

Levonorgestrel

Schedule

S4

 

1 Name of Medicine

Levonorgestrel.

2 Qualitative and Quantitative Composition

Levonorgestrel 52 mg.
The average in vivo release rate is 20 microgram/day during the first year.
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.

Mirena is inserted into the uterine cavity. It has been shown to be effective for up to 8 years for contraception, and up to 5 years for the indications of idiopathic menorrhagia, and protection from endometrial hyperplasia during estrogen replacement therapy. (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
For timing regarding removal/ replacement, see Removal/ replacement.
The in vivo levonorgestrel release rate 24 days after insertion is approximately 21 microgram/day, decreasing continuously to approximately 19 microgram/day after 1 year, to 11 microgram/day after 5 years and to 7 microgram/day after 8 years of use.
The average daily levonorgestrel release rates are approximately 20 microgram/day during the first year, 15 microgram/day during the first 5 years and 13 microgram/day over the complete 8 year period of use.

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.

Insertion.

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.

Removal/ replaccement.

Mirena is removed by gently pulling on the threads with forceps. The use of excessive force during removal may cause damage to the device. After removal of Mirena, the system should be examined to ensure that it is intact and that it has been removed in its entirety.
During difficult removals, there have been reported cases of the hormone cylinder sliding over the horizontal arms and hiding them together inside the cylinder. This situation does not require further intervention 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.
If the threads are not visible, determine the location of the system via ultrasound or another method. If the system is in the uterine cavity, it may be removed using narrow forceps or an IUD hook. This may require dilatation of the cervical canal or other surgical procedures.
Contraception. The system should be removed or replaced after 8 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.
Idiopathic menorrhagia. The system should be removed or replaced in case symptoms of idiopathic menorrhagia or dysmenorrhea return. If symptoms have not returned after 5 years of use, continued use of the system may be considered. Remove or replace after 8 years at the latest.
Protection from endometrial hyperplasia during estrogen replacement therapy. The system should be removed or replaced after 5 years.
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.
Mirena is supplied with a patient reminder card in the outer package. Complete the patient reminder card and give it to the patient, after insertion.
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.

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.
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.

Effects on the menstrual pattern.

In a study with women of fertile age using Mirena, oligomenorrhoea (infrequent menstrual periods) and amenorrhoea developed gradually in about 57% and 16% of women during the first year of use, respectively. By the end of year 8 of Mirena use, oligomenorrhoea and amenorrhoea were experienced by 26% and 34% of Mirena users, 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.
As irregular bleeding/spotting often occurs during the first few months of use, pathological endometrial changes must be excluded prior to insertion of Mirena. If bleeding irregularities occur after a prolonged period of use, appropriate diagnostic procedures should be undertaken.

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. 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 ultrasound 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 increased 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. These risk factors were confirmed in the subgroup followed up for 5 years. Both risk factors were independent of the type of IUD inserted. See Table 1.
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 progestin.

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 was 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. By the end of year 8 of Mirena use, prolonged bleeding and irregular bleeding were experienced by 3% and 10% of Mirena users, respectively; amenorrhoea occurred in 34%, and infrequent bleeding in 26% of Mirena users.
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 (synthetic progestogen) 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 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 contraceptive efficacy during extended use beyond 5 years has been studied in the Mirena extension trial with 362 women using Mirena, with 221 women completing year 8 of the study. During years 6 to 8 of Mirena use, the Pearl Index was 0.28 [95% CI (0.03, 1.00)].
The contraceptive efficacy of Mirena up to 8 years, when inserted according to the insertion instructions, is presented in Table 3 below.
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 4) 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. More than 90% of the released levonorgestrel is systemically available.
After insertion of Mirena, levonorgestrel is detectable in serum/ plasma after 1 hour. The maximum concentration is reached within 2 weeks after insertion and amounts to about 180 nanogram/L (CV 38.3%).
In correspondence with the declining release rate, the geometric mean serum/ plasma concentration of levonorgestrel declines continuously as shown in Table 5.
The high local drug exposure in the uterine cavity leads to a strong concentration gradient via the endometrium to the myometrium (gradient endometrium to myometrium > 100fold), and to low concentrations of levonorgestrel in serum (gradient endometrium to serum > 1000-fold).
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).
Less than 2% of the circulating levonorgestrel is present as free steroid. Levonorgestrel binds with high affinity to SHBG. Accordingly, changes in the concentration of SHBG in serum result in an increase (at higher SHBG concentrations) or in a decrease (at lower SHBG concentrations) of the total levonorgestrel concentration in serum. The concentration of SHBG declined on average by about 20% during the first two months after insertion of Mirena and remained stable thereafter increasing only slightly until the end of the 8 years of use.
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 most important metabolic pathways are the reduction of the Δ4-3-oxo group and hydroxylations at positions 2α, 1β and 16β, followed by conjugation. The major metabolites in plasma are the unconjugated and conjugated forms of 3α, 5β-tetrahydrolevonorgestrel. The available in vitro data suggest that CYP mediated biotransformation reactions may be of minor relevance for levonorgestrel compared to reduction and conjugation. CYP3A4 is the main enzyme involved in the oxidative metabolism of levonorgestrel.

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.

Linearity/ non-linearity.

The pharmacokinetics of levonorgestrel is dependent on the concentration of SHBG, which itself is influenced by estrogens and androgens. A decrease of SHBG concentration leads to a decrease of total levonorgestrel concentration in serum indicating non-linear pharmacokinetics of levonorgestrel with regard to time. Based on the mainly local action of Mirena, no impact on the efficacy of Mirena is expected.

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