Consumer medicine information

Kyleena

Levonorgestrel

BRAND INFORMATION

Brand name

Kyleena

Active ingredient

Levonorgestrel

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Kyleena.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Kyleena. 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 Kyleena 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 and the card describing the date of insertion, batch number, and latest date of removal in a safe place. You may need to read it again.

WHAT KYLEENA IS USED FOR

Kyleena consists of a small T-shaped frame made from a plastic called polyethylene. This carries 19.5 mg levonorgestrel, a hormone used in many contraceptive pills. The hormone is contained within a substance called dimethylsiloxane/methylvinylsil oxane 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 uterus (womb).

There are two fine threads, made of blue pigment 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.

Kyleena is used for the prevention of pregnancy. It is placed inside the womb where it slowly releases the hormone over a period of five years or until it is removed.

The hormone in Kyleena prevents pregnancy by:

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

Kyleena 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 KYLEENA

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

When you must not use it

Do not use Kyleena if you have an allergy to:

  • levonorgestrel, the active ingredient in Kyleena
  • 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.

Do not give it to a child.

Do not use Kyleena and speak to your doctor if you have or have had any of the following medical conditions:

  • 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 an increased risk of developing pelvic infections
  • if you have a lower genital tract infection that has not been successfully treated by your doctor
  • an infection of the womb following childbirth or after an abortion in the last three months
  • infection or cell abnormalities in the cervix
  • tumours in the cervix or womb
  • progestogen dependent tumours
  • undiagnosed vaginal bleeding
  • abnormal cervix or womb, or fibroids which distort the cavity of the womb
  • liver disease or liver tumours

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 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 Kyleena. A physical examination including pelvic examination, examination of the breasts and a Pap smear should be performed.

Your doctor should also rule out pregnancy and sexually transmitted infections (STIs), and any 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. Kyleena 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 of 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, Kyleena 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 Kyleena but this may need to be checked by your doctor

Pelvic infections have been reported with the use of intrauterine delivery systems such as Kyleena. You have an increased risk of pelvic infections if you or your partner 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 Kyleena 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 Kyleena.

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 Kyleena 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, barbiturates, primidone, carbamazepine
  • rifampicin for the treatment of tuberculosis
  • macrolide antibiotics (e.g. clarithromycin, erythromycin)
  • herbal medicines containing St John’s Wort
  • medicines used to treat HIV such as ritonavir 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
  • grapefruit juice

These medicines may be affected by Kyleena 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 KYLEENA

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

Kyleena is inserted by a professional, experienced in the insertion 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.

Kyleena 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 6 weeks after delivery.

WHILE USING KYLEENA

You should be protected from pregnancy as soon as Kyleena is placed. The current recommendation is to wait about 24 hours after having the Kyleena inserted before having sexual intercourse.

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

You should have Kyleena 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. Kyleena 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 Kyleena is removed.

Kyleena 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.

Magnetic resonance imaging (MRI)
The vertical stem of the IUS contains a silver ring. Before you have an MRI, tell any other doctors who treat you that you are using Kyleena, an intrauterine system. Kyleena can be scanned with MRI only under specific conditions.

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 or once a month, 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. Do not pull on the threads because you may accidentally pull it out. If you cannot feel the threads, go to 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.

If Kyleena is expelled, speak to you doctor immediately to receive guidance surrounding ongoing contraception and also what to do with the expelled system.

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 Kyleena 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.

Tell your doctor if bleeding remains heavy or irregular.

Perforation
Kyleena can perforate the wall of the womb (most often during placement). 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. If you experience excessive pain or bleeding during or after insertion, or any time while you are using Kyleena, tell your doctor immediately.

Ectopic pregnancy
It is very rare to become pregnant while using Kyleena. However if you become pregnant while using Kyleena, 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 Kyleena 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 Kyleena, even though removing it may cause a miscarriage. If Kyleena 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 Kyleena can cause long-term effects on the foetus if it stays in place during a pregnancy.

Pelvic infections
The Kyleena system and insertion technique have been designed to minimise the risk of infections. Despite this, there is an increased risk of pelvic infection immediately after and during the first month after insertion. Pelvic infections can occur with contamination of the IUS. You have an increased risk of pelvic infections if you or your partner has 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 infections may impair fertility and increase the risk of ectopic pregnancy.

Kyleena 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 Kyleena 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 Kyleena. 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 Kyleena. Should breast cancer be diagnosed, your doctor may consider removal of Kyleena.

If you are breastfeeding

There is a small amount of the progestogen hormone levonorgestrel, which will be absorbed by babies who are breastfeeding when Kyleena is used. This is an equivalent amount to 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 Kyleena.

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 Kyleena, 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 Kyleena. 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:

  • headache
  • abdominal/pelvic pain
  • acne, oily skin
  • bleeding changes including increased or decreased menstrual bleeding, spotting, infrequent or light periods, absence of bleeding
  • itching, redness and/or swelling of the vagina
  • depressed mood/depression
  • migraine
  • nausea
  • hair loss or excessive hairiness
  • vaginal infections and discharge
  • menstrual pain
  • breast pain or discomfort
  • expulsion of the IUS

This list above includes the more 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 pain or bleeding, which may indicate perforation of the womb
  • fever, chills or generally feeling unwell

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

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

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 Kyleena in a cool dry place where the temperature stays below 30°C. Do not leave it in the car.

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

Do not open the package before giving it to the doctor.

PRODUCT DESCRIPTION

What it looks like

Kyleena is a small, white coloured T-shaped plastic system. Two blue removal threads are attached to the lower end of the vertical arm. The vertical stem contains a silver ring located close to the horizontal arms, which is visible under ultrasound examination.

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

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

Ingredients

Active ingredient:

  • Kyleena – 19.5 mg of levonorgestrel per IUS

Inactive ingredients:

  • dimethylsiloxane/methylviny lsiloxane cross linked elastomer
  • colloidal anhydrous silica
  • polyethylene
  • polypropylene
  • barium sulfate
  • pigment blue 15
  • silver

Supplier

Made in Finland for:

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

Australian Registration Number

Kyleena - AUST R 270517

Date of preparation

March 2021

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

® Registered trademark of the Bayer Group, Germany

© Bayer Australia Ltd
All rights reserved.

Published by MIMS May 2021

BRAND INFORMATION

Brand name

Kyleena

Active ingredient

Levonorgestrel

Schedule

S4

 

1 Name of Medicine

Levonorgestrel.

2 Qualitative and Quantitative Composition

Kyleena is an intrauterine delivery system (IUS) that contains 19.5 mg levonorgestrel as the active ingredient.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Intrauterine drug delivery system.
Kyleena consists of a whitish or pale yellow drug core covered with a semi-opaque membrane, which is mounted on the vertical stem of a T-body. In addition, the vertical stem contains a silver ring located close to the horizontal arms. The white T-body has a loop at one end of the vertical stem and two horizontal arms at the other end. Blue coloured removal threads are attached to the loop. The vertical stem of the IUS is loaded in the insertion tube at the tip of the inserter. The inserter consists of a handle and slider that are integrated with flange, lock, prebent insertion tube and plunger. The removal threads are located within the insertion tube and handle. See Figure 1.

4 Clinical Particulars

4.1 Therapeutic Indications

Contraception for up to 5 years.

4.2 Dose and Method of Administration

Dosage.

Kyleena is inserted into the uterine cavity and is effective for up to five years.
The in vivo release rate is approximately 17.5 microgram/24 hours after 24 days and is reduced to approximately 15.3 microgram/24 hours after 60 days and to 9.8 microgram/24 hours after one year. It then declines progressively to 7.4 microgram/24 hours after five years. The average levonorgestrel in vivo release rate is approximately 12.6 microgram/24 hours over the first year and 9.0 microgram/24 hours over the period of five years.
Care must therefore be given to adequate training in the correct insertion technique and the availability of appropriate instruments for the insertion of Kyleena. For further information regarding training providers, please contact Bayer Australia Ltd.

Method of administration.

Medical examination/ consultation.

Before insertion, the woman must be informed of the efficacy, risks and side effects of Kyleena. A physical examination including pelvic examination and examination of the breasts should be conducted. A cervical smear should be performed as needed, according to the Healthcare Professional's evaluation. Standard testing procedures should be used to exclude pregnancy and sexually transmitted infections. Genital infections must have been successfully treated prior to insertion. The position of the uterus and the size of the uterine cavity should be determined. Fundal positioning of Kyleena 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 including performing a pelvic exam, checking for pelvic tenderness, inserting a speculum and checking the length of the threads. Follow-up should continue once a year thereafter or more frequently if clinically indicated.
Irregular bleeding and spotting are common in the first months of therapy with all LNG-IUSs including Kyleena. If bleeding becomes heavier and/or more irregular over time, appropriate diagnostic measures should be taken as irregular bleeding may be a symptom of endometrial polyps, hyperplasia or cancer.

Insertion and removal/ replacement.

It is recommended that healthcare providers keep a record of the insertion of the device including batch number in the patient's medical records.
Emphasis should be given to training in the correct insertion technique. It is recommended that Kyleena should only be inserted by physicians/healthcare professionals who are experienced in IUS insertions and/or have undergone training on the Kyleena insertion procedure.
Kyleena is to be inserted into the uterine cavity within seven days of the onset of menstruation. Kyleena can be replaced by a new system at any time in the cycle. Kyleena 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 Kyleena, the possibility of perforation should be considered and appropriate steps should be taken, such as physical examination and ultrasound.
Kyleena is not suitable for use as a postcoital contraceptive.
Kyleena can be distinguished from other IUSs by the visibility of the silver ring on ultrasound and the blue colour of the removal threads. The T-frame of Kyleena contains barium sulfate which makes it visible in X-ray examination.
Kyleena is removed by gently pulling on the threads with forceps. If the threads are not visible and the system is found to be in the uterine cavity on ultrasound examination, it may be removed using narrow forceps. This may require dilatation of the cervical canal or surgical intervention.
The system should be removed no later than by the end of the fifth year. If the woman wishes to continue using the same method, a new system can be inserted immediately following removal of the original system.
If pregnancy is not desired, the removal should be carried out within seven days of the onset of menstruation, 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 Kyleena, the system should be examined to ensure that it is intact.

Instructions for use/ handling.

Kyleena is supplied in a sterile package within an integrated inserter that enables single handed loading. The package should not be opened until required for insertion. The exposed product should be handled using aseptic techniques. If the seal of the sterile package is broken, or appears compromised, the product should not be used. Do not re-sterilise. Kyleena is for single use only. Do not insert after the expiry month and year shown on the label.
Special instructions for insertion are in the package.
Kyleena is supplied with a patient reminder card in the outer package. Complete the patient reminder card and give it to the patient after insertion.

4.3 Contraindications

Pregnancy.
Acute or recurrent pelvic inflammatory disease or conditions associated with increased risk for pelvic infections.
Lower genital tract infection.
Postpartum endometritis or infected abortion during the past three months.
Cervicitis.
Cervical intraepithelial neoplasia.
Uterine or cervical malignancy.
Confirmed or suspected hormone dependent tumours including breast cancer.
Abnormal uterine bleeding of unknown etiology.
Congenital or acquired uterine anomaly including fibroids which would interfere with insertion and/or retention of the intrauterine system (i.e. if they distort the uterine cavity).
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

Kyleena should 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.
Data on use with Kyleena in nulliparous women is limited to approximately 37% of the study population.

Pelvic infection.

While Kyleena and the inserter are sterile they may, due to bacterial contamination during insertion, become a vehicle for microbial transport in the upper genital tract. Pelvic infection has been reported during use of any IUS or IUD. In clinical trials, pelvic inflammatory disease was observed more frequently at the beginning of Kyleena use, which is consistent with published data for copper IUDs, where the highest rate of pelvic inflammatory disease occurs during the first 3 weeks after insertion and decreases thereafter.
Patients should be fully evaluated for risk factors associated with pelvic infection (e.g. multiple sexual partners, sexually transmitted infections, prior history of PID). Pelvic infections such as pelvic inflammatory disease 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 a woman experiences recurrent endometritis or pelvic inflammatory disease or if an acute infection is severe or does not respond to treatment, Kyleena must be removed.
Bacteriological examinations are indicated and monitoring is recommended, even with discrete symptoms indicative of infections.

Expulsion.

In clinical trials with Kyleena, the incidence of expulsion was low and in the same range as that reported for other IUDs and IUSs. Symptoms of the partial or complete expulsion of Kyleena may include bleeding or pain. However, partial or complete expulsion can occur without the woman noticing it, leading to decrease or loss of contraceptive protection. As Kyleena typically decreases menstrual bleeding over time, an increase of menstrual bleeding 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 women on possible signs of expulsion and instruct her on how to check the threads of Kyleena. Advise her to contact her healthcare professional if the threads cannot be felt and avoid intercourse of use a barrier contraceptive (such as condoms) until the location of Kyleena has been confirmed.
A partially expelled Kyleena 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 contraceptive may occur, most often during insertion, although it may not be detected until sometime later, and may decrease the effectiveness of Kyleena. Excessive pain or bleeding during insertion or while Kyleena is in situ may be indicative of a perforation. Such occurrences and/or lost threads should be further investigated. Should a perforation occur, the system must be removed as soon as possible, surgery may be required.
In a large, prospective, comparative, noninterventional cohort study in users of other IUDs (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 cohort of another LNG-IUS, 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 another LNG-IUS 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 cohort of another LNG-IUS 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/ consultation" (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 an increased risk of ectopic pregnancy. The possibility of ectopic pregnancy should be considered in the case of lower abdominal pain especially in connection with missed periods or if an amenorrhoeic woman starts bleeding. Women who become pregnant while using Kyleena should be evaluated for ectopic pregnancy. The absolute risk of ectopic pregnancy in Kyleena users is low. However, when a woman becomes pregnant with Kyleena 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)). In the event of an unplanned pregnancy, also see Section 4.6 Fertility, Pregnancy and Lactation, Unplanned pregnancy.
The overall incidence of ectopic pregnancy with Kyleena is approximately 0.20 per 100 women-years. This rate is lower than in women not using any contraception (0.3-0.5 per 100 women years).

Sexually transmitted infections.

Kyleena 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 removal 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 reappear during the next menstrual period. If pregnancy has been excluded, the threads may usually be located by gently probing the cervical canal with a suitable instrument. If they cannot be found, the possibility of expulsion or perforation should be considered. Ultrasound examination may be used to ascertain the position of the system. If ultrasound is not available or is not successful, X-ray may be used to locate Kyleena.

Ovarian cysts/ enlarged ovarian follicles.

Since the contraceptive effect of Kyleena is mainly due to its local effects within the uterus, there is generally no change in ovulatory function, including regular follicular development, oocyte release and follicular atresia 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 (including haemorrhagic and ruptured ovarian cysts) have been reported over the course of the clinical trials as an adverse event at least once in approximately 22.2% of women using Kyleena. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia.
In most cases, the enlarged follicles resolve spontaneously over two to three months' observation. Should an enlarged follicle fail to resolve spontaneously, continued ultrasound monitoring and other diagnostic/therapeutic measures may be appropriate. Rarely, surgical intervention may be required.

Magnetic resonance imaging (MRI).

Nonclinical testing of another LNG-IUS with the same size silver ring and T-body has demonstrated that a patient may be scanned after placement of Kyleena ("MR conditional") under the following conditions:
Static magnetic field of 3-Tesla or less.
Spatial gradient field of 36,000 Gauss/cm (360 T/m) or less.
Maximum whole body averaged specific absorption rate (SAR) of 4 W/kg in the First Level Controlled mode for 15 minutes of continuous scanning.
In nonclinical testing, the aforementioned LNG-IUS produced a temperature rise of equal or less than 1.8°C at a maximum whole body averaged specific absorption rate (SAR) of 2.9 W/kg, for 15 minutes of MR scanning at 3T using a transit/receive body coil. A small amount of imaging artefact may occur if the area of interest is in the same area or relatively close to the position of Kyleena.
No clinical data are currently available in women using Kyleena undergoing MRI.

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. An individual benefit-risk assessment should be made in women in whom breast cancer is diagnosed while using Kyleena. Removal of Kyleena should be considered.
Irregular bleeding may be a symptom of underlying pathologies such as endometrial polyps, hyperplasia or cancer. Endometrial pathology should therefore be excluded before insertion of Kyleena (also see Section 4.2 Dose and Method of Administration, Medical examination/ consultation).

Heart disease.

Kyleena should be used with caution in women who have congenital heart disease or valvular heart disease and who are 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 Kyleena. However, there is generally no need to alter the therapeutic regimen in Type I diabetics using LNG-IUS.

Infrequent bleeding.

Infrequent bleeding and/or amenorrhea develops gradually. By the end of the fifth year, about 26.4% and 22.6% of the users developed infrequent bleeding and/or amenorrhoea respectively. Pregnancy should be considered if menstruation does not occur within six weeks of the onset of previous menstruation. A repeated pregnancy test is not necessary in subjects who remain amenorrhoeic unless indicated by other signs of pregnancy.

Use in hepatic impairment.

Kyleena has not been studied in women with hepatic impairment. Kyleena is contraindicated in women with acute liver disease or liver tumour (see Section 4.3 Contraindications).

Use in renal impairment.

Kyleena has not been studied in women with renal impairment.

Use in the elderly.

There is no indication for the use of Kyleena in postmenopausal women.

Paediatric use.

Safety and efficacy of Kyleena has been studied in women aged 18 and over. Safety and efficacy is expected to be the same for postmenarcheal adolescents under the age of 18 as for users 18 years and older. The safety profile of another lower-dose LNG-IUS observed in a study of 304 adolescents was consistent with that in the adult population (see Section 5.1 Pharmacodynamic Properties). Kyleena is not indicated for use 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 microsomal enzymes, which can result in increased clearance of sex hormones.

Substances increasing the clearance of levonorgestrel, e.g.

Phenytoin, barbiturates, primidone, carbamazepine, rifampicin and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing St John's wort.
The influence of these medicines on the contraceptive efficacy of Kyleena 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, e.g.

When coadministered 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).

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 progestogen.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The use of an LNG-IUS does not alter the course of future fertility. Upon removal of the LNG-IUS, women return to their normal fertility (see Section 5.1 Pharmacodynamic Properties).
The insertion of Kyleena in pregnant women is contraindicated (see Section 4.3 Contraindications).
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 fetal resorption was increased when compared to sham-operated controls. There were no other effects on the fetuses that could be attributed specifically to the device or to levonorgestrel.

Unplanned pregnancy.

Kyleena, when inserted according to the insertion instructions, has a failure rate of approximately 0.2% at 1 year and a cumulative failure rate of approximately 1.4% at 5 years. The failure rate also includes pregnancies due to undetected expulsions and uterine perforations.
If a woman becomes pregnant while using Kyleena, removal of the system is recommended since any intrauterine contraceptive left in situ may increase the risk of abortion and preterm labour. Removal of Kyleena or probing of the uterus may also result in spontaneous abortion. Ectopic pregnancy should be excluded. 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 closely monitored. The woman should be instructed to report all symptoms that suggest complications of the pregnancy, like cramping abdominal pain with fever.
 In general, there appears to be no deleterious effect on infant growth or development when using any progestogen-only method after six weeks postpartum. An LNG-IUS does not affect the quantity or quality of breast milk. Small amounts of progestogen (about 0.1% of the levonorgestrel dose) pass into the breast milk in nursing mothers.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

The majority of women experience changes in menstrual bleeding pattern after insertion of Kyleena. Over time, the frequency of amenorrhoea and infrequent bleeding increases and the frequency of prolonged, irregular and frequent bleeding decreases. The following bleeding patterns were observed in clinical trials with Kyleena. See Table 2.
The frequencies of adverse drug reactions (ADRs) reported with Kyleena are summarised in Table 3. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 3 reports adverse reactions by MedDRA system organ classes (MedDRA SOCs). The frequencies are crude incidences of the events observed in clinical trials for the indication contraception in 1697 women (5225.52 women-years) using Kyleena.
Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000).
With the use of LNG-IUS, cases of hypersensitivity including rash, urticaria and angioedema have been reported.
If a woman becomes pregnant while using Kyleena, the relative risk of ectopic pregnancy is increased.
The removal threads may be felt by the partner during intercourse.
The following ADRs have been reported in connection with the insertion or removal procedure of Kyleena: Procedural pain, procedural bleeding, insertion-related vasovagal reaction with dizziness or syncope. The procedure may precipitate a seizure in an epileptic patient.
Cases of sepsis (including group A Streptococcal sepsis) have been reported following IUD insertion (see Section 4.4 Special Warnings and Precautions for Use).

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 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 Kyleena. This allows a very low daily dosage, as the hormone is released directly into the uterine cavity.
Kyleena has mainly local progestogenic effects in the uterine cavity. The high levonorgestrel concentration in the endometrium down-regulates the endometrial synthesis of estrogen and progesterone receptors. The endometrium becomes relatively insensitive to the circulating oestradiol and a strong antiproliferative effect is seen.
Morphological changes of the endometrium and a weak local foreign body reaction were observed during use. Thickening of the cervical mucus prevents passage of the sperm through the cervical canal. The local milieu of the uterus and of the fallopian tubes inhibits sperm mobility and function, preventing fertilisation.

Clinical trials.

A multicentre, open-label, randomised phase III study (Report No. PH-37274/Protocol No. 310442) was conducted to evaluate the efficacy and safety of Kyleena in women for long-term reversible contraception. The duration of the study was three years with an optional extension up to five years of use. A total of 1452 women aged 18 to 35 years with an insertion attempt were included in the efficacy and safety assessment of Kyleena for three years with 707 women continuing in the extension phase. Of the 1452 women, 39.5% (574) were nulliparous, of whom 84.0% (482) were nulligravid. The study evaluated contraceptive efficacy with the following parameters: the number of unintended pregnancies, Pearl Index (PI) and cumulative failure rates, as well as bleeding pattern, pharmacodynamics, pharmacokinetic and safety parameters. See Table 4.
The one year Pearl Index was 0.16 and the Pearl Index after 5 years was 0.29. The failure rate was approximately 0.2% at 1 year and the cumulative failure rate was approximately 1.4% at 5 years. The failure rate also includes pregnancies due to undetected expulsions and perforations. Because the use of Kyleena does not require daily intake compliance by the users, the pregnancy rates in "typical use" are similar to those observed in controlled clinical trials ("perfect use"). The use of Kyleena does not alter the course of the future fertility.
In the five-year, Phase III study with Kyleena, 116 of 163 women (71.2%) who discontinued because of the wish for pregnancy and for whom follow up was available, had become pregnant during the 12 month follow-up (Report No. PH-38002/Protocol No. 310442).
With Kyleena, the alterations in menstrual patterns are a result of the direct action of levonorgestrel on the endometrium and do not reflect the ovarian cycle. There is no clear difference in follicle development, ovulation or oestradiol and progesterone production in women with different bleeding patterns. In the process of inhibition of the endometrial proliferation, 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 Kyleena. Scanty flow frequently develops into oligomenorrhea or amenorrhea. Ovarian function remains normal and oestradiol levels are maintained, even when women are amenorrhoeic.
In clinical trials with Kyleena, ovulation was observed in the majority of the subset of women studied (Report No. PH-37274/Protocol No. 310442 and Report No. A46796/Protocol No. 308901). Evidence of ovulation was seen in 23 out of 26 women in the first year, in 19 out of 20 women in the second year and in all 16 women in the third year. In the fourth year, evidence of ovulation was observed in the one woman remaining in the subset and in the fifth year, no women remained in this subset.

5.2 Pharmacokinetic Properties

Levonorgestrel is released locally into the uterine cavity. Estimated in vivo release rates for different points in time are provided in Table 5.

Absorption.

Following insertion, levonorgestrel is released from the IUS into the uterine cavity without delay. More than 90% of the released levonorgestrel is systemically available. Maximum serum concentrations of levonorgestrel are reached within the first two weeks after insertion of Kyleena. Seven days after insertion, a mean levonorgestrel concentration of 162 picogram/mL was determined. Thereafter serum concentrations of levonorgestrel decline over time to reach mean concentrations of 91.3 picogram/mL after 3 years and 83.1 picogram/mL after 5 years. With the use of an levonorgestrel intrauterine delivery system (LNG-IUS), the high local drug exposure in the uterine cavity leads to a strong concentration gradient from the endometrium to the myometrium (gradient endometrium to myometrium > 100-fold), and to low concentrations of levonorgestrel in serum (gradient endometrium to serum > 1000-fold).

Distribution.

Levonorgestrel is bound nonspecifically to serum albumin and specifically to SHBG (sex-hormone-binding globulin). 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 together with an opposite change in the proportion of free levonorgestrel. The concentration of SHBG declined on average by about 30% during the first 3 months after insertion of Kyleena and remained relatively stable over the 5 year period of use. The mean apparent volume of distribution of levonorgestrel is about 106 L.
Bodyweight has also been shown to affect systemic levonorgestrel concentration i.e. low bodyweight increases levonorgestrel concentration. However, due to the mainly localised action of Kyleena, no impact on the efficacy is expected.

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. CYP3A4 is the main enzyme involved in the oxidative metabolism of levonorgestrel. The available in vitro data suggest that CYP mediated biotransformation reactions may be of minor relevance for levonorgestrel compared to reduction and conjugation.

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 in faeces and urine at an excretion ratio of about 1. The excretion half-life is about 1 day.

Linearity/ nonlinearity.

The pharmacokinetics of levonorgestrel are 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 nonlinear pharmacokinetics of levonorgestrel with regard to time. Based on the mainly localised action of Kyleena, no impact on the efficacy of Kyleena is expected.

Paediatric patients.

In a one-year Phase III study in postmenarcheal female adolescents (mean age 16.2, range 12 to 18 years) using another lower-dose LNG-IUS, the pharmacokinetic analysis of 283 adolescents showed estimated levonorgestrel serum concentrations slightly higher (approximately 10%) in adolescents compared to adults. This correlates to the generally lower body weight in adolescents. The ranges estimated for adolescents lie, however, completely within the ranges estimated for adults, showing high similarity.
No differences in the pharmacokinetics of adolescents and adults are expected with Kyleena.

Ethnic differences.

A three-year phase III study in the Asian-Pacific region (93% Asian women, 7% other ethnicities) using another lower-dose LNG-IUS has been performed. A comparison of pharmacokinetic characteristics of levonorgestrel of the Asian population in this study with the Caucasian population from another phase III study showed no clinically relevant difference in systemic exposure and other pharmacokinetic parameters. In addition, the daily release rate of the LNG-IUS was the same in both populations.
No pharmacokinetic differences in women of different ethnicities are expected with Kyleena.

5.3 Preclinical Safety Data

Genotoxicity.

The genotoxic potential of levonorgestrel has not been fully investigated, although limited data available to date suggest that it does not appear to be genotoxic. Saline, water, ethanol and/or DMSO extracts of the silver ring, elastomer, polyethylene, polypropylene or drug-elastomer components of Kyleena were without mutagenic activity in bacteria. Further assays for genotoxicity (e.g. mouse lymphoma assay, in vivo micronucleus test) conducted with extracts of the device materials, were also negative.

Carcinogenicity.

No studies on the carcinogenic potential of Kyleena have been performed.
A long-term study with orally administered levonorgestrel in dogs showed an increased incidence of mammary tumours, although a similar effect was not apparent in studies in mice, rats or monkeys. The occurrence of these mammary tumours in dogs may be due in part to a hormonal feedback mechanism. The clinical relevance of these findings is uncertain.
It should be borne in mind that sexual steroids can promote the growth of certain hormone-dependent tissues and tumours.
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). 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 progestogen 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, polypropylene, pigment blue 15 and silver.

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.

6.5 Nature and Contents of Container

Kyleena is packaged in a polyethylene terephthalate glycol (PETG) thermoformed blister package with a peelable polyethylene lid. 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: 312.44582 g/mol.

CAS number.

797-63-7.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicines.

Summary Table of Changes