REC32796_BP24009

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4.2 Posology and method of administration

[...]

Important information to consider during or after insertion

In case of a difficult insertion and/or exceptional pain or bleeding during or after insertion, the possibility of perforation should be considered and appropriate steps should be immediately taken, such as physical examination and ultrasound.

After insertion, women should be re-examined after 4 to 12 weeks to check the threads and ensure that the device is in the correct position. Physical examination alone (including checking of threads) may not be sufficient to exclude partial perforation and ultrasound may be considered (see section 4.4).

4.4 Special warnings and precautions for use

[...]

Medical examination/consultation

[...]

The woman should be re‑examined 4 to 12 weeks after insertion and once a year thereafter or more frequently if clinically indicated. Vaginal ultrasound examination may be considered to ascertain the correct position of the system. In case Mirena cannot be located in the uterine cavity, expulsion or complete perforation should be considered (see paragraph “perforation” below) and X-ray may be used. Thereafter, re-examination should be performed once a year or more frequently if clinically indicated.

Mirena is not suitable for use as a post-coital contraceptive.

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 Mirena. In some of these cases, the device may be located outside of the uterine cavity. Such a system must be removed; 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.

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 2). Both risk factors were independent of the type of IUD inserted.

Table 2: Incidence of perforation per 1000 insertions for the entire study cohort observed over 1 year, stratified by breastfeeding and time since delivery at insertion (parous women)

*Table 2*

Extending the observational period to 5 years in a subgroup of this study (N = 39,009 women inserted with Mirena or copper IUD, 73% of these women had information available over the complete 5 years of follow-up), 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. Breastfeeding at the time of insertion and insertion up to 36 weeks after giving birth were confirmed as risk factors also in the subgroup that were followed up for 5 years.

The risk of perforation may be increased in women with fixed retroverted uterus.

Re-examination after insertion should follow the guidance given above under the heading "Medical examination/consultation" including the consideration to use vaginal ultrasound examination to ascertain the correct position of the system 4 to 12 weeks thereafter which may be adapted as clinically indicated in women with risk factors for perforation.

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 reappear 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. Vaginal ultrasound examination 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.

[...]

Expulsion

[...]

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 Mirena. In some of these cases, the device may be located outside of the uterine cavity. Such a system must be removed; 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.

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 2). Both risk factors were independent of the type of IUD inserted.

Table 2: Incidence of perforation per 1000 insertions for the entire study cohort observed over 1 year, stratified by breastfeeding and time since delivery at insertion (parous women)

*Table 2*

Extending the observational period to 5 years in a subgroup of this study (N = 39,009 women inserted with Mirena or copper IUD, 73% of these women had information available over the complete 5 years of follow-up), 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. Breastfeeding at the time of insertion and insertion up to 36 weeks after giving birth were confirmed as risk factors also in the subgroup that were followed up for 5 years.

The risk of perforation may be increased in women with fixed retroverted uterus.

Re-examination after insertion should follow the guidance given above under the heading "Medical examination/consultation" including the consideration to use vaginal ultrasound examination to ascertain the correct position of the system 4 to 12 weeks thereafter which may be adapted as clinically indicated in women with risk factors for perforation.

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 reappear 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. Vaginal ultrasound examination 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.

10. DATE OF REVISION OF THE TEXT

July 2024 March 2025

REC30572+REC31963_BP23039

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3 Pharmaceutical form

The product levonorgestrel intrauterine delivery system consists of a white or almost white drug core covered with an semi-opaque membrane, which is mounted on the vertical stem of a T-body.

[….]

4.2 Posology and method of administration

Removal/Replacement

[….]

Mirena is removed by gently pulling on the threads with forceps. The use of excessive force/sharp instruments during removal may cause breakage of the system device. After removal of Mirena, the system device should therefore be examined to ensure that it is intact and has been completely removed entirely. […..]

If the threads are not visible, determine the location of the system via ultrasound or other method. and If the system is in the uterine cavity, it may be removed using a narrow forceps tenaculum. […..]

4.4 Special warnings and precautions for use

Precautions at time of removal

The use of excessive force/sharp instruments during removal may cause breakage of the system device (see section 4.2). After removal of Mirena, the system device should therefore be examined to ensure that it is intact and has been completely removed entirely.

10 Date of revision of the text

April 2023July 2024

REC30572+REC31963_BP23039

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4 Possible side effects

Very common side effects: may affect more than 1 in 10 people

[….]

Common side effects: may affect up to 1 in 10 people

[….]

Uncommon side effects: may affect up to 1 in 100 people

[….]

6 Contents of the pack and other information

This leaflet was last revised in June 2023July 2024.

The following information is intended for healthcare professionals only:

Removal/ replacement

For removal/replacement, please consult the Summary of Product Characteristics for Mirena prescribing information.

[….]

After removal of Mirena, the system device should be examined to ensure that it is intact and has been completely removed entirely. See Summary of Product Characteristics for further information.

[….]

DATE OF REVISION OF THE TEXT: March 2023July 2024

BP23021, REC31616

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3. How to use Mirena

How quickly does Mirena work?

Contraception:

You are protected from pregnancy as soon as Mirena is fitted. Mirena will work right away and will prevent you from getting pregnant when:

-         it is inserted within 7 days from the start of your menstrual period. If this is not possible, or if your menstrual period comes at unpredictable times, see section 3 “Starting to use Mirena”.

-         it is inserted immediately after an abortion or miscarriage if the pregnancy was less than 3 months along, provided that there are no genital infections.

-         it is replacing a previously fitted Mirena at any time in your menstrual cycle.

For more information see section 3 “When should Mirena be inserted?”.

6. Contents of the pack and other information

This leaflet was last revised in March June 2023.

Updated document "Name field" on medicines.ie to be more descriptive.

Re-added document

BP22001, REC20852+REC30572+REC30681

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4.2 Posology and method of administration

Method of administration

Mirena is inserted into the uterine cavity. It and is effective for 86 years in the indication contraception and 5 years in the indications idiopathic menorrhagia and protection from endometrial hyperplasia during oestrogen replacement therapy. For timing regarding removal/replacement see section “Removal/Replacement”.

Insertion

[….]

Insertion and removal/replacement

It is strongly 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. Mirena must be inserted using aseptic technique.

Removal/Replacement

Mirena is removed by gently pulling on the threads with a forceps. If the threads are not visible and the system is in the uterine cavity, it may be removed using a narrow tenaculum. This may require dilatation of the cervical canal or other surgical intervention.

Contraception: The system should be removed or replaced after 86 years in the indication contraception and after 5 years in the indication idiopathic menorrhagia and protection from endometrial hyperplasia during oestrogen replacement therapy. If the user wishes to continue using the same method, a new system can be inserted at the same time.

[….]

Idiopathic menorrhagia: The system should be removed or replaced in case symptoms of idiopathic menorrhagia 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 oestrogen replacement therapy: The system should be removed or replaced after 5 years.

Mirena is removed by gently pulling on the threads with forceps. The use of excessive force/sharp instruments during removal may cause breakage of the device. After removal of Mirena, the device should therefore be examined to ensure that it is removed entirely. During difficult removals, single cases have been reported 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 and the system is in the uterine cavity, it may be removed using a narrow tenaculum. This may require dilatation of the cervical canal or other surgical intervention.

If the user wishes to continue using the same method, a new system can be inserted at the time of removal.

After removal of Mirena, the system should be checked to be intact. During difficult removals, single cases have been reported 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 intrauterine system (IUS) has been ascertained. The knobs of the horizontal arms usually prevent complete detachment of the cylinder from the T-body.

[….]

4.4 Special warnings and precautions for use

[….]

Infrequent bleedingOligo/amenorrhoea

Women of fertile age

Infrequent bleeding Oligomenorrhoea and/or amenorrhoea develops gradually in 57 % and 16 % of women during the first year of use respectively. By the end of Year 86 of Mirena use, infrequent bleeding oligomenorrhoea and amenorrhea are experienced by 2631 % and 3424 % of Mirena users, respectively.

[….]

Precautions at time of removal

The use of excessive force/sharp instruments during removal may cause breakage of the device (see section 4.2). After removal of Mirena, the device should therefore be examined to ensure that it is removed entirely.

4.8 Undesirable Effects

Summary of the safety profile

[….]

By the end of Year 86 of Mirena use, prolonged bleeding and irregular bleeding are experienced by 32 % and 1015 % of Mirena users, respectively; amenorrhea occurs in 3424 %, and infrequent bleeding in 2631 % of Mirena users.

[….]

Table 2: adverse drug reactions

[….]

A separate study with 362 women who have used Mirena for more than 5 years showed a consistent adverse reaction profile in Years 6 through 8.

[….]

5.1 Pharmacodynamic Properties

[….]

The contraceptive efficacy of Mirena has been studied in 5 major clinical studies with 3330 women using Mirena. The Pearl Index was approximately 0.2 at 1 year and the cumulative failure rate was approximately 0.7 % at 5 years. The contraceptive efficacy of Mirena beyond 5 years has been studied in a clinical study with 362 women in a clinical trial 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 is summarised in table 3. During year 6 of Mirena use, the Pearl Index was 0.35 [95 % CI (0.01; 1.95)].

[….]

*Kaplan Meier method

[….]

5.2 Pharmacokinetic Properties

[….]

Table 4: Estimated in vivo release rates for Mirena:

Absorption

[….]

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 ng/L (CV 38.3%). In correspondence with the declining release rate, the geometric mean median serum/plasma concentration of levonorgestrel declines continuously, as shown in table 5. from 206 pg/ml (25^th to 75^th percentiles: 151 pg/ml to 264 pg/ml) at 6 months to 194 pg/ml (146 pg/ml to 266 pg/ml) at 12 months, and to 131 pg/ml (113 pg/ml to 161 pg/ml) at 60 months in women of reproductive age weighing above 55 kg. After 72 months (6 years) median levonorgestrel concentration amounted to 113 pg/ml (87.3 pg/ml to 155 pg/ml).

[….]

Distribution

[….]

The concentration of SHBG declined on average by about 20 30% during the first two months after insertion of Mirena and remained stable thereafter during the first year and increased increasing only slightly until the end of the 8 years of use thereafter. During Year 6 of use SHBG concentration remained stable.

[….]

10 Date of revision of the text

September November 2022

BP22001, REC20852+REC30572+REC30681

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1. What Mirena is and what it is used for

Mirena is an intrauterine delivery system (IUS) placed inside the womb (uterus) where it slowly releases the hormone levonorgestrel. It can be used in the following three ways:

1. As an effective long-term and reversible method of contraception.

It is can be used for contraception (prevention of pregnancy) (contraception) for a maximum of  6 8 years, unless it is removed earlier.

2. For reducing menstrual blood flow, so it can be used if you suffer from heavy periods (heavy menstrual bleeding). This is called menorrhagia.

It is can be used for heavy menstrual bleeding (idiopathic menorrhagia) (excessive menstrual bleeding) for up to a maximum of 5 years,unless it is removed earlier.

3. If you are going through the menopause, a gradual process which usually takes place between the ages of about 45 and 55.

It is can be used for protection from endometrial hyperplasia ( excessive growth of the lining of the womb (endometrial hyperplasia)) during oestrogen replacement therapy for a maximum of 5 years, unless it is removed earlier.

[….]

3. How to use Mirena

[….]

The initial release of levonorgestrel is about 2019 micrograms per day 1 year after insertion, reducing to about 1110 micrograms per day after 5 years and 79 micrograms per day after 86 years. Therefore you receive an average of 15 micrograms per day levonorgestrel for 5  years and an average of 135 micrograms per day levonorgestrel for 86 years.

[….]

6. Contents of the pack and other information

[….]

This leaflet was last revised in September October 2022.

[….]

The following information is intended for healthcare professionals only:

[….]

Removal/ replacement

For removal/replacement, please consult the Mirena prescribing information.

Mirena is removed by gently pulling on the threads with a forceps (Figure 8).

You may insert a new Mirena immediately following removal.

After removal of Mirena, the device should be examined to ensure that it is removed entirely. See Summary of Product Characteristics for further information.

[….]

DATE OF REVISION OF THE TEXT: December 2021 October 2022

BP22036, REC30610

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7. Marketing Authorisation holder

Bayer Limited

1st Floor

The Grange Offices

The Grange

Brewery Road

Stillorgan

Co. Dublin

A94 H2K7

The Atrium

Blackthorn road

Dublin 18

Ireland

10. Date of revision of text

December 2021 September 2022

BP22036, REC30610

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6. Contents of the pack and other information

[….] 

Marketing Authorisation Holder

Bayer Limited

1st Floor

The Grange Offices

The Grange

Brewery Road

Stillorgan

Co. Dublin

A94 H2K7

The Atrium

Blackthorn road

Dublin 18

Ireland

[….]

This leaflet was last revised in May September 2022.

[….]

(REC30360, BP22014)

The Mirena Patient information leaflet was updated to implement the additional wording requested by PRAC, following the outcome of the finished PSUSA procedure of all levonorgestrel-containing products (PSUSA/00010828/202105).

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2. What you need to know before you use Mirena

[….]

Pregnancy, breast-feeding and fertility

Pregnancy

[….]

If you do become pregnant with Mirena in place, contact your healthcare professional immediately so that ectopic pregnancy can be excluded and to have Mirena removed. The removal may cause a miscarriage. However, if Mirena is left in place during pregnancy, not only is the risk of having a miscarriage higher, but also the risk of preterm labour. If Mirena cannot be removed, talk with your healthcare professional about the benefits and risks of continuing the pregnancy, and possible effects of the hormone on the developing baby. If the pregnancy is continued, you will be closely monitored during your pregnancy and you should contact your doctor right away if you experience stomach cramps, pain in your stomach or fever.

Mirena contains a hormone, called levonorgestrel, and there have been isolated reports of effects on the genitalia of female babies if exposed to levonorgestrel intra-uterine devices while in the womb.

[….]

6. Contents of the pack and other information

[….]

This leaflet was last revised in March May 2022.

[….]

REC30414

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3. How to use Mirena

[….]

How quickly does Mirena work?

Contraception:

You are protected from pregnancy as soon as Mirena is fitted. The possibility of becoming pregnant is approximately 0.2 % (2 in 1000) in the first year. The failure rate may increase in case of expulsion (see section 2 “Expulsion”) or perforation (see section 2 “Perforation”).

[….]

6. Contents of the pack and other information

What Mirena contains

- The active substance is levonorgestrel 52 mg.

- The other ingredients are: polydimethylsiloxane elastomer and tubing, polyethylene, barium sulfate, iron oxide (E 172).

[….]

This leaflet was last revised in December 2021March 2022.

BEC20783+BEC18310

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1. NAME OF THE MEDICINAL PRODUCT

Mirena 52 mg iIntrauterine dDelivery sSystem

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Active substance:

 lLevonorgestrel 52 mg.

For the full list of excipients, see sSection 6.1.

For details on release rates, see section 5.2.

4.2 Posology and method of administration

4.2.1 Method of administration

[….]

4.2.1.1 Contraception and idiopathic menorrhagia

[….]

4.2.1.2 Protection from endometrial hyperplasia during oestrogen replacement therapy

[….]

4.2.1.3 Insertion and removal/replacement

[….]

Instructions for use and handling

Mirena is supplied in a sterile pack which should not be opened until required for insertion. The exposed product should be handled with aseptic precautions. If the seam of the sterile package is broken, the product should be discarded.

Do not insert after the date which is stated on the outer carton and foil package after “To be inserted before”. The “To be inserted before” date refers to the last day of that month.

[….]

4.2.2 Additional information on special populations

4.2.2.1 Paediatric population

[….]

Elderly patients 4.2.2.2 Geriatric patients

[….]

4.2.2.3Patients with hepatic impairment

[….]

4.2.2.4Patients with renal impairment

[….]

4.3 Contraindications

[….]

• Hypersensitivity to the active substance levonorgestrel or to any of the excipients listed in section 6.1

4.4 Special warnings and precautions for use

[….]

Medical examination/consultation

Before insertion, the woman must be informed of the efficacy, risks including signs and symptoms of these risks as described in the pPackage leaflet booklet and side effects of Mirena.

[….]

4.5 Interaction with other medicinal products and other forms of interaction

[….]

4.5.1 Effects of other medicinal products on Mirena

[….]

4.6 Fertility, pregnancy and lactation

4.6.1 Pregnancy

[….]

 4.6.2 Lactation Breast-feeding

[….]

4.6.3 Fertility

[….]

4.8 Undesirable effects

4.8.1 Summary of the safety profile

[….]

4.8.2 Tabulated list of adverse reactions

[….]

4.8.3 Description of selected adverse reactions

[….]

6. PHARMACEUTICAL PARTICULARS

6.1 List of eExcipients

Polydimethylsiloxane elastomer

Polydimethylsiloxane tubing

Polyethylene

Barium sulphate

Iron oxide (E 172)

6.6 Special precautions for disposal Instruction for Use and other hHandling

[….]

For further information see also sSection 4.2, Posology and Method Administration “Insertion and removal/replacement”.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

10. DATE OF REVISION OF THE TEXT

DecemberSeptember 2021

BEC20783+BEC18310

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Package leafletbooklet: Iinformation for the user

Mirena 52 mg iIntrauterine dDelivery sSystem

lLevonorgestrel

Read all of this leafletbooklet carefully before you start using this medicine decide to have Mirena fitted because it contains important information for you.

• Keep this leafletbooklet. You may need to read it again.

[…]

• This medicine has been prescribed for you only. Do not pass it on to others.

[…]

What is in this leafletbooklet:

[…]

2. What you need to know before you have Mirena fitteduse Mirena

3. How to useand when Mirena is used

[….]

1. What Mirena is and what it is used for

Mirena is an intrauterine delivery system (IUS) placed inside the womb (uterus) where it slowly releases the hormone lLevonorgestrel.

[…]

Children and adolescents

Mirena is not indicated for use before the first menstural bleeding (menarehe)

[…]

2. What you need to know before you have Mirena fitteduse Mirena

[…]

Do not use Mirena and please tell your doctor if you:

[….]

• are allergic to sensitive to the hormone levonorgestrel or to any of the other ingredients in Mirenaof this medicine (listed in seesection 6), “What Mirena contains”.

Warnings and precautions

Mirena may not be suitable for all women.

Talk to your doctor before using Mirena is fitted if you:

[….]

Expulsion

[….]

See also section 3 “How to use and when Mirena is used – How can I tell whether Mirena is in place?”.

[….]

Perforation

[….]

• you can no longer feel the Mirena threads (see section 3 “How and when Mirena is usedto use Mirena - How can I tell whether Mirena is in place?”).

[….]

Children and adolescents

Mirena is not indicated for use before the first menstrual bleeding (menarche).

Other medicines and Mirena

[….]

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Including medicines obtained without prescription.

Pregnancy, and breast-feeding and fertility

[….]

Fertility

If you wish Mirena to be removed so that you can get pregnant, your usual level of fertility will return very quickly after it is removed.

Driving and using machines

No studies on the effects on the ability to drive or use machines have been performed.

3. How to and when Mirena is used Mirena

[….]

If you have any concerns over its usage, you should discuss it with your doctor (see section 2 “What you need to know before you usehave Mirena fitted – Perforation”).

[….]

How will Mirena affect my periods?

[….]

There is a calendar on the last page of this patient information leafletbooket.

[….]

4. Possible side effects

[….]

Very cCommon: (may affect more than 1 in 10 people women)

[….]

Common: (may affect up to 1 in 10 people women)

[….]

Uncommon: (may affect up to 1 in a 100 peoplewomen)

[….]

Not Unknown: frequency cannot be estimated from the available data

[….]

5. How to store Mirena

Keep this medicine out of the sight and reach of children.

[….]

Mirena should not be insertedused after the date which is stated printed on the outer carton and foil package afteras indicated by  “To be inserted before”. The “To be inserted before” expiry date refers to the last day of that month.

[….]

Do not dispose via household waste, your doctor or nurse will dispose Mirena for you. These measures will help protect the environment.

6. Contents of the pack and other information

What Mirena contains

[….]

iron oxide (E 172).

[….]

What Mirena looks like and contents of the pack

[….]

Pack size:

1x1 intrauterine delivery system

Product Marketing Authorisation Holder

[….]

Manufacturer Mirena is manufactured by:

[….]

This leafletbooklet was last revised in SeptemberDecember 2021.

BEC18534

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4.4 Special Warnings and Precautions for Use

[….]

Expulsion

In clinical trials with Mirena in the indication contraception, the incidence of expulsion was low (<4% of insertions) and in the same range as that reported for other IUDs and IUSs. Symptoms of the partial or complete expulsion of any IUDMirena may include bleeding or pain. However, the system can be expelled from the uterine cavity without the woman noticing it, leading to loss of contraceptive protection. Partial explusion may decrease the effectiveness of Mirena. 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 (including women who use Mirena for treatment of heavy menstrual bleeding)
• Women with greater than normal BMI at the time of insertion; this risk increases gradually with increasing BMI

The woman should be counselled on possible signs of expulsion and how to check the threads of Mirena and advised to contact a healthcare professional if the threads cannot be felt. A barrier contraceptive (such as a condom) should be used until the location of Mirena has been confirmed.

After expulsion, Mirena may be replaced within 7 days from the onset of the next menstruation.

Partial expulsion may decrease the effectiveness of Mirena.

A displaced partially expelled Mirena should be removed. A new system can be inserted at thatthe time of removal, provided pregnancy has been excluded.

The woman should be advised how to check the threads of Mirena.

[….]

10 Date of revision of the text

July 2021September 2021

BEC18534

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2. What you need to know before you have Mirena fitted

Warnings and precautions

[….]

Expulsion

The muscular contractions of the womb during your period may sometimes push Mirena out of place or expel it. This is more likely to occur if you are overweight at the time of Mirena insertion or have a history of heavy periods. If Mirena is out of place, it may not work as intended and therefore, the risk of pregnancy is increased. If Mirena is expelled, you are not protected against pregnancy anymore.

Possible symptoms of an expulsion are pain and abnormal bleeding but Mirena may also come without you noticing. If it is expelled, you are not protected against pregnancy anymore. It is recommended that you check for the threads with your finger, for example while having a shower. If you have signs indicative of an expulsion or you cannot feel the threads, you should avoid intercourse or use another contraceptive, and consult your doctor. As Mirena makes periods lighter, heavier periods than usual may mean that Mirena is no longer in place. 

It is recommended that you check for the threads with your finger for example while having a shower. See also section 3 “How and when Mirena is used – How can I tell whether Mirena is in place?”. If you have signs indicative of an expulsion or you cannot feel the threads, you should avoid intercourse or use another contraceptive (such as condoms), and consult your healthcare professional doctor.

[….]

3. How and when Mirena is used

[….]

How can I tell whether Mirena is in place?

You can check yourself if the threads are in place. Gently put a finger into your vagina and feel for the threads at the end of your vagina near the opening of your womb (cervix).

Do not pull the threads because you may accidentally pull it out. If you cannot feel the threads, this may mean that it is no longer in place or has pierced the wall of the womb. In this case you should either not have intercourse or avoid sex or use a barrier contraceptive (such as condoms), and contact your doctor.

[….]

6. Contents of the pack and other information

[….]

This booklet was revised: July 2021September 2021

(BP20061_BEC17811+BEC14962)

Patient Information Leaflet

2. What you need to know before you have Mirena fitted

[…]

Can tampons or menstrual cups be used?

[…]

If you think you may have pulled Mirena out of place (see “What happens if Mirena comes out by itself?” and “How can I tell whether Mirena is in place?” for possible signs), avoid intercourse or use a barrier contraceptive (such as condoms), and contact your doctor.

[…]

Pregnancy and breastfeeding

Pregnancy

[…]

If you do become pregnant with Mirena in place, contact your healthcare professional doctor immediately so that ectopic pregnancy can be excluded and to have Mirena removed to reduce the risk of miscarriage. The removal may cause a miscarriage. However, if Mirena is left in place during pregnancy, not only is the risk of having a miscarriage higher, but also the risk of preterm labour. If Mirena cannot be removed, talk with your healthcare professional about the benefits and risks of continuing the pregnancy, and possible effects of the hormone on the developing baby.

[…]

3. How and when Mirena is used

[…]

After insertion of Mirena you should receive a patient reminder card from your doctor for follow-up examinations. Bring this with you to every scheduled appointment.

[…]

How often should I have Mirena checked?

[…]

Bring the patient reminder card you have received from your doctor to every scheduled appointment.

6. Contents of the pack and other information

[…]

This booklet was revised: February July 2021

(BP20061_BEC17811+BEC14962)

Summary of Product Characteristics

4.2.1.3 Insertion and removal/replacement

[…]

Mirena is supplied with a patient reminder card in the outer carton. Complete the patient reminder card and give it to the patient, after insertion.

[…]

4.6 Fertility, pregnancy and lactation

4.6.1 Pregnancy

[…]

If the woman becomes pregnant when using Mirena, the system should be removed as soon as possible removal of the system is recommended, since any intrauterine contraceptive left in situ may increase the risk of abortion and preterm labour. Removal of Mirena or probing of the uterus may also result in spontaneous abortion.

[…]

Because of the intrauterine administration and the local exposure to the hormone the possible occurrence of virilising effects in the foetus should be taken into consideration. Clinical experience of the outcomes of pregnancies under Mirena is limited due to the high contraceptive efficacy, but the woman should be informed that, to date, there is no evidence of birth defects caused by Mirena use in cases where pregnancy continues to term with Mirena in place.

In addition, an increased risk of virilising effects in a female foetus because of the intrauterine exposure to levonorgestrel cannot be excluded. There have been isolated cases of masculinization of the external genitalia of the female foetus following local exposure to levonorgestrel during pregnancy with an LNG-IUS in place.

[…]

10. Date of Revision of the Text

February July 2021

Mirena 52 mg IUS (BEC16376) Type II – C.I.4II 

Reasons for Changes:

To extend the duration of use of Mirena in the indication contraception up to 6 years.

PIL

1. What Mirena is and what it is used for

[…]

1. As an effective long-term and reversible method of contraception.

It can be used for contraception (prevention of pregnancy) for a maximum of 6 years, unless it is removed earlier.

2. For reducing menstrual blood flow, so it can be used if you suffer from heavy periods (heavy menstrual bleeding). This is called menorrhagia.

It can be used for idiopathic menorrhagia (excessive menstrual bleeding) for a maximum of 5 years, unless it is removed earlier.

It can be used for contraception and reducing menstrual blood flow until it is removed or up to a maximum of 5 years.

[…]

3. If you are going through the menopause, a gradual process which usually takes place between the ages of about 45 and 55.

It can be used for protection from endometrial hyperplasia (excessive growth of the lining of the womb) during oestrogen replacement therapy for a maximum of 5 years, unless it is removed earlier.

[…]

3. How and when Mirena is used

[…]

The initial release of Levonorgestrel is about 20 micrograms per day, reducing to about 10 micrograms per day after 5 years and 9 micrograms per day after 6 years. Therefore you receive an average of 15 micrograms per day levonorgestrel for 65 years.

[…]

How quickly does Mirena work?

Contraception:

You are protected from pregnancy as soon as Mirena is fitted. The possibility of becoming pregnant is approximately 0.2% (2 in 1000) in the first year increasing to 0.7% (7 in 1000) by year 5. The failure rate may increase in case of the Mirena coming out by itself (page 13) or perforation (see section 4 “Side Effects”).

[…]

4. Possible side effects
[…]
Reporting of side effects

[…]

You can also report side effects directly (see details below) via. By reporting side effects, you can help provide more information on the safety of this medicine.
:
Ireland
HPRA Pharmacovigilance
Website: www.hpra.ie.

Malta
ADR Reporting
Website: www.medicinesauthority.gov.mt/adrportal

By reporting side effects, you can help provide more information on the safety of this medicine.

[…]

6. Contents of the pack and other information
[…]

Product Authorisation Holder:
Bayer Limited
The Atrium
Blackthorn Road
Dublin 18
Ireland

[…]
This booklet was revised: August 2020February 2021

Mirena 52 mg IUS (BEC16376) Type II – C.I.4

Reasons for Changes:

To extend the duration of use of Mirena in the indication contraception up to 6 years.

Summary of Product Characteristics

2. Qualitative and Quantitative Composition

Active substance:

Levonorgestrel 52mg.

The in-vivo dissolution rate is about 20 μg/24 hours initially and is reduced to approximately 18 μg/24 hours after 1 year and to 10μg/24 hours after five years. The mean dissolution rate of levonorgestrel is about 15 μg/24 hours over the time up to five years.

 For the full list of excipients, see Section 6.1 List of excipients.

[…]

4.2 Posology and Method of Administration

4.2.1 Method of Administration

Mirena is inserted into the uterine cavity and is effective for five6 years in the indication contraception and 5 years in the indication idiopathic menorrhagia and protection from endometrial hyperplasia during oestrogen replacement therapy..

The failure rate (Pearl Index) was approximately 0.2 per 100 women at 1 year and the cumulative failure rate was approximately 0.7 per 100 women at 5 years. The failure rate also includes pregnancies due to undetected expulsions and perforations. (See Section 5.1 Pharmacodynamic Properties).

[…]

4.2.1.2 Protection from endometrial hyperplasia during oestrogen replacement therapy

[…]

Use of this product before menarche is not indicated. (See Section 4.4 Special Warnings and Precautions for use).

4.2.1.3 Insertion and removal/replacement

[…]

The system should be removed after 6five years in the indication contraception and after 5 years in the indication idiopathic menorrhagia and protection from endometrial hyperplasia during oestrogen replacement therapy. If the user wishes to continue using the same method, a new system can be inserted at the same time.

[…]

4.2.2.3 Patients with hepatic impairment

Mirena is contraindicated in women with acute liver disease or liver tumor (see Section 4.3).

Contraindications).

[…]

4.4 Special Warnings and Precautions for Use

[…]

Medical Examination/consultation

[…]

Because the insertion technique is different from other intrauterine devices, special emphasis should be given to training in the correct insertion technique (See Section 4.2 Posology and Method of Administration).

[…]

The procedure may precipitate fainting as a vasovagal reaction, or a seizure in an epileptic patient. See section 4.8 Undesirable effects.

[…]

Oligo/amenorrhoea

Women of fertile age

Oligomenorrhoea and/or amenorrhoea develops gradually in 57% and 16% of women during the first year of use respectively. By the end of Year 6 of Mirena use, oligomenorrhea and amenorrhea are experienced by 31% and 24% of Mirena users, respectively……

[…]

4.6 Fertility, pregnancy and lactation

4.6.1 Pregnancy

The use of Mirena during an existing or suspected pregnancy is contraindicated (see section 4.3 Contraindications).

[…]

4.8 Undesirable Effects

4.8.1 Summary of the safety profile

[…]

By the end of Year 6 of Mirena use, prolonged bleeding and irregular bleeding are experienced by 2% and 15% of Mirena users, respectively; amenorrhea occurs in 24%, and infrequent bleeding in 31% of Mirena users.

[…]

4.8.2 Tabulated list of adverse reactions

[…]

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).

4.8.3 Description of selected adverse reactions

Pregnancy, puerperium and perinatal conditions:

When a woman becomes pregnant with Mirena in situ, the relative risk of ectopic pregnancy is increased (see Section 4.4 Special warnings and special precautions of use).

Reproductive system and breast disorders:

Cases of breast cancer have been reported (frequency unknown, see Section 4.4 Special warnings and special precautions of use).

[…]

Reporting of suspected adverse reactions

[…]

Ireland

HPRA Pharmacovigilance,

wWebsite: www.hpra.ie.

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

[…]

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

[…]

The contraceptive efficacy of Mirena has been studied in 5 major clinical studies with 3330 women using Mirena. The Pearl Index was approximately 0.2 at 1 year and the cumulative failure rate was approximately 0.7% at 5 years. The failure rate (Pearl Index) was approximately 0.2 % at 1 year and the cumulative failure rate was approximately 0.7 % at 5 years.The contraceptive efficacy of Mirena beyond 5 years has been studied in a clinical study with 362 women using Mirena. During year 6 of Mirena use, the Pearl Index was 0.35 [95% CI (0.01; 1.95)].

Table 3 Cumulative Failure Rate (%) and Pearl Index

*Kaplan Meier method

 The failure rates also includes pregnancies due to undetected expulsions and perforations.

[…]

5.2 Pharmacokinetic Properties

The active ingredient of Mirena is levonorgestrel. Levonorgestrel is directly released into the uterine cavity. Estimated in vivo release rates for different points in time are provided in table 43.

Table 43: Estimated in vivo release rates for Mirena:

Absorption

[…]

After 72 months (6 years) median levonorgestrel concentration amounted to 113 pg/ml (87.3 pg/ml to 155 pg/ml).

[…]

Distribution

[…]

During Year 6 of use SHBG concentration remained stable.

[…]

6.2 Incompatibilities

None known Not applicable

[…]

7. Marketing Authorisation Holder

Bayer Limited

The Atrium

Blackthorn Road

Dublin 18

Ireland

[…]

8. Marketing Authorisation Number

PA 1410/008/001

10. Date of Revision of the Text

August 2020February 2021

Reason for update: Implementation of the outcome of the finished PSUSA procedure of all levonorgestrel-containing products (PSUSA/00001856/ 201905).

Section 2: Warning and precautions

Can tampons or menstrual cups be used?

Use of sanitary pads is recommended. If tampons or menstrual cups are used, you should change them with care so as not to pull the threads of Mirena.

Section 4: Possible side effects

Common side effects added:

Dizziness

Weight increase

Libido decreased

Section 6: Contents of the pack and other information

This booklet was revised: May August 2020

Section 4 Reporting of side effects

[....]

HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2

Tel: +353 1 6764971; Fax: +353 1 6762517.

Website: www.hpra.ie;

Email: medsafety@hpra.ie.

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie.

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

[…..]

Section 6

[…..]

The booklet was last revised in December 2018 May 2020

[…..]

Other sources of information

Detailed and updated information on this medicine is available by scanning the QR Code included in the package leaflet, outer carton and patient reminder card with a smartphone. The same information is also available on the following URL: www.pi.bayer.com/mirena/ie-mt and on the HPRA website: www.hpra.ie.

[QR code to package leaflet]

[www.pi.bayer.com/mirena/ie-mt]

Calendar diagram has also been added.

Sections 4.4 and 4.8 to include the new final study results of EURAS-IUD (5-year sub-study) (perforation information updated). Small editorial differences were made in spelling and layout (spacing) in other sections.

Added            Deleted

2. Qualitative and Quantitative Composition

[…]

The in-vivo dissolution rate is about 20 µg/24 hours initially and is reduced to about 11 approximately 18 µg/24 hours after 1 year and to 10µg/24 hours after five years. The mean dissolution rate of levonorgestrel is about 1415 µg/24 hours over the time up to five years.

3. Pharmaceutical Form

[…]

The levonorgestrel intrauterine delivery system 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 Removal threads are attached to the loop. The T-frame of Mirena contains barium sulphate, which makes it visible in X-ray examination. The vertical stem of the intrauterine delivery system is loaded in the insertion tube at the tip of the inserter.

4.2 Posology and Method of Administration

4.2.1 Method of administration

4.2.1.1 Contraception and idiopathic menorrhagia

[…]

Post-partum insertion

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, the possibility of perforation should be considered and appropriate steps should be immediately taken, such as physical examination and ultrasound. physical examination and ultrasound should be performed immediately to exclude perforation. Physical examination alone (including checking of threads) may not be sufficient to exclude partial perforation.

4.2.1.2   Protection from endometrial hyperplasia during oestrogen replacement therapy

[…]

Mirena is not the contraceptive method of first choice for young nulligravid women nor for should be used with caution in postmenopausal women with advanced uterine atrophy. Controlled clinical trials were done in previously parous women aged mainly over 18 years. Use of this product before menarche is not indicated. (See Section 4.4 Special Warnings and Precautions for use).

4.2.1.3 Insertion and removal/replacement

[…]

If pregnancy is not desired, the removal should be carried out during menstruation in women of fertile age, provided that there appears to be a menstrual cycle. If the system is removed in the mid-cycle and the woman has had intercourse within a week, she is at a risk of pregnancy unless a new system is inserted immediately following removal.

Removal of Mirena can occur at any time during the cycle. If ongoing contraception is desired, the timing of initiation of the method chosen will depend upon when in the cycle Mirena is removed.

If removal is to occur within the first 7 days of the onset of menstruation, a new Mirena, another levonorgestrel-intrauterine system (LNG-IUS) or other hormonal contraceptive can be initiated immediately.

If removal is to occur beyond the first 7 days of the onset of menstruation or the menses are irregular, the woman may be at risk of pregnancy if she has had intercourse in the past week. If the woman chooses another Mirena or LNG-IUS continuous contraception is provided.  If other hormonal contraception is desired it should be started 7 days before the removal to ensure continuous contraception; otherwise, a barrier method of contraception should be used or the patient should abstain from vaginal intercourse for 7 days to prevent pregnancy.

[…]

4.4 Special Warnings and Precautions for Use

[…]

•             Marked increase in of blood pressure

[…]

Mirena should be used with caution in postmenopausal women with advanced uterine atrophy.

Mirena may be used with caution in women who have congenital heart disease or valvular heart disease at risk of infective endocarditis. Antibiotic prophylaxis should be administered to these patients when inserting or removing the IUS. The need for antibiotic prophylaxis during insertion and removal of Mirena should be considered in patients with congenital or valvular heart disease. It is recommended that physicians consult local guidelines.

[…]

Mirena is not the method of first choice for young nulligravid women or for postmenopausal women with advanced uterine atrophy.

[…]

Medical examination/consultation

[…]

A physical examination including pelvic examination and, examination of the breasts should be conducted. Cervical smear should be performed as needed, according to Healthcare Professional’s evaluation. and a cervical smear should be performed.

[…]

Oligo/amenorrhoea

Women of fertile age

Oligomenorrhoea and/or amenorrhoea develops gradually in 57% and 16% of women during the first year of use respectively.  

[…]

4.5 Interaction with other Medicinal Products and other forms of Interaction

Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.

4.5.1 Effects of other medicinal products on Mirena

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, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, and products containing St. Jphn’s wort.

The influence of these drugs on the 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.

The metabolism of progestogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz). 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.

4.6 Fertility, pregnancy and lactation

4.6.1 Pregnancy

[…]

If the woman becomes pregnant when using Mirena, removal of the system is recommended, since any intrauterine contraceptive 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 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. Ectopic pregnancy should be excluded. The woman should be instructed to report all symptoms that suggest complications of the pregnancy, like cramping abdominal pain with fever.

[…]

5.2 Pharmacokinetic Properties

The active ingredient of Mirena is levonorgestrel. Levonorgestrel is directly released into the

uterine cavity. Estimated in vivo release rates for different points in time are provided in table 3.

Table 3: Estimated in vivo release rates for Mirena:

Absorption

Following insertion, levonorgestrel is released 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 after 1 hour. The maximum concentration is reached within 2 weeks after insertion. In correspondence with the declining release rate, the median serum concentration of levonorgestrel declines from 206 pg/ml (25th to 75th percentiles: 151 pg/ml to 264 pg/ml) at 6 months to 194 pg/ml (146 pg/ml to 266 pg/ml) at 12 months, and to 131 pg/ml (113 pg/ml to 161 pg/ml) at 60 months in women of reproductive age weighing above 55 kg.

[…]

The in vivo release rate of levonorgestrel in the uterine cavity is initially approximately 20 µg/24 hours and declines to 10 µg/24 hours after 5 years. The mean dissolution rate of levonorgestrel is about 14 µg/24 hours over the time up to five years.

In postmenopausal women using Mirena together with non-oral oestrogen treatment, the median serum concentration of levonorgestrel declines from 257 pg/ml (25th to 75th percentiles: 186 pg/ml to 326 pg/ml) at 12 months to 149 pg/ml (122 pg/ml to 180 pg/ml) at 60 months. When Mirena is used together with oral oestrogen treatment, the serum levonorgestrel concentration at 12 months is increased to approx. 478 pg/ml (25th to 75th percentiles: 341 pg/ml to 655 pg/ml) due to the induction of SHBG by oral oestrogen treatment.

Distribution

Levonorgestrel is bound non-specifically to serum albumin and specifically to the 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 20-30% during the first month of insertion of Mirena, remained stable during the first year and increased slightly thereafter. About 1-2 % of the circulating levonorgestrel is present as free steroid and 42-62 % is specifically bound to SHBG. During the use of Mirena, the concentration of SHBG declines. Accordingly, the fraction bound to SHBG decreases during the treatment and the free fraction increases. The mean apparent volume of distribution of levonorgestrel is about 106 L.

After insertion of Mirena, levonorgestrel is detectable in serum after 1 hour. The maximum concentration is reached within 2 weeks after insertion. In correspondence with the declining release rate, the median serum concentration of levonorgestrel declines from 206 pg/ml (25th to 75th percentiles: 151 pg/ml to 264 pg/ml) at 6 months to 194 pg/ml (146 pg/ml to 266 pg/ml) at 12 months and to 131 pg/ml (113 pg/ml to 161 pg/ml) at 60 months in women of reproductive age weighing above 55 kg.

[…]

In postmenopausal women using Mirena together with non-oral oestrogen treatment, the median serum concentration of levonorgestrel declines from 257 pg/ml (25th to 75th percentiles: 186 pg/ml to 326 pg/ml) at 12 months to 149 pg/ml (122 pg/ml to 180 pg/ml) at 60 months. When Mirena is used together with oral oestrogen treatment, the serum levonorgestrel concentration at 12 months is increased to approx. 478 pg/ml (25th to 75th percentiles: 341 pg/ml to 655 pg/ml) due to the induction of SHBG by oral oestrogen treatment.

Biotransformation

Levonorgestrel is extensively metabolized. 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.  CYP3A4 is the main enzyme involved in the oxidative metabolism of LNG. The available in vitro data suggest that CYP mediated biotransformation reactions may be of minor relevance for LNG compared to reduction and conjugation. The major metabolites in the plasma are the unconjugated and conjugated forms of 3a, 5b-tetrahydrolevonorgestrel. Based on in vitro and in vivo studies, CYP3A4 is the main enzyme involved in the metabolism of levonorgestrel, CYP2E1, CYP2C19 and CYP2C9 may also be involved, but to a smaller extent

Elimination

[…]

The excretion half-life which is mainly represented by metabolites, is about 1 day.

Linearity/ non-linearity

[…]

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. 

During use of Mirena a mean SHBG decrease of about 30% was observed, which leads to a decrease of levonorgestrel in serum indicating non-linear pharmacokinetics of levonorgestrel with regard to time.

[…]

5.3 Preclinical Safety Data

The preclinical safety evaluations revealed no special hazard for humans based on studies of safety pharmacology, pharmacokinetics, toxicity, genotoxicity and carcinogenic potential of levonorgestrel. Levonorgestrel is a well-established progestogen with anti-oestrogenic activity. The safety profile following systemic administration is well documented. A studyStudies in monkeys with intrauterine delivery of levonorgestrel for 9 to 12 months confirmed local pharmacological activity with good local tolerance and no signs of systemic toxicity. No embryotoxicity was seen in the rabbit following intrauterine administration of levonorgestrel. The safety evaluation of the elastomer components of the hormone reservoir, polyethylene materials of the product, and combination of elastomer and levonorgestrel, based on both the assessment of genetic toxicology in standard in vitro and in vivo test systems and on biocompatibility tests in mice, rats, guinea pigs, rabbits and in vitro test systems has not revealed bio-incompatibility.

10 Date of Revision of the Text

April 2016 March 2018

In section - 4.2.2 Additional information on special populations

Subsection - 4.2.2.1 Children and adolescents Paediatric population

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

In section - 4.4 Special Warnings and Precautions for Use

             Subsection - Medical examination/consultation       

Mirena should only by be inserted be by physicians/health care professionals who are experienced in Mirena insertions and/or have undergone sufficient training for Mirena insertion.

In Subsection - 4.8.2 Tabulated list of adverse reactions (Table)

Musculosceletal Musculoskeletal, connective tissue and bone disorders (Edited to English (UK))

10. Date of Revision of the Text

May 2015 April 2016

Mirena – PA 1410/68/1
14045
BEC 6323 + 6412
www.medicines.ie

(Inserted Text; Deleted Text)

4.2          Posology and method of administration

4.2.2.1 Contraception and idiopathic menorrhagia

…

Post-partum insertion

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, physical examination and ultrasound should be performed immediately to exclude perforation. Physical examination alone (including checking of threads) may not be sufficient to exclude partial perforation.

4.4          Special warnings for use

…

Medical examination/consultation

Before insertion, the woman must be informed of the efficacy, risk including signs and symptoms of these risks as described in the Package BookletPatient Leaflet and side effects of Mirena.

Perforation

Perforation or penetration of the uterine corpus or cervix by an intrauterine contraceptive may occur rarely, most often during insertion, although it may not be detected until sometime later, and may decrease the effectiveness of Mirena. Such a system must be removed; surgery may be required. The risk of perforations is increased in breastfeeding women, and may be increased in post-partum insertions (see Section 4.2, Posology and method of administration) and in women with fixed retroverted uterus.

In a large prospective comparative non-interventional cohort study in IUD users (N = 61,448 women), 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. 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 independent of the type of IUD inserted.

Table 1: Incidence of perforation per 1000 insertions for the entire study cohort, stratified by breastfeeding and time since delivery at insertion (parous women)

The risk of perforation may be increased in women with fixed retroverted uterus.

Re-examination after insertion should follow the guidance given above under the heading “Medical examination/consultation” which may be adapted as clinically indicated in women with risk factors for perforation.

Removal of a perforated device may require surgery and may be associated with complications such as adhesions, peritonitis or intestinal perforations.

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 reappear 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 the system may have been expelled. 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.

…

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 ectopic pregnancy should be considered in the case of lower abdominal pain – especially in connection with missed periods or if an amenorrheic woman starts bleeding. The absolute risk of ectopic pregnancy in Mirena users is low due to the overall reduced likelihood of pregnancy in Mirena users compared to non-users of any contraception. In a large prospective comparative non-interventional cohort study with an observation period of 1 year, the ectopic pregnancy rate with Mirena was 0.02%. In clinical trials, Tthe absolute rate of ectopic pregnancies with Mirena was is approximately 0.1% per year, compared to 0.3-0.5% per year in women not using any contraception. However, if a woman becomes pregnant with Mirena in situ, the relative likelihood of this pregnancy being ectopic is increased.

4.8          Undesirable effects

…

4.8.2 Tabulated list of adverse reactions

….

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

*Endometrial protection trials: “common”

** Endometrial protection trials: “very common”

*** This frequency is based on clinical trials that excluded breastfeeding women. In a large prospective comparative non-interventional cohort study in IUD users, the frequency of perforation in women who were breastfeeding or had an insertion up to 36 weeks after delivery was “uncommon” (see section 4.4 Special warnings and precautions for use).

4.8.3 Description of selected adverse reactions

…

Reproductive system disorders:

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

Breast breast disorders:

Cases of breast cancer have been reported (frequency unknown, see Section 4.4 Special warnings and special precautions of use).

Injury, poisoning and procedural complications:

Clinical trials with Mirena excluded breast feeding women. A large post-authorization safety study shows an increased risk of perforation in breast feeding women (see section 4.4 Special warnings and precautions for use).

…

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 via HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: http://www.hpra.ie/; E-mail: medsafety@hpra.ie

5.1          Pharmacodynamic properties

…

The contraceptive efficacy of Mirena has been studied in 5 major clinical studies with 3330 women using Mirena. The failure rate (Pearl Index) was approximately 0.2% at 1 year and the cumulative failure rate was approximate 0.7% at 5 years. The failure rate also includes pregnancies due to undetected expulsions and perforations. Similar contraceptive efficacy has been observed in a large post-marketing study with more than 17000 women using Mirena. In a large prospective comparative non-interventional cohort study with an observation period of 1 year including more than 43,000 Mirena users, the Pearl Index of Mirena was 0.06 (95% CI: 0.04 0.09). Because the use of Mirena 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”).

10           Date of revision of the text

October 2014 May 2015

In section 2 the final line has been modified to read “For the full list of excipients, see Section 6.1 List of excipients”

Section 4.2 has been subdivided into the following headings and the following information has been inserted:

                4.2.1 Method of administration

·         In this section the following text was deleted, “In women on hormone replacement therapy, Mirena can be used in combination with oral or transdermal oestrogen preparations without progestogens.

Mirena is not the method of first choice for young nulligravid women nor for postmenopausal women with advanced uterine atrophy. (See Section 4.4 Special Warnings and Precautions for use).”

“4.2.1.1 Contraception and idiopathic menorrhagia” has replaced “Insertion and removal/replacement”

·         Under this section a subheading “Post-partum insertion” has been inserted

4.2.1.2 Protection from endometrial hyperplasia during oestrogen replacement therapy

Under this section the below text has been inserted.

In women on hormone replacement therapy, Mirena can be used in combination with oral or transdermal oestrogen preparations without progestogens.

Mirena is not the contraceptive method of first choice for young nulligravid women nor for postmenopausal women with advanced uterine atrophy. Controlled clinical trials were done in previously parous women aged mainly over 18 years. Use of this product before menarche is not indicated. (See Section 4.4 Special Warnings and Precautions for use).

                4.2.1.3 Insertion and removal/replacement

                4.2.2 Additional information on special populations

                                4.2.2.1 Children and adolescents

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

                `               4.2.2.2 Geriatric patients

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

4.2.2.3 Patients with hepatic impairment

Mirena is contraindicated in women with acute liver disease or liver tumor (see 4.3 Contraindications).

4.2.2.4 Patients with renal impairment

Mirena has not been studied in women with renal impairment.

In section 4.3 “Hypersensitivity to the constituents of the preparation” has been replaced by “Hypersensitivity to the active substance or to any of the excipients” and the order of the contraindications has been changed

In section 4.4

·         Bulleted information has been capitalised

·         The following pieces of text have been deleted:

In women using progestogen-only pills some recent epidemiological studies indicated

that there may be a slightly increased risk of venous thromboembolism but the

results were statistically not significant. However, appropriate diagnostic and

therapeutic measures should be undertaken immediately if there are symptoms or

signs of thrombosis. An individual benefit-risk assessment in relation to continued

use of Mirena should be carried out in the event of thrombosis. Discontinuation of

Mirena should also be considered in case of long-term immobilisation due to surgery

or illness. Women with a history of thrombo-embolic disorders should be made aware

of the possibility of a recurrence.

Symptoms of venous or arterial thrombosis can include: unilateral leg pain and/or

swelling; sudden severe pain in chest, whether or not it radiates to the left arm;

sudden breathlessness; sudden onset of coughing; any unusual, severe, prolonged

headache; sudden partial or complete loss of vision; diplopia; slurred speech or

aphasia; vertigo; collapse with or without focal seizure; weakness or very marked

numbness suddenly affecting one side or one part of the body; motor disturbances;

‘acute’ abdomen. Symptoms or signs indicating retinal thrombosis are: unexplained

partial or complete loss of vision, onset of proptosis or diplopia, papilloedema, or

retinal vascular lesions.

There is no consensus about the possible role of varicose veins and superficial

thrombophlebitis in venous thromboembolism.

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 oestrogenprogestogen

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 COCs. However, for progestogen-only

preparations, the evidence is based on much smaller populations of users and so is

less conclusive than that for COCs. These studies do not provide evidence for

causation. The observed pattern of increased risk may be due to an earlier diagnosis

of breast cancer in OC users, the biological effects of OCs or a combination of both.

The breast cancers diagnosed in ever-users tend to be less advanced clinically than

the cancers diagnosed in never-users. 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.

·         In the paragraph entitled “Medical examination/ consultation” the lines

“See section 4.8 Undesirable effects” and “Mirena is not suitable for use as a post-coital contraceptive” have been inserted and

“Because irregular bleeding/spotting is common during the first months of therapy, it is recommended to exclude endometrial pathology before insertion of Mirena. If the woman continues the use of Mirena inserted earlier for contraception, endometrial pathology has to be excluded in case bleeding disturbances appear after commencing oestrogen replacement therapy. If bleeding irregularities develop during prolonged treatment, appropriate diagnostic measures should also be taken” has been deleted

·         In the section Oligo/amenorrhoea the first paragraph is titled Women of fertile age and the first line has been changed to read “Oligomenorrhoea and/or amenorrhoea develops gradually in 57% and 16% of women respectively.”

And the following text has been inserted, “Because irregular bleeding/spotting is common during the first months of therapy, it is recommended to exclude endometrial pathology before insertion of Mirena”

The next paragraph in the section has been titled “Menopausal women” and the following text has been inserted, “If the woman continues the use of Mirena inserted earlier for contraception, endometrial pathology has to be excluded in case bleeding disturbances appear after commencing oestrogen replacement therapy. If bleeding irregularities develop during prolonged treatment, appropriate diagnostic measures should also be taken”

·         In the section Pelvic infection the word “protect” has been replaced with “to prevent”

The text “In general, pelvic infection is more likely to occur within the first 20 days following insertion and the rates of infection decrease thereafter to very low levels corresponding to that of non-users and remain low for the duration of use of the product” has been replaced with “In users of copper intrauterine devices (IUDs), the highest rate of pelvic infections occurs during the first month after insertion and decreases later”

The second paragraph in this section now reads “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.” And the below text has been inserted.

“As with other gynecological or surgical procedures, severe infection or sepsis (including group A streptococcal sepsis) can occur following IUD insertion, although this is extremely rare.”

In the same section the below pieces were deleted:

“During spontaneous post marketing reporting, Group A streptococcal sepsis (GAS) has been reported in less than one in one million users of Mirena. Group A streptococcal sepsis (GAS) is a condition which may occur after surgery, delivery, and from minor trauma” and “Bacteriological examinations are indicated and monitoring is recommended, even with discrete symptoms indicative of infections” and the following text has been deleted, “PID can be asymptomatic but can still result in tubal damage and ectopic pregnancy, infertility”

·         The section discussing perforation in section 4.4 has been entitled Perforation and the  paragraph been changed to read as below

“Perforation, partial perforation (e.g. embedment in the myometrium) or penetration of the uterine corpus or cervix by an intrauterine contraceptive may occur rarely, most often during insertion and may decrease the effectiveness of Mirena. Such a system must be removed. The risk of perforations is increased in breastfeeding women, and may be increased in post-partum insertions (see Section 4.2, Posology and method of administration), in lactating women and in women with fixed retroverted uterus.”

·         The text below has been inserted in section 4.4. The paragraph on Lost threads has been cut and modified from later in section 4.4.

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 reappear 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 system may have been expelled. 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.

Breast cancer

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 oestrogen-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.

The paragraph Ectopic pregnancy has changed to read “Women with a previous history of ectopic pregnancy, tubal surgery or pelvic infection carry a higher 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. The absolute risk of ectopic pregnancy with Mirena users is low due to the overall reduced likelihood of pregnancy in Mirena users compared to non-users of any contraception. The absolute rate of ectopic pregnancies with Mirena is approximately 0.1% per year, compared to 0.3-0.5% per year in women not using any contraception. However, if a woman becomes pregnant with Mirena in situ, the relative likelihood of this pregnancy being ectopic pregnancy is increased.”

·         The paragraph heading Delayed follicular atresia has been renamed Ovarian cysts.

Within this paragraph the sentence “Ovarian cysts have been reported as adverse drug reactions in approximately 7% of women using Mirena” has been inserted and “Enlarged follicles have been diagnosed in about 12 % of subjects using Mirena” has been deleted

Follicles have been renamed cysts and enlarged follicle have been renamed ovarian cysts

Section 4.6 has been renamed Fertility, pregnancy and lactation

·         This section now contains the subheadings

4.6.1 Pregnancy

4.6.2 Lactation

4.6.3          Fertility

·         Under 4.6.1 Pregnancy: The line “Mirena is not to be used during an existing or suspected pregnancy” has changed to “The use of Mirena during an existing or suspected pregnancy is contraindicated (see 4.3 Contraindications)”. The line “If the intrauterine contraceptive cannot be gently removed, the woman should be informed about the risks and the possible consequences of premature birth to the infant” has been changed to “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”

·         In section 4.6.2 Lactation the line “Levonorgestrel daily dose and blood concentrations are lower with Mirena than with any other hormonal contraceptive, although levonorgestrel has been identified in breast milk” has been inserted. The line “Hormonal contraceptives are not recommended as the contraceptive method of choice during lactation” has been deleted

·         Under 4.6.3 Fertility “Upon removal of Mirena, women return to their normal fertility. Clinical data from 310 women discontinuing use of Mirena for want of pregnancy has demonstrated a pregnancy rate of 79-96% after 12 months. “ has been inserted

Section 4.7 has changed to read “No studies on the effects on the ability to drive and use machines have been performed”

Section 4.8 has changed to

4.8 Undesirable Effects

4.8.1 Summary of the safety profile

The majority of women experience changes in menstrual bleeding pattern after insertion of Mirena. During the first 90 days, prolonged bleeding is experienced by 22% and irregular bleeding by 67% of women after postmenstrual insertion of Mirena, decreasing to 3% and 19% at the end of the first year of use, respectively. Concomitantly, amenorrhoea is experienced by 0% and infrequent bleeding by 11% during the first 90 days, increasing to 16% and 57% at the end of the first year of use, respectively.

When Mirena is used in combination with continuous oestrogen replacement therapy, a non-bleeding pattern gradually develops in most women during the first year.

4.8.2 Tabulated list of adverse reactions

The frequencies of adverse drug reactions (ADRs) reported with Mirena are summarized in the table below. Frequencies are defined as very common (≥ 1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000) and unknown. The table below reports adverse reactions by MedDRA system organ classes (MedDRA SOCs). The frequencies are crude incidences of the events observed in clinical trials in the indications contraception and idiopathic menorrhagia/ heavy menstrual bleeding, including 5091 women and 12,101 woman-years.

Adverse reactions in clinical trials in the indication protection from endometrial hyperplasia during oestrogen replacement therapy (including 514 women and 1218.9 woman-years) were observed at a similar frequency unless specified by footnotes.

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

*Endometrial protection trials: “common”

** Endometrial protection trials: “very common”

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).

4.8.3 Description of selected adverse reactions

Pregnancy, puerperium and perinatal conditions:

When a woman becomes pregnant with Mirena in situ, the relative risk of ectopic pregnancy is increased (see Section 4.4 Special warnings and special precautions of use).

Reproductive system disorders:

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

Breast disorders:

Cases of breast cancer have been reported (frequency unknown, see Section 4.4 Special warnings and special precautions of use).

Injury, poisoning and procedural complications:

Clinical trials with Mirena excluded breast-feeding women. A large post authorization safety study shows an increased risk of perforation in breast-feeding women (see section 4.4 Special warnings and precautions for use).

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: http://www.hpra.ie/; E-mail: medsafety@hpra.ie.

In section 5.1

 “Mirena can be successfully used in the treatment of idiopathic menorrhagia. The volume of menstrual bleeding was decreased by 88% in menorrhagic women by the end of three months of use. Menorrhagia caused by submucosal fibroids may respond less favourably. Reduced bleeding increases the concentration of blood haemoglobin. Mirena also alleviates dysmenorrhoea“ is replaced by “Mirena can be successfully used in the treatment of idiopathic menorrhagia. In menorrhagic women, the 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. Compared to endometrial ablation or resection, Mirena demonstrated equal efficacy in reducing the menstrual blood loss up to two years. Menorrhagia caused by submucosal fibroids may respond less favorably. Reduced bleeding increases the concentration of blood hemoglobin. Mirena also alleviates dysmenorrhoea”

201 is replaced by “a total of 634! And 259 is deleted. New line of text reads “The efficacy of Mirena in preventing endometrial hyperplasia during continuous oestrogen treatment has been equally good when administering oestrogen either orally or transdermally. The observed hyperplasia rate under oestrogen therapy alone is as high as 20%. 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.”

In section 5.2

·         “The active ingredient of Mirena is levonorgestrel. Levonorgestrel is directly released into the uterine cavity” replaces “The in vivo release rate of levonorgestrel is initially approximately 20 μg/24 hours and declines to 10 μg/24 hours after 5 years”

·         Wording of the information regarding absorbtion of the active has been modified #

·         The paragraph below has been inserted

Linearity/ non-linearity

The pharmacokinetics of levonorgestrel is dependent on the concentration of SHBG which itself is influenced by oestrogens and androgens. 

During use of Mirena a mean SHBG decrease of about 30% was observed, which leads to a decrease of levonorgestrel 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.

The date of revision has been updated.

4.2 Posology and Method of Administration

Text Deleted:

The in-vivo dissolution rate is about 20 µg/24 hours initially and is reduced to about 11 µg/24 hours after five years. The mean dissolution rate of levonorgestrel is about 14 µg/24 hours over the time up to five years.

Additional text:

Mirena is not the method of first choice for young nulligravid women nor for postmenopausal women with advanced uterine atrophy. (See Section 4.4 Special Warnings and Precautions for use).

The failure rate (Pearl Index) was approximately 0.2 per 100 women at 1 year and the cumulative failure rate was approximately 0.7 per 100 women at 5 years. The failure rate also includes pregnancies due to undetected expulsions and perforations. (See Section 5.1, Pharmacodynamic Properties).

Mirena must be inserted using aseptic technique.

After removal of Mirena, the system should be checked to be intact. During difficult removals, single cases have been reported of the 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.

4.4. Special Warnings and Precautions for Use

Additional text:

Mirena does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Medical examination/consultation

Mirena should only be inserted be physicians/health care professionals who are experienced in Mirena insertions and/or have undergone sufficient training for Mirena insertion. Mirena must be inserted using aseptic technique.

Updated text:

Pelvic infection

A decision to use Mirena must include consideration of the risks of pelvic inflammatory diseases (PID).

In general, pelvic infection is more likely to occur within the first 20 days following insertion and the rates of infection decrease thereafter to very low levels corresponding to that of non-users and remain low for the duration of use of the product.

Known risk factors for pelvic inflammatory disease are multiple sexual partners, frequent intercourse and young age. Pelvic infection may have serious consequences, including impairment of fertility, increase in the risk of ectopic pregnancy, and on rare occasions, hysterectomy.

During spontaneous post marketing reporting, Group A streptococcal sepsis (GAS) has been reported in less than one in one million users of Mirena. Group A streptococcal sepsis (GAS) is a condition which may occur after surgery, delivery, and from minor trauma.

PID can be asymptomatic but can still result in tubal damage and ectopic pregnancy, infertility.

Signs and symptoms of PID should be investigated appropriately and treated promptly.

Expulsion

Section updated:

Symptoms of the partial or complete expulsion of any IUD may include bleeding or pain. However, the system can be expelled from the uterine cavity without the woman noticing it leading to loss of contraceptive protection. Partial expulsion may decrease the effectiveness of Mirena. As Mirena decreases menstrual flow, increase of menstrual flow may be indicative of an expulsion.

After expulsion, Mirena may be replaced within 7 days from the onset of the  next menstruation.

Ectopic pregnancy

An ectopic pregnancy may lead to a higher risk of a subsequent pregnancy being ectopic or to impaired fertility.

Text Deleted:

Mirena may not be suitable for use as a post-coital contraceptive.

4.6   Pregnancy and Lactation

Section updated:

Lactation

About 0.1 % of the levonorgestrel dose is transferred to the infant during breast-feeding.  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.

5.1 Pharmacodynamic Properties

Section updated/Additional text

The contraceptive efficacy of Mirena has been studied in 5 major clinical studies with 3330 women using Mirena. The failure rate (Pearl Index) was approximately 0.2 % at 1 year and the cumulative failure rate was approximately 0.7 % at 5 years. The failure rate also includes pregnancies due to undetected expulsions and perforations. Similar contraceptive efficacy has been observed in a large post-marketing study with more than 17000 women using Mirena. Because the use of Mirena 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 Mirena does not alter the course of future fertility. About 80% of women wishing to become pregnant conceived within 12 months after removal of the system.

The menstrual pattern is a result of the direct action of levonorgestrel on the endometrium and does not reflect the ovarian cycle. There is no clear difference in follicle development, ovulation or estradiol and progesterone production in women with different bleeding patterns. 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. Scanty flow frequently develops into oligomenorrhoea and amenorrhoea. Ovarian function is normal and estradiol levels are maintained, even when users of Mirena are amenorrhoeic.

5.2 Pharmacokinetic Properties

Section updated:

Following insertion Mirena releases levonorgestrel without delay. The high local drug exposure in the uterine cavity which is important for the local action of Mirena on the endometrium, leads to a strong concentration gradient via 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).

The in vivo release rate of levonorgestrel in the uterine cavity is initially approximately 20 µg/24 hours and declines to 10 µg/24 hours after 5 years. The mean dissolution rate of levonorgestrel is about 14 µg/24 hours over the time up to five years.

Distribution

Levonorgestrel is bound non-specifically to serum albumin and specifically to SHBG. About 1-2 % of the circulating levonorgestrel is present as free steroid and 42-62 % is specifically bound to SHBG. During the use of Mirena, the concentration of SHBG declines. Accordingly, the fraction bound to SHBG decreases during the treatment and the free fraction increases. The mean apparent volume of distribution of levonorgestrel is about 106 L.

After insertion of Mirena, levonorgestrel is detectable in serum after 1 hour. The maximum concentration is reached within 2 weeks after insertion. In correspondence with the declining release rate, the median serum concentration of levonorgestrel declines from 206 pg/ml (25^th to 75^th percentiles: 151 pg/ml to 264 pg/ml) at 6 months to 194 pg/ml (146 mg/ml to 266 pg/ml) at 12 months and to 131 pg/ml (113 pg/ml to 161 pg/ml) at 60 months in women of reproductive age weighing above 55 kg.

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.

In postmenopausal women using Mirena together with non-oral oestrogen treatment, the median serum concentration of levonorgestrel declines from 257 pg/ml (25^th to 75^th percentiles: 186 pg/ml to 326 pg/ml) at 12 months to 149 pg/ml (122 pg/ml to 180 pg/ml) at 60 months. When Mirena is used together with oral oestrogen treatment, the serum levonorgestrel concentration at 12 months is increased to approx. 478 pg/ml (25^th to 75^th percentiles: 341 pg/ml to 655 pg/ml) due to the induction of SHBG by oral oestrogen treatment.

Biotransformation

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

Elimination

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

5.3 Preclinical Safety Data

Deleted wording:

With anti-estrogenic activity

6.2 Incompatibilities

Section updated:

None known

6.4 Special Precautions for Storage

Section updated:

Store in the original package.

10.0 Date revision  

Date of (Partial) Revision of the Text

December 2009

Section 2. Qualitative and Quantitative Composition

The following text was inserted:

“The in-vivo dissolution rate is about 20 µg/24 hours initially and is reduced to about 11 µg/24 hours after five years. The mean dissolution rate of levonorgestrel is about 14 µg/24 hours over the time up to five years.”

Section 3. Pharmaceutical Form

The following text was deleted:

“White or almost white intrauterine delivery system consisting of a T-shaped polyethylene body on the vertical section of which is mounted an elastomeric sleeve.”

The following text was inserted:

“The levonorgestrel intrauterine delivery system 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 T-body has a loop at one end of the vertical stem and two horizontal arms at the other end. Removal threads are attached to the loop. The vertical stem of the intrauterine delivery system is loaded in the insertion tube at the tip of the inserter.”

Section 6.6 Instructions for Use and Handling

The following text was inserted:

“The exposed product should be handled with aseptic precautions.”

“For further information see also Section 4.2, Posology and Method of Administration, Insertion and removal/replacement

Any unused product or waste material should be disposed of in accordance with local requirements.”

Section 10. Date of Revision of the Text

The date was changed from “January 2007” to “April 2007”

Main Changes to the SPC include:

Section 4.2 Posology and method of administration

Addition of instructions for ‘Insertion and Removal/Replacement’ and ‘Instructions for Use and Handling’.

Section 4.3 Contraindications

Update of contraindications in line with the most recent safety information.

Deletion of the following contra-indications:

-         Presence or history of severe hepatic disease as long as liver function values have not returned to normal

-         Undiagnosed vaginal bleeding

Section 4.4 Special warnings and precautions for use

Revised/additional text regarding:

-         Risk of breast cancer

-         Risk of venous/ arterial thromboembolic events

-         Use in women with diabetes

-         Medical examination/ consultation

-         Perforation

-         Ectopic pregnancy

Instructions for ‘Insertion and Removal/Replacement’ have been revised and are now included in Section 4.2.

Section 4.5 Interaction with other medicinal products and other forms of interaction

Revised text regarding possible interaction with drugs which induce cytochrome P450 enzymes.

Section 4.6 Pregnancy and lactation

Revised text regarding the use of Mirena during lactation.

Section 4.8 Undesirable effects

Undesirable effects have been revised according to the most recently available information and have been tabulated according to the MedDRA System Organ Class affected and the frequency of occurrence.

The following possible undesirable effects have been newly included: vulvovaginitis, pelvic inflammatory disease. endometritis.

Section 5.2 Pharmacokinetic properties

Revised information regarding the metabolism of the active substance.