Mirena 52mg Intrauterine Delivery System

  • Name:

    Mirena 52mg Intrauterine Delivery System

  • Company:
    info
  • Active Ingredients:

    Levonorgestrel

  • Legal Category:

    Product subject to medical prescription which may be renewed (B)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 06/12/18

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Summary of Product Characteristics last updated on medicines.ie: 6/12/2018

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Bayer Limited

Bayer Limited

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 6 December 2018 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions

Updated on 6 December 2018 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 6 June 2018 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

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.

Updated on 25 April 2018 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 4 - possible side effects

Updated on 4 April 2018 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 4 April 2018 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

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:

Time

Estimated in vivo release rate [µg/24 hours]

Initial

20

1 year after insertion

18

5 years after insertion

10

Average over 5 years

15

 

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

Updated on 28 March 2018 PIL

Reasons for updating

  • New PIL for new product

Updated on 28 March 2018 PIL

Reasons for updating

  • Change to section 2 - what you need to know - contraindications
  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 3 - how to take/use
  • Change to section 6 - what the product contains
  • Change to section 6 - what the product looks like and pack contents
  • Change to section 6 - date of revision

Updated on 28 April 2016 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 28 April 2016 PIL

Reasons for updating

  • Change to date of revision
  • Change to dosage and administration

Updated on 28 April 2016 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

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


Updated on 9 June 2015 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change to date of revision

Updated on 9 June 2015 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

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)

 

Breastfeeding at time of insertion

Not breastfeeding at time of insertion

Insertion ≤ 36 weeks after delivery

5.6 (95% CI 3.9-7.9; n=6047 insertions)

1.7 (95% CI 0.8-3.1; n=5927 insertions)

Insertion > 36 weeks after delivery

1.6 (95% CI 0.0-9.1; n=608 insertions)

0.7 (95% CI 0.5-1.1; n=41,910 insertions)

 

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

….

System Organ Class

Very Common

Common

Uncommon

Rare

Unknown

Reproductive system and breast disorders

Bleeding changes including increased and decreased menstrual bleeding, spotting, oligomenorrhea and amenorrhea, Vulvovaginitis*, Genital discharge*

Upper genital tract infection
Ovarian cyst
Dysmenorrhea
Breast pain**
Intra-uterine contraceptive device expelled (complete and partial)

 

Uterine perforation ***

 

 

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

Updated on 26 November 2014 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change of contraindications
  • Change to side-effects
  • Change to how the medicine works
  • Change to date of revision
  • Change to dosage and administration

Updated on 20 October 2014 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text
  • Correction of spelling/typing errors

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

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.

 

 

System Organ Class

Very Common

Common

Un-common

Rare

Unknown

Immune system disorders

 

 

 

 

Hypersensitivity including rash, urticaria and angioedema

Psychiatric disorders

 

Depressed mood/ Depression

 

 

 

 

Nervous system disorders

Headache

Migraine

 

 

 

Gastrointestinal disorders

Abdominal/ pelvic pain

Nausea

 

 

 

Skin and subcutaneous tissue disorders

 

Acne

Hirsutism

 

Alopecia

Chloasma/ skin hyper-pigmentat-ion

 

 

 

 

 

Musculosceletal, connective tissue and bone disorders

 

Back pain**

 

 

 

 

 

 

 

 

Reproductive system and breast disorders

Bleeding changes including increased and decreased menstrual bleeding, spotting, oligomenorr-hoea and amenorrhoea

Vulvovaginitis*

Genital discharge*

Upper genital tract infection

Ovarian cyst

Dysmenorrhea

Breast pain**

Intra-uterine contraceptive device expelled (complete and partial)

 

Uterine perforation

 

Investigations

 

 

 

 

Blood pressure increased

 

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.

 

 

Updated on 7 June 2012 PIL

Reasons for updating

  • Change to packaging
  • Correction of spelling/typing errors

Updated on 28 October 2011 PIL

Reasons for updating

  • Change to date of revision
  • Change due to user-testing of patient information

Updated on 1 November 2010 SmPC

Reasons for updating

  • Change to section 9 - Date of renewal of authorisation

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Date of Last renewal updated to : 28 August 2008

Updated on 24 February 2010 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.2 - Incompatibilities
  • Change to section 6.4 - Special precautions for storage
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

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 (25th to 75th 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 (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 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

Updated on 27 January 2010 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to information about pregnancy or lactation
  • Change to further information section
  • Change to date of revision
  • Change to improve clarity and readability
  • Improved electronic presentation

Updated on 25 June 2009 SmPC

Reasons for updating

  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text
  • Change to section 6.2 - Incompatibilities

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Section 6.2 Incompatibilities changed to Not applicable
Section 9: Date of last renewal: 28 August 2008
Seciton 10: Date of revision of the text May 2009

Updated on 20 June 2008 PIL

Reasons for updating

  • Change to how the medicine works

Updated on 20 June 2008 SmPC

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Changes to Section 5.1:

Addition of the following paragraph regarding the failure rate to Section 5.1:

'Mirena, when inserted according to the insertion instructions, has a failure rate of approximately 0.1% per year. The failure rate may increase in case of expulsion or perforation'  

Updated on 8 October 2007 PIL

Reasons for updating

  • Change to marketing authorisation holder
  • Change to marketing authorisation holder address
  • Change of manufacturer

Updated on 8 October 2007 SmPC

Reasons for updating

  • Change to section 8 - MA number
  • Change to section 7 - Marketing authorisation holder
  • Change to section 6.4 - Special precautions for storage

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Section 7:  The  MA was transferred to Bayer Limited. 

Section 8:  The MA number was updated following the transfer.
 
Section 6.4 (special precautions for storage) Storage conditions now state: 'store in the original package',' in order to protect from moisture and direct sunlight', has been removed.

Updated on 28 August 2007 PIL

Reasons for updating

  • Change of trade or active ingredient name
  • Change of licence holder
  • Change to date of revision

Updated on 27 August 2007 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

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”

Updated on 3 April 2007 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change of contraindications
  • Change to drug interactions
  • Change to information about pregnancy or lactation
  • Change to how the medicine works

Updated on 3 April 2007 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.9 - Overdose
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

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.

Updated on 19 July 2006 PIL

Reasons for updating

  • Change to marketing authorisation holder

Updated on 18 July 2006 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 26 October 2005 PIL

Reasons for updating

  • Improved electronic presentation

Updated on 15 August 2005 SmPC

Reasons for updating

  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 6 August 2004 PIL

Reasons for updating

  • New PIL for medicines.ie

Updated on 29 June 2004 SmPC

Reasons for updating

  • Change to section 1 - Name of medicinal product
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.5 - Nature and contents of container
  • Change to section 7 - Marketing authorisation holder
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 2 July 2003 SmPC

Reasons for updating

  • Improved electronic presentation

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 10 June 2003 SmPC

Reasons for updating

  • New SPC for medicines.ie

Legal category: Product subject to medical prescription which may be renewed (B)