Active ingredients: Levonorgestrel
MIRENA 20 micrograms / 24 hours intrauterine delivery system
Why is Mirena used? What is it for?
Mirena is a T-shaped intrauterine delivery system (IUS), which after insertion releases the hormone levonorgestrel into the uterus. The function of the T-body is to adapt the system to the shape of the uterus. The vertical arm carries a drug reservoir containing levonorgestrel. Two wires are attached to the eyelet at the lower end of the vertical arm for removal.
Mirena is used for contraception (prevention of conception), idiopathic menorrhagia (excessive blood loss during menstruation) and to protect against endometrial hyperplasia (excessive growth of the lining of the womb) during hormone replacement therapy with estrogen.
Contraindications When Mirena should not be used
General notes
Before you start using Mirena, your doctor will ask you a few questions about your personal health history and that of your family members.
About 2 in 1000 women who use Mirena correctly become pregnant within the first year.
About 7 in 1000 women who use Mirena correctly become pregnant within 5 years.
This leaflet describes various situations in which Mirena must be removed or the reliability of Mirena may decrease. In such situations it is necessary to refrain from sexual intercourse or to take additional non-hormonal contraceptive measures, such as a condom or other barrier method. Do not use the rhythm method or the basal temperature method, in fact these methods may be insufficient, as Mirena alters the monthly changes in body temperature and cervical mucus.
Mirena, like all other hormonal contraceptives, offers no protection against HIV infection (AIDS) or other sexually transmitted diseases.
Do not use Mirena under any of the following conditions:
- if you are pregnant or think you may be;
- if you have tumors dependent on progestogen hormones;
- if you currently or periodically have pelvic inflammatory disease (infection of the female reproductive organs);
- if you have an infection of the cervix (the neck of the womb);
- if you have a "lower genital tract infection;
- if you have a "womb infection" after giving birth;
- if you have had a "womb infection" after a miscarriage within the previous three months;
- if you have conditions associated with increased susceptibility to infections;
- if you have abnormal cells in the cervix;
- if you have known or suspected cancer of the uterus or cervix;
- if you have abnormal vaginal bleeding of unknown origin;
- if you have abnormalities of the cervix or uterus, including fibroids that deform the uterine cavity;
- if you have acute liver disease or liver cancer;
- if you are hypersensitive (allergic) to levonorgestrel or any of the other ingredients of Mirena;
Precautions for use What you need to know before taking Mirena
Using Mirena together with an estrogen for hormone replacement therapy.
In the event that Mirena is used together with an estrogen for hormone replacement therapy, the information regarding the safety of estrogen applies in addition and should be followed.
Consult a specialist, who will decide whether to continue using Mirena or to remove the device, if it is present, or appears for the first time while using Mirena, one of the following conditions:
- migraine, asymmetrical vision loss or other symptoms that may be signs of transient cerebral ischaemia (temporary interruption of the blood supply to the brain);
- exceptionally severe headache;
- jaundice (yellowing of the skin, eyes and / or nails);
- marked increase in blood pressure;
- severe arterial disease such as stroke or myocardial infarction.
- acute venous thromboembolism.
Mirena should be used with caution in women with congenital heart disease or heart valve disease at risk for bacterial endocarditis. These patients should undergo antibiotic prophylaxis upon insertion and removal of the intrauterine device.
In diabetic patients using Mirena, blood glucose should be monitored. However, it is generally not necessary to change antidiabetic therapy while using Mirena.
Irregular bleeding may mask some symptoms and signs of polyps or cancer of the endometrium and in these cases the necessary diagnostic measures should be considered.
Mirena is not the method of choice for nulliparous young women, nor for postmenopausal women with advanced uterine atrophy.
Medical examination / consultation
Pre-insertion examination may include pelvic examination, PAP test, breast examination, and other tests, for example for infections, including sexually transmitted diseases, if necessary. A gynecological examination should be performed to determine the position and size of the uterus. Mirena is not suitable as a post-coital contraceptive (used after intercourse).
Infections
The insertion tube contributes to the protection of Mirena from microbial contamination during the application maneuver and the inserter has been designed to minimize the risk of infection. However, there is an increased risk of pelvic infection immediately and in the first month. after the insertion of copper intrauterine devices in women. Pelvic infections in women using intrauterine devices (IUDs) are often associated with sexually transmitted diseases. The risk of infection is increased if the woman or her partner have unprotected sex. Pelvic infections should be treated without delay. Pelvic infections can impair fertility and increase the risk of ectopic pregnancy (pregnancy outside of pregnancy). uterus). In extremely rare cases, serious infections or sepsis can occur soon after insertion of the intrauterine device (serious infections can be fatal). The device must be removed in case of recurrent episodes of pelvic infection or endometritis or in the case of an infection acute severe that does not respond to treatment within a few days.
See a doctor immediately if you have persistent lower abdominal pain, fever, pain during intercourse or abnormal bleeding.
Breast cancer
A meta-analysis that considered data from 54 epidemiological studies showed a slightly increased relative risk (RR = 1.24) of breast cancer diagnosed in women on combined oral contraceptives (COCs), mainly for women who use estrogen-progestogen preparations. The excess risk gradually disappears over the 10 years following the discontinuation of the COCs. Because breast cancer is rare in women under the age of 40, the extra number of breast cancers diagnosed in women who use or have recently used COCs is small in relation to the overall risk of breast cancer. The risk of breast cancer in women using progestogen-only contraceptives is likely to be similar to that associated with combined oral contraceptives (COCs). However, for progestogen-only preparations, the evidence is based on a much smaller user population and is therefore less conclusive than for COCs.
Risk in postmenopausal women
The risk of breast cancer is increased in postmenopausal women using systemic (e.g. oral or transdermal) hormone replacement therapy (HRT). This risk is higher with combined estrogen-progestogen HRT than with estrogen-only HRT. The information relating to the product with estrogen component should be consulted for further information.
Expulsion
Muscle contractions of the uterus during menstruation can sometimes displace the device from its seat or cause it to be expelled. Possible symptoms are pain and abnormal bleeding. If the device is incorrectly positioned, its effectiveness is reduced. If the device is expelled, the protection against pregnancy is lost. It is recommended to check the wires with your fingers, for example when taking a shower. expulsion or no longer feel the threads, must avoid intercourse or use another contraceptive and consult your doctor. Since Mirena induces a decrease in menstrual flow, its increase may indicate expulsion.
Uterine perforations
Mirena can penetrate or puncture the wall of the uterus, resulting in decreased protection against pregnancy. Such perforation is more likely to occur during insertion, although it may not be detected until some time later. In these cases the device is not effective and must be removed as soon as possible. Surgery may be required to remove Mirena. The risk of uterine perforation increases during breastfeeding and in women who have given birth up to 36 weeks before insertion, and may increase in women with a fixed retroverted (bowel-oriented) uterus. If you suspect perforation, seek advice immediately. to the doctor and remind him that you have Mirena inserted especially if it is not the person who inserted it.
Possible signs and symptoms of uterine perforation may include:
- severe pain (similar to menstrual cramps) or more pain than expected
- very heavy bleeding (after insertion)
- pain and bleeding that persist for more than a few weeks
- sudden change in the menstrual cycle
- pain during sexual intercourse
- you may no longer feel Mirena's threads (see section 3 "How to use Mirena - How can I feel that Mirena is positioned correctly?"
Ectopic pregnancy
It is very rare for Mirena to become pregnant while using Mirena.
In users of Mirena, the risk of an ectopic pregnancy, although low in absolute terms, is relatively increased.
The absolute risk of ectopic pregnancy in users of Mirena is low due to the reduced overall probability of pregnancy in users of Mirena compared to non-users of any contraceptive. The absolute ectopic pregnancy rate with Mirena is approximately 0.1% per year, compared with 0.3-0.5% per year in women who are not using any contraceptives. However, if a woman becomes pregnant with Mirena in situ, the relative probability that this is an ectopic pregnancy is increased.
A woman who has previously had an ectopic pregnancy, has been operated on the fallopian tubes, or has had a "pelvic infection" is at a higher risk. Ectopic pregnancy is a serious condition that requires immediate medical attention. The following symptoms may indicate the presence of an ectopic pregnancy; contact your doctor immediately:
- if menstrual periods have stopped and persistent bleeding or pain occurs;
- if you have pain in your lower abdomen;
- if you have the normal signs of pregnancy but also have bleeding and dizziness.
Weakness
Some women feel dizzy after inserting Mirena. This is a normal physical response. Your doctor will tell you to rest for a while.
Enlarged ovarian follicles (cells that surround a maturing egg in the ovary)
Since the contraceptive action of Mirena is mainly due to a local effect, ovulatory cycles with follicle rupture generally occur in women of childbearing age. Sometimes follicle degeneration is delayed and follicle development continues. Most of these follicles it has no symptoms, although some may be accompanied by pelvic pain or pain during intercourse.These follicular enlargements may require medical attention, but usually disappear spontaneously.
Interactions Which drugs or foods can change the effect of Mirena
Tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. The metabolism of levonorgestrel may be enhanced by concomitant use of other medicines, such as epilepsy medicines (eg phenobarbital, phenytoin, carbamazepine) and some antibiotics (eg rifampicin, rifabutin, nevirapine, efavirenz). As the mechanism of action of Mirena is mainly local, the influence of these drugs on the contraceptive efficacy of Mirena is not believed to be of particular importance.
Warnings It is important to know that:
Pregnancy
Mirena should not be used if an existing pregnancy is known or suspected.
It is very rare for a woman to become pregnant if Mirena is positioned correctly. However, if Mirena is expelled, she is no longer protected and must use another method of contraception until she sees her doctor.
Some women may not menstruate while using Mirena. Missing menstruation is not necessarily a sign of pregnancy. If you are not menstruating and have other pregnancy symptoms (eg nausea, fatigue, breast tightness) you should contact your doctor for a visit and take a pregnancy test.
If she becomes pregnant with Mirena inserted, the device must be removed as soon as possible. Leaving Mirena inserted during pregnancy increases the risk of miscarriage, infection, or premature birth. Mirena's hormone is released in the uterus. This means that the fetus is locally exposed to a relatively high concentration of the hormone, although the amount of hormone received through the placenta is low. are evidence of neonatal abnormalities caused by the use of Mirena in cases where the pregnancy was carried to term with Mirena inserted.
Feeding time
Mirena can be used during breastfeeding. Levonorgestrel has been found in small amounts in the milk of breastfeeding women (0.1% of the dose is transferred to the newborn). There appears to be no harmful effect on growth and development. of the baby when Mirena is used 6 weeks after delivery.
The progestogen-only methods do not appear to affect the quantity or quality of breast milk. Ask your doctor or pharmacist for advice before taking any medicine if you are pregnant or breastfeeding.
Fertility
After the removal of Mirena, the woman returns to her normal fertility condition.
Driving and using machines
No studies on the effects related to the ability to drive and use machines have been performed. Important information about some of the ingredients of Mirena The T-body of Mirena contains barium sulfate, which makes it visible on X-rays.
Dose, Method and Time of Administration How to use Mirena: Posology
How effective is Mirena?
In contraception, Mirena is as effective as the most effective copper device available today. Clinical studies have shown that about two pregnancies occurred in every 1000 women who used Mirena in the first year. This percentage may increase in case of expulsion or perforation (see section 2 "Medical examination / consultation")
In the treatment of idiopathic menorrhagia, Mirena causes a marked reduction in menstrual bleeding as early as three months. Some users have no menstrual periods at all.
When should Mirena be inserted?
Insertion and removal
Mirena can be inserted within seven days of the onset of menstruation. The device can also be inserted immediately after an abortion in the first trimester of pregnancy, as long as no genital infections are present. After delivery because the risk of perforation may increase, insertion must be postponed until complete involution of the uterus (see paragraph "Uterine perforations"). In these cases, the possibility of postponing the insertion to 12 weeks after delivery should be considered and in any case not to perform it before six weeks (see paragraph 2 "Before using Mirena - Perforation"). Mirena can be replaced with a new system at any point in the cycle. When Mirena is used to protect the lining of the uterus during estrogen replacement therapy, it can be inserted at any time in women with amenorrhea (women who do not have a monthly period), or during the last day of menstruation or at the end of bleeding. suspension. Mirena must be inserted by a specialist who has experience in inserting Mirena.
How does Mirena fit in?
After a gynecological examination, an instrument called a speculum is inserted into the vagina, and the cervix is cleaned with an antiseptic solution. The device is then inserted into the uterus with a thin, flexible plastic tube (the inserter). If deemed appropriate, a "local anesthesia to the cervix can be performed before insertion". Some women may feel pain and dizziness after insertion. If these do not go into the rest position within half an hour, the device may not be positioned correctly. An examination should be performed and, if necessary, the device should be removed.
When should I contact the doctor?
You should have your device checked 4-12 weeks after insertion and thereafter at regular intervals at least annually. The doctor can determine the frequency and type of checks necessary in your particular case. Also, you should contact your doctor if any of the following occur:
- does not feel the threads in the vagina;
- feels the final part of the device;
- think you are pregnant;
- have persistent abdominal pain, fever, unusual vaginal discharge;
- you or your partner experience pain or discomfort during sexual intercourse;
- you experience sudden changes in your menstrual cycles (for example, if you have little or no menstruation and start to have persistent bleeding or pain or start to have heavy bleeding);
- if you have other medical problems, such as intense and recurring migraines or headaches, sudden vision problems, jaundice or high blood pressure;
- you have been diagnosed with any of the conditions mentioned in section 2 'Before using Mirena'.
Remind your doctor that you have Mirena inserted, especially if it is not the person who inserted it.
How long can I use Mirena?
Mirena is effective for five years, after which the device must be removed. If desired, a new device can be inserted when the old one is removed.
What if you want to have a baby or want Mirena removed for another reason?
The device can be easily removed by the doctor at any time, after which pregnancy is possible. Removal is usually a painless procedure. After removal of Mirena, fertility returns to normal. If pregnancy is not desired, Mirena should not be removed after the 7th day of the menstrual cycle, unless contraception is ensured by other methods (e.g. condoms) for at least 7 days prior to removal. If the woman is not menstruating, she should use a barrier method of contraception for 7 days prior to removal until menstruation returns. A new Mirena can also be inserted immediately after removal, in which case no additional protection is required.
Can I become pregnant after stopping the use of Mirena? Yes. After it has been removed, Mirena does not interfere with your normal fertility. You can become pregnant during the first menstrual cycle following removal of Mirena.
Can Mirena Affect Your Period?
Mirena affects the menstrual cycle: she may have spotting (a small loss of blood), shorter or longer periods, shorter or heavier periods, or not having a period. Many women have frequent spotting or light bleeding in addition to their menstrual cycles for the first 3-6 months after the insertion of Mirena. Some women may have heavy or prolonged bleeding during this period. Tell your doctor, especially if these symptoms persist. In general, there is likely to be a gradual reduction in the number of bleeding days and the amount of blood lost each month. In some women, the period stops altogether. As the amount of menstrual bleeding is usually reduced with use. of Mirena, most women have increased hemoglobin values in their blood.
The cycle returns to normal when the device is removed.
Is it abnormal not to have menstrual periods?
Not when using Mirena. The effect of the hormone on the mucosa of the uterus means that the cycle can be interrupted. The monthly thickening of the mucosa does not occur and, consequently, there is nothing to eliminate with the menstruation. This does not necessarily mean that she is in menopause or pregnant. His hormone levels remain normal.
In fact, not having menstrual periods can be a great advantage for a woman's health.
How do i know if i am pregnant?
Pregnancy is unlikely in women using Mirena, even if they don't have periods. If she does not have a period for six weeks and is worried, she should consider taking a pregnancy test. If this is negative, there is no need for other tests unless she has other signs of pregnancy, such as nausea and pregnancy. morning vomiting, fatigue or breast tenderness.
Can Mirena cause pain or discomfort?
Some women experience pain (such as menstrual cramps) in the first few weeks after insertion. If you have severe pain or if the pain continues for more than three weeks after you have Mirena inserted, you should go back to your doctor.
Does Mirena interfere with sexual intercourse?
Neither you nor your partner should feel the device during intercourse. If not, avoid having intercourse until your doctor has checked that the device is still in the correct position.
How long should I wait before having sex after insertion?
It is best to wait approximately 24 hours after inserting Mirena to rest your body before having intercourse. However, soon after inserting Mirena begins to prevent pregnancy.
Can I use tampons (tampons)?
The use of external pads is recommended. If you use internal pads, you must change them very carefully so as not to pull the threads of Mirena.
What happens if Mirena goes out alone?
It is rare but possible for Mirena to be expelled during menstruation without you noticing. An unusual increase in flow during menstruation may mean that Mirena has been expelled from the vagina. It is also possible that part of Mirena has been expelled from the womb (she or your partner may notice this during intercourse). If Mirena is fully or partially expelled, she is no longer protected from pregnancy.
How can I feel that Mirena is positioned correctly?
You can check yourself if the wires are in place. She must gently insert a finger into the vagina and feel the threads at the end of the vagina near the opening of the uterus (cervix). Don't pull the strings, as it may accidentally let Mirena out. If you do not feel the threads it may mean that an "expulsion or perforation has occurred. In this case, you should avoid sexual intercourse or use a barrier method of contraception (such as a condom) and contact your doctor."
Overdose What to do if you have taken too much Mirena
Not relevant.
Side Effects What are the side effects of Mirena
Like all medicines, Mirena can cause side effects, although not everybody gets them. Below are the side effects that may occur when Mirena is used for contraception (prevention of conception) and idiopathic menorrhagia (excessive blood loss during menstruation).
Possible side effects associated with the use of Mirena for protection from endometrial hyperplasia (overgrowth of the lining of the womb) during hormone replacement therapy have been observed with a similar frequency, except where noted with a note.
Very common: may affect 10 or more in 100 patients:
- Headache Abdominal / pelvic pain
- Changes in bleeding, including increased and decreased menstrual bleeding, spotting, oligomenorrhea (infrequent menstruation) and amenorrhea (absence of menstruation)
- Vulvovaginitis * (inflammation of the external genitalia or vagina)
- Genital loss *
Common: may affect 1 to 10 in 100 patients:
- Depressed mood / depression
- Migraine
- Nausea
- Acne
- Hirsutism (excessive hair growth)
- Back pain§ .
- Upper genital tract infection
- Ovarian cysts
- Dysmenorrhea (painful menstruation)
- Breast pain§
- Expulsion of the intrauterine contraceptive device (complete or partial)
Uncommon: may affect 1 to 10 in 1,000 patients:
- Alopecia (hair loss)
- Chloasma / skin pigmentation
Rare: may affect 1 to 10 users in 10,000:
- Uterine perforation **.
Frequency not known:
- Hypersensitivity (allergic reaction) including skin rash, hives and angioedema (characterized by sudden swelling e.g. of the eyes, mouth, throat)
- Increased blood pressure
* Studies in protection from "endometrial hyperplasia:" common "
§ Studies in protection from "endometrial hyperplasia:" very common "** The risk of perforation is higher (between 1 and 10 per 1000 patients) in women who are breastfeeding at the time of insertion of Mirena and when Mirena has been inserted up to at 36 weeks postpartum.
Description of particular adverse reactions:
Removal threads can be felt by the partner during sexual intercourse. When a woman becomes pregnant with Mirena in situ, the relative risk of ectopic pregnancy is increased. The risk of breast cancer when Mirena is used in the prevention of endometrial hyperplasia during estrogen replacement therapy is not known.
Breast cancer has been reported (frequency not known, see section Take special care with Mirena).
The following possible side effects have been reported in association with the insertion or removal of Mirena:
Procedural pain, procedural bleeding, vaso-vagal reaction with dizziness or syncope (fainting). The procedure can trigger a seizure in epileptic patients.
Cases of sepsis (very serious systemic infection which can be fatal) have been reported following the insertion of intrauterine devices.
The risk of breast cancer when Mirena is used in the indication protection from endometrial hyperplasia (overgrowth of the lining of the womb) during hormone replacement therapy is not known.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep out of the reach and sight of children.
No special storage precautions.
Do not use Mirena after the expiry date which is stated on the pack. The expiry date refers to the last day of the month.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
What Mirena contains
- The active ingredient is levonorgestrel 52 mg.
- The other ingredients are polydimethylsiloxane elastomer, polydimethylsiloxane tubing, T-body and polyethylene thread.
What Mirena looks like and contents of the pack
Packaging: a sterile intrauterine system for intrauterine use. If you have any further questions, consult your doctor or pharmacist.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
MIRENA 20 mcg / 24 HOURS INTRAUTERINE RELEASE SYSTEM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each intrauterine delivery system contains:
52 mg of levonorgestrel, and has an initial levonorgestrel release of 20 mcg / 24h.
For the full list of excipients, see section 6.1
03.0 PHARMACEUTICAL FORM
Intrauterine delivery system.
The levonorgestrel intrauterine delivery system consists of a white or almost white drug core, covered by an opaque membrane, mounted on the vertical arm of a T-body. The T-body has an eyelet at one "end of the vertical arm and two horizontal arms at the other end. The removal threads are attached to the eyelet. The vertical arm of the intrauterine system is contained in the distal part of the inserter tube. Both the intrauterine system and the inserter are essentially free from visible impurities.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Contraception, idiopathic menorrhagia, prevention of endometrial hyperplasia during estrogen replacement therapy.
04.2 Posology and method of administration
Mirena is inserted into the uterine cavity and is effective for a period of 5 years. The initial release of levonorgestrel in alive it is about 20 mcg / 24h and reduces to 10 mcg / 24h after 5 years. The average release of levonorgestrel over 5 years is approximately 14 mcg / 24 h.
In women on HRT, Mirena can be used in combination with estrogen-only oral or transdermal preparations.
Mirena, when inserted correctly according to the instructions, has a failure rate of approximately 0.2% at one year and a cumulative failure rate of approximately 0.7% at 5 years.
Insertion and removal / replacement
In women of childbearing age, the insertion of Mirena into the uterine cavity must take place within 7 days of the start of menstruation. Mirena can be replaced with a new device at any point in the cycle. The device can also be inserted immediately after an abortion in the first trimester of pregnancy.
After delivery, the insertion must be postponed until the uterus is completely involution and in any case not earlier than 6 weeks after delivery. If uterus involution is delayed, the possibility of postponing insertion to 12 weeks after delivery should be considered.In case of difficult insertion and / or with particular pain or bleeding during or after insertion, a gynecological examination and an ultrasound should be performed immediately to rule out perforation. The gynecological examination alone (including the control of the threads) may not be sufficient to exclude partial perforation.
In the prevention of endometrial hyperplasia during estrogen replacement therapy, Mirena can be inserted at any time if the woman is amenorrhoeic, or in the last days of menstruation or withdrawal bleeding.
It is strongly recommended that Mirena be placed only by experienced doctors (midwives / healthcare professionals (as appropriate)) who have experience with Mirena insertion and / or who are properly trained.
Mirena is removed by gently pulling the threads with dressing forceps. If the wires are not visible and the device is in the uterine cavity, it can be removed using a narrow-opening ring forceps. Cervical canal dilation or other surgical maneuver may be required.
The device must be removed after a period of five years. If you want to continue using it, it can be immediately replaced with a new one.
In women of childbearing age, if you want to avoid pregnancy, you must remove the device during menstruation, provided there is a menstrual cycle. If the device is removed in the middle of the cycle and the woman has had sexual intercourse during the week prior to removal, she may become pregnant unless a new device is inserted immediately.
After removing Mirena, you need to check that the device is intact. In individual cases, during difficult removals, it has been reported that the cylinder containing the hormone has slipped over the horizontal arms, hiding them inside. Once the integrity of the device has been ascertained, this situation requires no further intervention. The protuberances of the horizontal arms usually prevent the complete detachment of the cylinder from the T-body.
Instructions for use and handling
Mirena is supplied in a sterile package which must not be opened until the moment of insertion. The product must be handled under aseptic conditions. If the sterile package appears damaged, the product must be discarded.
Additional information for particular categories of patients
Children and adolescents
The safety and efficacy of Mirena have been established in women of reproductive age. There is no indication for the use of Mirena before menarche.
Elderly patients
Mirena has not been studied in women over the age of 65.
Patients with impaired hepatic function
Mirena is contraindicated in women with acute liver disease or liver cancer (see section 4.3).
Patients with impaired renal function
Mirena has not been studied in women with impaired renal function.
04.3 Contraindications
• Known or suspected pregnancy;
• progestogen-dependent tumors, for example breast cancer;
• current or recurrent pelvic inflammatory disease;
• cervicitis;
• lower genital tract infections;
• postpartum endometritis;
• septic abortion within the previous three months;
• conditions associated with an "increased susceptibility to infections;
• cervical dysplasia;
• malignant tumors of the uterus or cervix;
• undiagnosed abnormal uterine bleeding;
• congenital or acquired uterine abnormalities including fibroids that deform the uterine cavity;
• acute liver disease or liver cancer;
• hypersensitivity to the active substance or to any of the excipients;
04.4 Special warnings and appropriate precautions for use
Using Mirena together with an estrogen for hormone replacement therapy
In the event that Mirena is used together with an estrogen for hormone replacement therapy, the information regarding the safety of estrogen applies in addition and should be followed.
Mirena should only be used with caution after specialist advice, or its removal should be considered, if any of the following conditions are present or occur for the first time:
• migraine, focal migraine with asymmetrical vision loss or other symptoms suggestive of transient cerebral ischaemia,
• exceptionally severe headache,
• jaundice,
• marked increase in blood pressure,
• severe arterial diseases such as stroke or myocardial infarction,
• acute venous thromboembolism.
Mirena should be used with caution in women with congenital heart disease or heart valve disease at risk of bacterial endocarditis. These patients should undergo antibiotic prophylaxis upon insertion and removal of the intrauterine device.
Even low doses of levonorgestrel can affect glucose tolerance. It is therefore advisable to monitor blood glucose in diabetic patients using Mirena. However, it is generally not necessary to change the treatment regimen in diabetic patients using Mirena.
Irregular bleeding can mask the symptoms and signs of a polyposis or endometrial tumor and in this case it will be necessary to consider all measures to clarify the diagnosis.
Mirena is not the first choice method for nulliparous young women, nor for postmenopausal women with advanced uterine atrophy.
Medical examination / consultation
Prior to insertion, the woman should be informed of the efficacy, risks including the signs and symptoms of these risks as described in the Package Leaflet and the side effects of Mirena. A complete gynecological examination including pelvic examination, breast examination and cervical smear should be performed. An ongoing pregnancy and sexually transmitted diseases must be ruled out and any infections of the genital organs must be adequately treated until recovery. The position of the uterus and the size of the uterine cavity must be determined. The correct positioning of Mirena in the fundus of the uterus is of particular importance to ensure uniform exposure of the endometrium to the progestogen, prevent expulsion of the device and optimize its "effectiveness. Therefore, the instructions for insertion must be followed carefully. Since the insertion technique is different from other intrauterine systems, training in proper insertion technique is essential. Insertion and removal of the device may involve a bit. pain and bleeding Fainting episodes due to a vaso-vagal reaction or convulsions may occur in epileptic patients.
The woman will have to be seen again 4-12 weeks after insertion and, subsequently, once a year or more frequently where clinically indicated.
Mirena is not suitable for use as a post-coital method of contraception.
Since irregular bleeding or spotting is common in the first months after insertion of Mirena, any endometrial pathology must be ruled out prior to insertion.
If in women who are already users of Mirena for contraceptive purposes and who want to continue its use, irregular vaginal bleeding occurs after the start of estrogen replacement therapy, the presence of endometrial pathologies must be excluded.
Even if irregular bleeding occurs during prolonged treatment, a careful diagnostic examination is necessary.
Oligo / amenorrhea
Oligomenorrhea and amenorrhea develop gradually in 57% and 16% of women of childbearing age, respectively. The possibility of pregnancy should be considered if the period does not appear within 6 weeks of the onset of the previous one. It is not necessary to repeat a pregnancy test in amenorrhoeic women unless other signs of pregnancy are present.
When Mirena is used in combination with continuous estrogen replacement therapy, amenorrhea gradually develops in most women during the first year after insertion.
Pelvic infection
The insertion tube contributes to the protection of Mirena from microbial contamination during the application maneuver and the inserter has been designed to minimize the risk of infections. In users of copper intrauterine devices, the incidence of pelvic infections is higher in the former. month after insertion and decreases over time.
Some studies indicate a lower incidence of pelvic infections in women using Mirena than that seen with copper intrauterine devices.
A known risk factor for pelvic inflammatory disease is unprotected sexual intercourse with multiple partners. Pelvic infection can have serious consequences and can compromise fertility and increase the risk of ectopic pregnancy.
As with other gynecological or surgical procedures and although it is extremely rare, severe infection or sepsis (including group A streptococcal sepsis) can occur following the insertion of the IUD.
Mirena should be removed if you have recurrent episodes of endometritis or pelvic infections or if you have a severe acute infection that does not respond to treatment within a few days.
Bacteriological examination and careful monitoring are recommended even when there are discontinuous symptoms indicative of infection.
Expulsion
Symptoms of partial or complete expulsion of an intrauterine device may include bleeding or pain. However, the device may be expelled from the uterine cavity without the woman noticing, leading to a loss of contraceptive protection. "Effectiveness of Mirena. Since Mirena induces a decrease in menstrual flow, the increase in menstrual flow may be indicative of a" expulsion.
If the device is not in the correct position, it must be removed and a new one can be inserted.
The woman should be advised on how to check for the presence of Mirena's threads.
Uterine perforations
Cases of perforation or penetration of the body of the uterus or cervix by an intrauterine device occur predominantly during insertion, although they may not be detected until some time later, and may decrease the effectiveness of Mirena. the device must be removed; surgery may be required.
In a large prospective comparative non-interventional cohort study conducted in users of intrauterine devices (IUDs) (N = 61,448 women), the incidence of perforation was 1.3 (95% CI: 1.1-1.6). every 1000 insertions in the entire study cohort; 1.4 (95% CI: 1.1-1.8) for every 1000 insertions in the Mirena cohort and 1.1 (95% CI: 0.7-1.6) for every 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 delivery were associated with an increased risk of perforation (see table 1). These risk factors were independent of IUD type. inserted.
Table 1: Incidence of perforation per 1000 insertions for the entire cohort study, stratified by lactation and insertion time from delivery (women who have given birth)
The risk of perforation may be increased in women with a fixed retroverted uterus.
Post-insertion review should follow the instructions given in the "Medical Exam / Consultation" section which can be adapted as clinically indicated in women with risk factors for perforation.
Breast cancer
A meta-analysis that considered data from 54 epidemiological studies demonstrated a slightly increased relative risk (RR = 1.24) of breast cancer diagnosed in women on combined oral contraceptives (COCs), mainly for women who use estrogen-progestogen preparations. The excess risk gradually disappears over the 10 years following the discontinuation of the COCs. Because breast cancer is rare in women under the age of 40, the extra number of breast cancers diagnosed in women who use or have recently used COCs is small in relation to the overall risk of breast cancer. The risk of breast cancer in women using progestogen-only contraceptives is likely to be similar to that associated with combined oral contraceptives (COCs). However, for progestogen-only preparations, the evidence is based on a much smaller user population and is therefore less conclusive than for COCs.
Risk in postmenopausal women The risk of breast cancer is increased in postmenopausal women using systemic (e.g. oral or transdermal) hormone replacement therapy (HRT). This risk is higher with combined estrogen-progestogen HRT than with estrogen-only HRT. The information relating to the product with estrogen component should be consulted for further information.
Ectopic pregnancy
Women with a history of ectopic pregnancy, tubal surgery, or pelvic infection are at an increased risk of ectopic pregnancy. The possibility of an ectopic pregnancy should be considered in case of lower abdominal pain, especially in conjunction with the cessation of menstruation or the appearance of bleeding in a previously amenorrhoeic woman.
The absolute risk of ectopic pregnancy in users of Mirena is low due to the reduced overall probability of pregnancy in users of Mirena compared to non-users of any contraceptive. In a large prospective comparative non-interventional cohort study with an observation period of 1 year, the absolute ectopic pregnancy rate with Mirena was 0.02%. In clinical studies, the absolute ectopic pregnancy rate with Mirena was approximately 0.1% per year compared with 0.3-0.5% per year in women who are not using any contraceptives. However, if a woman becomes pregnant with Mirena in situ, the relative probability that this is an ectopic pregnancy is increased.
Failure to identify the wires
If the removal threads are not visible in the cervix during follow-up examinations, an ongoing pregnancy should be excluded. The threads may have been drawn into the uterus or cervical canal and may reappear in the next menstrual period. If pregnancy has been ruled out, the threads can generally be identified by gently probing with a suitable instrument. If the wires are not identifiable, the possibility of ejection or perforation should be considered. Ultrasound can be used to check for correct positioning of the device. If ultrasound is not available or unsuccessful, an x-ray can be taken to locate Mirena.
Enlarged follicles
Since the contraceptive action of Mirena is mainly due to a local effect, ovulatory cycles with follicle rupture generally occur in women of childbearing age. Sometimes follicular atresia is delayed and follicle growth continues. These enlarged follicles cannot be clinically distinct from ovarian cysts Ovarian cysts have been reported as an adverse reaction in approximately 7% of women using Mirena In most cases these follicles are asymptomatic, although in some cases they may be associated with pelvic pain or dyspareunia.
In most cases, ovarian cysts disappear spontaneously in 2-3 months. If this does not occur, ultrasound monitoring and any other diagnostic and therapeutic measures are recommended. Surgery may rarely be required.
04.5 Interactions with other medicinal products and other forms of interaction
The metabolism of progestogens may be enhanced by the concomitant use of substances capable of inducing drug-metabolizing enzymes, in particular cytochrome P450 enzymes, such as anticonvulsants (eg phenobarbital, phenytoin, carbamazepine) and anti-infectives (eg rifampin, rifabutin, nevirapine, efavirenz).
The influence of these drugs on Mirena's contraceptive efficacy is not known, but it is not believed to be of particular importance given Mirena's local mechanism of action.
04.6 Pregnancy and lactation
Pregnancy
The use of Mirena is contraindicated in cases of confirmed or suspected pregnancy (see section 4.3 Contraindications).
If a woman becomes pregnant with Mirena in situremoval of the device is recommended as an intrauterine contraceptive left in place may increase the risk of miscarriage or premature birth. Removal of Mirena, as well as uterine exploration, can lead to miscarriage. If the intrauterine device cannot be removed, termination of pregnancy should be considered.
If a woman wishes to continue her pregnancy and the device cannot be removed, she should be informed about the risks and possible consequences of a premature birth. In this case the pregnancy must be closely monitored. In addition, an ectopic pregnancy should be excluded and the woman should be advised of the need to report all symptoms indicative of pregnancy complications, such as cramping abdominal pain with fever.
The possibility of virilizing effects on the fetus due to intrauterine administration and local exposure to the hormone should be considered. Clinical experience regarding the outcome of pregnancies with Mirena in situ is limited due to its high contraceptive efficacy. However, the woman should be informed that, to date, there is no evidence of congenital anomalies in women using Mirena who have completed a pregnancy.
Feeding time
Levonorgestrel daily dose and plasma concentrations are low with Mirena compared to other hormonal contraceptives, although levonorgestrel has been identified in breast milk.
Approximately 0.1% of the levonorgestrel dose is transferred to the infant during breastfeeding. However, it is unlikely that there is a risk to the infant with the dose delivered by Mirena when the device is inserted into the uterine cavity.
There does not appear to be any harmful effects on the growth or development of the baby when Mirena is started 6 weeks after delivery.
Progestogen-only contraceptive methods do not appear to affect the quantity or quality of breast milk.
Uterine bleeding has been reported rarely in breastfeeding women using Mirena.
Fertility
After the removal of Mirena, the woman returns to her normal fertility condition.
04.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
04.8 Undesirable effects
Summary of the safety profile
After the insertion of Mirena, the bleeding profile changes in most women. During the first 90 days following the postmenstrual insertion of Mirena, 22% of women report prolonged bleeding and 67% irregular bleeding. These percentages drop to 3% and 19% respectively at the end of the first year of use. At the same time, amenorrhea and oligomenorrhea, present respectively in 0% and 11% of women in the first 90 days, affect 16% and 57% of women at the end of the first year of use.
When Mirena is used in combination with estrogen replacement therapy, amenorrhea develops gradually over the first year in most women.
In fertile women, the average number of spotting days per month gradually decreases from 9 to 4 days during the first 6 months of use. The percentage of women with prolonged bleeding (more than 8 days) decreases from 20% to 3% during the first 6 months of use. first 3 months of use. In clinical studies during the first year of use, 17% of women have amenorrhea lasting at least 3 months.
Side effects are most common during the first few months after insertion, and lessen with prolonged use. In addition to the adverse events listed in section 4.4, the following undesirable effects have been reported with the use of Mirena.
Adverse Ration List Table
The frequency of adverse reactions observed with the use of Mirena is presented in the following table. Frequency categories are defined according to the following convention: very common (≥1 / 10); common (≥1 / 100, heavy periods, having involved 5,091 women and 12,101 woman-years
Adverse reactions in clinical trials in the prevention indication of endometrial hyperplasia during estrogen replacement therapy (involving 514 women and 1218.9 woman-years) were observed with a similar frequency, except where noted with a note.
The most appropriate MedDRA term is used to describe a particular reaction, its synonyms and related conditions.
* Studies on the prevention of "endometrial hyperplasia:" common "
** Studies on the prevention of "endometrial hyperplasia:" very common "
*** This frequency is based on clinical studies that exclude breastfeeding women. In a large prospective comparative non-interventional cohort study conducted in IUD users, the frequency of perforation in women who were breastfeeding or had insertion up to 36 weeks after delivery was "uncommon" (see section "Special warnings and precautions for use ")
Infections and infestations
Cases of sepsis (including group A streptococcal sepsis) have been reported following the insertion of intrauterine devices (see section 4.4 Special warnings and precautions for use).
Description of particular adverse reactions
• Pregnancy, puerperium and perinatal conditions:
When a woman becomes pregnant with Mirena in situ, the relative risk of ectopic pregnancy is increased.
• Diseases of the reproductive system:
The risk of breast cancer when Mirena is used in the prevention of endometrial hyperplasia during estrogen replacement therapy is not known.
Cases of breast cancer have been reported (frequency not known, see section 4.4 Special warnings and precautions for use).
Removal threads can be felt by the partner during sexual intercourse.
The following adverse reactions have been reported in association with the insertion or removal of Mirena:
Procedure pain, procedural bleeding, insertion-related vaso-vagal reaction with dizziness or syncope. The procedure may trigger a seizure in epileptic patients.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
Not relevant.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other gynecologicals, intrauterine contraceptives.
ATC code: G02BA03
Pharmacotherapeutic group: Plastic intrauterine system with progestogen.
Levonorgestrel is a progestin with anti-estrogenic activity with various uses in gynecology: as a progestin component in oral contraceptives and hormone replacement therapies; in contraception, as a single component of minipills and in subcutaneous implants. Levonorgestrel can also be administered directly into the uterine cavity via an intrauterine delivery device. With this method, a very low daily dosage can be used, as the hormone is released directly into the target organ.
Mirena exerts a mainly local progestin effect in the uterine cavity. The high concentrations of levonorgestrel in the endometrium inhibit the endometrial synthesis of estrogen and progesterone receptors, making the endometrium insensitive to circulating estradiol, with a marked antiproliferative action. During the use of Mirena, morphological changes of the endometrium have been observed. and a weak local foreign body reaction. Thickening of the cervical mucus prevents the passage of spermatozoa into the cervical canal. Inside the uterus and tubes the motility and function of the spermatozoa are inhibited, preventing conception. In some women, ovulation is suppressed.
The contraceptive efficacy of Mirena was studied in 5 main clinical studies with 3330 women who used Mirena. The failure rate (Pearl Index) was approximately 0.2% at one year, with a cumulative failure rate of approximately 0.7% at 5 years. The failure rate also includes pregnancies due to unrecognized expulsions and perforations. A "similar contraceptive efficacy was observed in a large post-marketing study with more than 17,000 women using Mirena. Since the use of Mirena does not require the user to comply with a daily intake, the pregnancy rate under "typical use" conditions is similar to that observed in controlled clinical trials ("perfect use").
The use of Mirena does not affect future fertility. About 80% of women wishing to become pregnant conceive within 12 months of removing the device.
The menstrual profile derives from the direct action of levonorgestrel on the endometrium and does not reflect the ovarian cycle. In women with different menstrual profiles there was no evident difference in follicular development, ovulation and the production of estradiol and progesterone. During the process of inactivation of the proliferation of the endometrium there may be an initial increase in spotting episodes in the first months after insertion of the device. Subsequently, marked suppression of the endometrium results in a reduction in the duration and volume of menstrual bleeding while using Mirena. A reduction in menstrual flow frequently turns into oligomenorrhea or amenorrhea. ovarian disease is normal and estradiol levels remain normal, even in women using Mirena with amenorrhea.
Mirena can be used successfully in the treatment of idiopathic menorrhagia. Menstrual blood loss in women with menorrhagia was reduced by 62-94% at the end of the first 3 months of use and by 71-95% at the end of the first 6 months. When compared with ablation or resection of the endometrium, Mirena has been shown to be equally effective in reducing menstrual blood loss for up to two years. Menorrhagia due to submucosal fibroids may respond less favorably. The decrease in menstrual flow increases the blood concentration of hemoglobin. Mirena can also relieve dysmenorrhea.
The efficacy of Mirena in preventing endometrial hyperplasia during continuous estrogen treatment was equally good both when estrogen was administered orally and when administered transdermally. Estrogen monotherapy induced hyperplasia in 20% of cases. In studies performed on a total of 634 perimenopausal and postmenopausal women using Mirena, no cases of endometrial hyperplasia were reported in the postmenopausal group during an observation period ranging from 1 to 5 years.
05.2 Pharmacokinetic properties
The active ingredient in Mirena is levonorgestrel, which is released directly into the uterine cavity. The speed of release in vivo of levonorgestrel in the uterine cavity is initially around 20 mcg / 24 hours and decreases to 10 mcg / 24 hours after 5 years.
• Absorption
The release of levonorgestrel into the uterine cavity begins immediately after the insertion of Mirena, as evidenced by the measurements of the serum concentrations. The high local exposure to the drug in the uterine cavity, which is important for the local action of Mirena on the endometrium , leads to a strong concentration gradient from endometrium to myometrium (endometrium-myometrium gradient> 100 times), and to low concentrations of levonorgestrel in serum (endometrium to serum gradient> 1000 times).
• Distribution
Levonorgestrel is nonspecifically bound to serum albumin and specifically to SHBG. Approximately 1-2% of circulating levonorgestrel is present as a free steroid and 42-62% is specifically bound to SHBG. During the use of Mirena, the concentration of SHBG decreases. Consequently, during treatment, the SHBG-bound fraction decreases and the free fraction increases. The mean apparent volume of distribution of levonorgestrel is approximately 106 L.
After the insertion of Mirena, levonorgestrel is detectable in the serum after 1 hour. The maximum concentration is reached within 2 weeks of insertion. Corresponding to the decrease in release rate, the median serum concentration of levonorgestrel decreases from 206 pg / mL (25th - 75th percentile: 151 pg / mL - 264 pg / mL) at 6 months to 194 pg / mL (146 pg / ml 266 pg / ml) at 12 months and 131 pg / ml (113 pg / ml 161 pg / ml) at 60 months in women of reproductive age weighing more than 55 kg.
Body weight and serum SHBG concentrations have been observed to influence systemic levonorgestrel concentration, meaning that low body weight and / or high SHBG level increases levonorgestrel concentration. In women of reproductive age with a low body weight (37 to 55 kg) the median serum concentration of levonorgestrel is approximately 1.5 times higher.
In postmenopausal women using Mirena in conjunction with non-oral estrogen treatment, the median serum concentration of levonorgestrel decreases from 257 pg / mL (25th-75th percentile: 186 pg / mL 326 pg / mL) at 12 months to 149 pg / ml (122 pg / ml 180 pg / ml) at 60 months. When Mirena is used in conjunction with oral estrogen treatment, the serum concentration of levonorgestrel at 12 months increases to approximately 478 pg / ml (25th-75th percentile: 341 pg / ml 655 pg / ml) due to the induction of SHBG. by oral estrogen.
• Biotransformation
Levonorgestrel is extensively metabolised. The major metabolites in plasma are the conjugated and non-conjugated forms of 3α, 5β-tetrahydrolevonorgestrel. Based on the studies in vitro And in vivo, CYP3A4 is the major enzyme involved in the metabolism of levonorgestrel. CYP2E1, CYP2C19 and CYP2C9 may also be involved, but to a lesser extent.
• Elimination
Total clearance of levonorgestrel from plasma is approximately 1.0 ml / min / kg. Only minimal amounts of levonorgestrel are excreted in unmodified form. The metabolites are excreted with the faeces and urine at a ratio of approximately 1. The half-life of excretion, which is mainly represented by the metabolites, is approximately 1 day.
Linearity / non-linearity
The pharmacokinetics of levonorgestrel depend on the concentration of SHBG which, in turn, is affected by estrogen and androgen levels. An average reduction in SHBG of approximately 30% was observed during use of Mirena, resulting in a reduction in serum levonorgestrel, indicating non-linear pharmacokinetics of levonorgestrel in relation to time. Since the action of Mirena is mainly local , no impact on its effectiveness is expected from this.
05.3 Preclinical safety data
The preclinical safety evaluation does not reveal any special risks for humans based on studies of safety pharmacology, toxicity, genotoxicity, and carcinogenic potential of levonorgestrel.
Levonorgestrel is a well known progestin. Its safety profile following systemic administration is well documented. A study performed in monkeys with intrauterine administration of levonorgestrel over a period of 12 months confirmed local pharmacological activity, good local tolerability and the absence of signs of systemic toxicity. In rabbits, following intrauterine administration of levonorgestrel, no signs of embryotoxicity were found. The evaluation of the safety of the elastomeric components of the cylinder containing the hormone, of the polyethylene material of the device body and of the mixture of elastomer and levonorgestrel, carried out both with regard to genotoxicity, with standard in vitro and in vivo tests, and biocompatibility, with tests in mice, guinea pigs, rabbits and in vitro showed no signs of bioincompatibility.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Polydimethylsiloxane elastomer, polydimethylsiloxane tubing, T-body and polyethylene thread.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
No particular precautions for storage.
06.5 Nature of the immediate packaging and contents of the package
The outer packaging contains an intrauterine delivery system.
The system is packaged in a sterile thermoformed blister-type container. The transparent film is made of APET or PETG and the white film is made of polyethylene.
06.6 Instructions for use and handling
Mirena is placed in a sterile container that must be opened only before insertion. The device, once removed from the packaging, must be used in an aseptic environment. If the container is damaged, the intrauterine device must be disposed of in the manner appropriate for the drugs. Even after removal, the intrauterine device must be disposed of in the appropriate manner for medications as it contains hormonal residues. The inserter must be disposed of as hospital waste, while the outer and inner containers must be disposed of as household waste. Special instructions for insertion are included in the package. For more information, carefully read the paragraph on insertion in paragraph "4.4 Special warnings and precautions for use".
Since the insertion technique is different from that of other intrauterine devices, particular attention must be paid to learning it.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
MA holder: Bayer Oy - Turku - Finland.
Representative in Italy: Bayer S.p.A., Viale Certosa, 130 - 20156 Milan.
08.0 MARKETING AUTHORIZATION NUMBER
AIC n. 029326016
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
19.01.1996/29.01.2011
10.0 DATE OF REVISION OF THE TEXT
04/2015
