Mirena^® (Intrauterine System) Instructions for Use

Marketing Authorization Holder

Bayer, AG (Germany)

Manufactured By

Bayer, OY (Finland)

Contact Information

Bayer AG (Germany)

ATC Code

G02BA03 (Plastic IUDs with gestagens)

Active Substance

Levonorgestrel

Dosage Form

Mirena®

Intrauterine therapeutic system 20 mcg/24 h: 1 unit

Dosage Form, Packaging, and Composition

Intrauterine therapeutic system (IUS) is a T-shaped levonorgestrel-releasing structure placed in an inserter tube (inserter components: insertion tube, plunger, index ring, handle, and slider). The IUS consists of a white or almost white hormonal-elastomer core placed on a T-shaped body and covered with an opaque membrane regulating the release of levonorgestrel (20 mcg/24 h). The white T-shaped body is equipped with a loop at one end and two arms at the other; brown removal threads are attached to the loop. The T-shaped structure contains barium sulfate, making it visible on X-ray examination. The IUS is free from visible impurities.

Excipients: core made of polydimethylsiloxane elastomer; membrane made of polydimethylsiloxane elastomer containing 30-40% w/w colloidal anhydrous silicon dioxide.

Other components: T-shaped body made of polyethylene containing 20-24% w/w barium sulfate, thin brown polyethylene thread colored with ≤1% w/w black iron oxide.
Delivery device: inserter – 1 pc.
The composition is given per 1 IUS with inserter.

IUS (1) – sterile blisters (1) – cardboard packs.

Clinical-Pharmacological Group

Gestagen

Pharmacotherapeutic Group

Other agents used in gynecology; contraceptives for topical use; intravaginal contraceptives

Pharmacological Action

The Mirena^® IUS, releasing levonorgestrel, exerts mainly a local gestagenic action. The gestagen (levonorgestrel) is released directly into the uterine cavity, allowing for its use in an extremely low daily dose. High concentrations of levonorgestrel in the endometrium contribute to a decrease in the sensitivity of its estrogen and progesterone receptors, making the endometrium unresponsive to estradiol and exerting a strong antiproliferative effect. When using the Mirena^® IUS, morphological changes in the endometrium and a weak local reaction to the presence of a foreign body in the uterus are observed. An increase in the viscosity of cervical mucus prevents the penetration of sperm into the uterine cavity; due to reduced sperm motility and changes in the endometrium, the likelihood of egg fertilization decreases. In some women, ovulation is suppressed.

Previous use of the Mirena^® IUS does not affect reproductive function. Approximately 80% of women wishing to have a child become pregnant within 12 months after IUS removal.

In the first months of using the Mirena^® IUS, due to the process of inhibiting endometrial proliferation, an initial increase in vaginal “spotting” bleeding may be observed. Following this, pronounced suppression of endometrial proliferation leads to a reduction in the duration and volume of menstrual bleeding in women using the Mirena^® IUS. Scanty bleeding often transforms into oligo- or amenorrhea. In this case, ovarian function and plasma estradiol concentrations remain normal.

The Mirena^® IUS can be used for the treatment of idiopathic menorrhagia, i.e., menorrhagia in the absence of hyperplastic processes in the endometrium (endometrial cancer, metastatic lesions of the uterus, submucous or large interstitial myomatous node leading to deformation of the uterine cavity, adenomyosis), endometritis, extragenital diseases and conditions accompanied by severe hypocoagulation (e.g., von Willebrand disease, severe thrombocytopenia), the symptoms of which include menorrhagia. After 3 months of using the Mirena^® IUS, menstrual blood loss in women with menorrhagia decreases by 62-94% and by 71-95% after 6 months of use. When using the Mirena^® IUS for 2 years, the effectiveness of the drug (reduction in menstrual blood loss) is comparable to surgical treatment methods (endometrial ablation or resection). A less favorable response to treatment is possible with menorrhagia caused by submucous uterine fibroids. The reduction in menstrual blood loss reduces the risk of iron deficiency anemia. The Mirena^® IUS reduces the severity of dysmenorrhea symptoms.

The effectiveness of the Mirena^® IUS in preventing endometrial hyperplasia during continuous estrogen therapy was equally high with both oral and transdermal estrogen application.

Pharmacokinetics

The active substance of the Mirena^® IUS – levonorgestrel, is released directly into the uterine cavity. The calculated in vivo release rate at various time points is presented in Table 1.

Table 1. Calculated in vivo release rate for Mirena^® IUS

Absorption

After insertion of the Mirena^® IUS, levonorgestrel begins to be released immediately into the uterine cavity, as evidenced by measurements of its plasma concentration. The systemic bioavailability of the released levonorgestrel is over 90%.

After insertion of the Mirena^® IUS, levonorgestrel is detected in plasma within 1 hour. C_max is 414 pg/ml and is reached within 2 weeks after insertion. In accordance with the decreasing release rate, the median plasma concentration of levonorgestrel in women of reproductive age with a body weight above 55 kg decreases from 206 pg/ml (25th-75th percentiles: 151 pg/ml-264 pg/ml), measured at 6 months, to 194 pg/ml (146 pg/ml-266 pg/ml) at 12 months and to 131 pg/ml (113 pg/ml-161 pg/ml) at 60 months. The median levonorgestrel concentration at 72 months (6 years) was 113 pg/ml (87.3 pg/ml-155 pg/ml).

The high local drug exposure in the uterine cavity, necessary for the local effect of the Mirena^® IUS on the endometrium, provides a high concentration gradient from the endometrium to the myometrium (the concentration of levonorgestrel in the endometrium exceeds its concentration in the myometrium by more than 100 times) and low concentrations of levonorgestrel in plasma (the concentration of levonorgestrel in the endometrium exceeds its concentration in plasma by more than 1000 times).

In postmenopausal women using the Mirena^® IUS simultaneously with estrogen use, the median plasma concentration of levonorgestrel decreases from 257 pg/ml (25th-75th percentiles: 186 pg/ml-326 pg/ml), measured at 12 months, to 149 pg/ml (122 pg/ml-180 pg/ml) at 60 months. When using the Mirena^® IUS simultaneously with oral estrogen intake, the plasma concentration of levonorgestrel, measured at 12 months, increases to approximately 478 pg/ml (25th-75th percentiles: 341 pg/ml-655 pg/ml), which is due to the induction of SHBG synthesis.

Distribution

Levonorgestrel binds non-specifically to plasma albumin and specifically to sex hormone-binding globulin (SHBG). Less than 2% of circulating levonorgestrel is present as free steroid.

Levonorgestrel binds to SHBG with high affinity. Therefore, changes in plasma SHBG concentration lead to an increase (with higher SHBG concentration) or decrease (with lower SHBG concentration) in the total plasma concentration of levonorgestrel. SHBG concentration decreases on average by approximately 20-30% within 1 month after insertion of the Mirena^® IUS, remains at this level during the first year of use, and increases slightly thereafter. SHBG concentration remains stable during the 6th year of use. The mean apparent V_d of levonorgestrel is about 106 L.

It has been shown that body weight and plasma SHBG concentration affect the systemic concentration of levonorgestrel, i.e., with low body weight and/or high SHBG concentration, the levonorgestrel concentration is higher. In women of reproductive age with low body weight (37-55 kg), the median plasma concentration of levonorgestrel is approximately 1.5 times higher.

Metabolism

Levonorgestrel is extensively metabolized. The most important metabolic pathways are reduction of the Δ4-3-oxo-group and hydroxylation at positions 2α, 1β, and 16β, followed by conjugation. CYP3A4 is the main enzyme involved in the oxidative metabolism of levonorgestrel. Available in vitro data suggest a minor significance of CYP-mediated biotransformation reactions for levonorgestrel compared to reduction and conjugation.

Excretion

The total clearance of levonorgestrel from plasma is approximately 1 ml/min/kg. Levonorgestrel is excreted unchanged only in trace amounts. Metabolites are excreted via the intestine and kidneys with an excretion ratio of approximately 1.77. T_1/2 in the terminal phase, represented mainly by metabolites, is about one day.

Linearity/non-linearity

The pharmacokinetics of levonorgestrel depend on SHBG concentration, which, in turn, is influenced by estrogen and androgen concentrations. A decrease in SHBG concentration leads to a decrease in the total plasma concentration of levonorgestrel, indicating non-linearity of levonorgestrel pharmacokinetics over time. Given the predominantly local action of the Mirena^® IUS, the influence of changes in systemic levonorgestrel concentrations on the effectiveness of the Mirena^® IUS is unlikely.

Indications

• Contraception;
• Idiopathic menorrhagia;
• Prevention of endometrial hyperplasia during estrogen replacement therapy (HRT).

ICD codes

Dosage Regimen

The Mirena^® IUS is inserted into the uterine cavity and remains effective for 6 years for the indication of contraception and for 5 years for the indications of idiopathic menorrhagia, prevention of endometrial hyperplasia during estrogen HRT.

The in vivo release rate of levonorgestrel at the beginning of use is approximately 20 mcg/24 hours and decreases to approximately 18 mcg/24 hours after 1 year, to 10 mcg/24 hours after 5 years, and to 9 mcg/24 hours after 6 years. The average release rate of levonorgestrel is approximately 15 mcg/24 hours for up to 5 years and 15 mcg per day for up to 6 years.

The Mirena^® IUS can be used in women receiving oral or transdermal preparations for HRT containing estrogen only.

With correct insertion of the Mirena^® IUS, performed in accordance with the instructions for medical use, the Pearl Index (an indicator reflecting the number of pregnancies in 100 women using the contraceptive for 1 year) is approximately 0.2%. The cumulative failure rate is approximately 0.7% over 5 years. When using the Mirena^® IUS for more than 5 years, the contraceptive failure rate during the 6th year was 0.29%.

Instructions for use of the Mirena^® IUS

The Mirena^® IUS is supplied in sterile packaging, which is opened only immediately before insertion. Aseptic rules must be observed when handling the opened system. If the sterility of the packaging appears to be compromised, the IUS should be disposed of as medical waste. The same applies to the IUS removed from the uterus, as it contains hormone residues.

Insertion, removal and replacement of the IUS

It is recommended that the Mirena^® IUS be inserted only by a physician experienced with this IUS or well-trained in performing this procedure.

Before insertion of the Mirena^® IUS, the woman should be informed about the effectiveness, risks, and adverse reactions of IUS use. A general and gynecological examination should be performed, including examination of the pelvic organs and mammary glands. If necessary, as decided by the doctor, a cervical smear test should be performed. Pregnancy and sexually transmitted diseases should be ruled out, and pelvic inflammatory diseases must be completely cured. The position of the uterus and the dimensions of its cavity are determined. If visualization of the uterus is necessary before insertion of the Mirena^® IUS, a pelvic ultrasound should be performed. After a gynecological examination, a speculum is inserted into the vagina and the cervix is treated with an antiseptic solution. Then, the Mirena^® IUS is inserted into the uterus through a thin flexible plastic tube. Correct placement of the Mirena^® IUS in the fundus of the uterus is especially important, as it ensures uniform exposure of the gestagen on the endometrium, prevents expulsion of the IUS, and creates conditions for its maximum effectiveness. Therefore, the requirements of the insertion instructions for the Mirena^® IUS should be carefully followed. Since the insertion technique for different IUSs varies, special attention should be paid to practicing the correct insertion technique for this specific system. The woman may feel the insertion of the system, but it should not cause severe pain. Before insertion, if necessary, a paracervical block and/or analgesics can be used.

In some cases, patients may have cervical stenosis. Excessive force should not be used when inserting the Mirena^® IUS in such patients.

Sometimes after insertion of the IUS, pain, dizziness, sweating, and pallor are noted. Women are advised to rest for some time after insertion of the Mirena^® IUS. If these phenomena do not subside after half an hour in a calm position, the IUS may be incorrectly positioned. A gynecological examination should be performed; if necessary, the system is removed. In some women, the use of the Mirena^® IUS causes skin allergic reactions.

The woman should be re-examined 4-12 weeks after insertion, and then once a year or more frequently if clinically indicated.

In women of reproductive age, the Mirena^® IUS should be inserted into the uterine cavity within 7 days from the start of menstruation.

The Mirena^® IUS can be replaced with a new IUS on any day of the menstrual cycle. The IUS can also be inserted immediately after a first-trimester abortion, provided there are no inflammatory diseases of the genital organs.

Use of the IUS is recommended for women with a history of at least one delivery. Insertion of the Mirena^® IUS in the postpartum period should be performed only after complete involution of the uterus, but not earlier than 6 weeks after delivery. In case of prolonged subinvolution of the uterus, postpartum endometritis and other causes of significant delay in involution must be ruled out, and the decision to insert the Mirena^® IUS should be postponed until the involution of the uterus is complete. Due to the high risk of uterine perforation in the postpartum period, insertion of the Mirena^® IUS is preferably performed 12 weeks after delivery.

In case of difficulties during IUS insertion and/or very severe pain or bleeding during or after the procedure, the possibility of perforation should be considered and appropriate measures taken, such as physical examination and ultrasound.

For the prevention of endometrial hyperplasia during HRT with estrogen-only preparations in women with amenorrhea, the Mirena^® IUS can be inserted at any time; in women with preserved menstruation, insertion is performed in the last days of menstrual bleeding or “withdrawal” bleeding.

Removal of the Mirena^® IUS is performed by gently pulling on the threads grasped with forceps. If the threads are not visible and the system is in the uterine cavity, it can be removed using an IUS retrieval hook. This may require dilation of the cervical canal.

The system used for the indication of contraception should be removed 6 years after insertion, or 5 years after insertion if the system is used for the indications of idiopathic menorrhagia, prevention of endometrial hyperplasia during estrogen HRT. If the woman wishes to continue using the same method, a new system can be inserted immediately after removal of the previous one.

If further contraception is required in women of reproductive age, removal of the IUS should be performed within 7 days of the start of menstruation, provided the woman has regular periods. If the system is removed at another time in the cycle, or if the woman has irregular periods and has had sexual intercourse during the preceding week, the woman is at risk of pregnancy. To ensure continuous contraception, a new IUS must be inserted immediately after removal of the previous IUS, or an alternative method of contraception must be initiated.

Insertion and removal of the IUS may be accompanied by certain pain sensations and bleeding. The procedure may cause fainting due to a vasovagal reaction, bradycardia, or a seizure in patients with epilepsy, especially in the presence of a predisposition to these conditions or in case of cervical stenosis.

After removal of the Mirena^® IUS, the system should be checked for integrity. In cases of difficult removal, isolated cases of the hormonal-elastomer core slipping onto the horizontal arms of the T-shaped body have been noted, resulting in them being hidden inside the core. Once the integrity of the IUS is confirmed, this situation does not require additional intervention. The stoppers on the horizontal arms usually prevent complete separation of the core from the T-shaped body.

Additional Information for Specific Patient Groups

Children and Adolescents Under 18 Years of Age

The safety and efficacy of the Mirena^® IUD in adolescent girls under 18 years of age have not yet been established. There are no indications for the use of the Mirena^® IUD prior to menarche (establishment of the menstrual cycle).

Elderly Patients

The Mirena^® IUD has not been studied in women over 65 years of age; therefore, the use of the Mirena^® IUD is not recommended for this patient group.

The Mirena^® IUD is not a first-choice drug for women in the postmenopausal period up to 65 years of age with severe uterine atrophy.

Patients with Liver Function Impairment

The Mirena^® IUD is contraindicated in women with acute liver diseases or liver tumors (see the “Contraindications” section).

Patients with Renal Function Impairment

The Mirena^® IUD has not been studied in patients with renal function impairment.

Insertion Instructions

To be inserted only by a physician using sterile instruments.

The Mirena^® IUD is supplied together with an inserter in sterile packaging, which must not be opened until insertion.

Do not resterilize. For single use only. Do not use the Mirena^® IUD if the inner packaging is damaged or opened. Do not insert the Mirena^® IUD after the expiration date printed on the packaging.

Before insertion, read the information on the use of the Mirena^® IUD.

Preparation for Insertion

• Perform a gynecological examination to determine the size and position of the uterus and to rule out any signs of acute inflammatory diseases of the genital organs, pregnancy, or other gynecological contraindications for the insertion of the Mirena^® IUD.
• The cervix should be visualized using a speculum, and the cervix and vagina should be thoroughly cleansed with an antiseptic solution.
• If necessary, assistance from an assistant should be utilized.
• The anterior lip of the cervix should be grasped with a tenaculum. Gentle traction with the tenaculum should be applied to straighten the cervical canal. The tenaculum should remain in this position throughout the insertion of the Mirena^® IUD to ensure gentle traction of the cervix towards the inserting instrument.
• By carefully advancing a uterine sound through the cavity to the uterine fundus, the direction of the cervical canal and the depth of the uterine cavity (distance from the external os to the uterine fundus) should be determined, and the presence of uterine septa, synechiae, or submucosal fibroids should be ruled out. If the cervical canal is too narrow, dilation of the canal is recommended, and possibly the use of analgesics/paracervical block.

Insertion

1. Open the sterile packaging (Figure 1). After this, all manipulations should be performed using sterile instruments and sterile gloves.

Fig. 1

2. Move the slider forward in the direction of the arrow to the farthest position to retract the IUD into the insertion tube (Figure 2).

Fig. 2

Important Information. Do not move the slider downwards, as this may lead to premature release of the Mirena^® IUD. If this occurs, the system cannot be reinserted into the inserter.

3. While holding the slider in the farthest position, set the top edge of the index ring to correspond with the distance from the external os to the uterine fundus as measured by the sound (Figure 3).

Fig. 3

4. While continuing to hold the slider in the farthest position, advance the inserter carefully through the cervical canal into the uterus until the index ring is approximately 1.5-2 cm from the cervix (Figure 4).

Fig. 4

Important Information. Do not force the inserter. If necessary, the cervical canal should be dilated.

5. Holding the inserter steady, move the slider back to the mark to open the horizontal arms of the Mirena^® IUD (Figure 5). Wait 5-10 seconds for the horizontal arms to open completely.

Fig. 5

6. Carefully advance the inserter inward until the index ring touches the cervix. The Mirena^® IUD should be positioned in the uterine fundus (Figure 6).

Fig. 6

7. While holding the inserter in the same position, release the Mirena^® IUD by moving the slider all the way down (Figure 7). While holding the slider in the same position, carefully remove the inserter by pulling it. Cut the threads so that their length is 2-3 cm from the external os of the uterus.

Fig. 7

Important Information. If the physician has doubts that the system is correctly positioned, the position of the Mirena^® IUD should be checked, for example, using ultrasound, or if necessary, the system should be removed and a new, sterile system inserted. The system should be removed if it is not entirely within the uterine cavity. A removed system must not be reused.

Removal/Replacement of the Mirena^® IUD

Before removal/replacement of the Mirena^® IUD, read the instructions for use of the Mirena^® IUD.

The Mirena^® IUD is removed by gently pulling on the threads grasped with forceps (Figure 8).

Fig. 8

A new Mirena^® IUD can be inserted immediately after the removal of the previous one.

Adverse Reactions

Most women experience changes in the pattern of cyclic bleeding after insertion of the Mirena^® IUD. During the first 90 days of Mirena^® IUD use, increased duration of bleeding is reported by 22% of women, and irregular bleeding is reported by 67% of women; the frequency of these events decreases to 3% and 19%, respectively, by the end of the first year of use. Simultaneously, amenorrhea develops in 0%, and infrequent bleeding in 11% of patients during the first 90 days of use. By the end of the first year of use, the frequency of these events increases to 16% and 57%, respectively. By the end of the 6th year of Mirena^® IUD use, increased duration of bleeding and irregular bleeding are reported by 2% and 15% of women, respectively, amenorrhea occurs in 24%, and infrequent bleeding in 31% of patients.

When the Mirena^® IUD is used in combination with continuous estrogen HRT, cyclic bleeding gradually ceases in most women during the first year of use.

Table 2 presents data on the frequency of adverse reactions (ARs) reported with the use of the Mirena^® IUD. The frequency of ARs is categorized as very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000), and frequency not known. In the table, ARs are distributed by system-organ class according to MedDRA. The frequency data reflect the approximate frequency of ARs recorded during clinical trials of the Mirena^® IUD for the indications “contraception” and “idiopathic menorrhagia” involving 5091 women.

ARs reported during clinical trials of the Mirena^® IUD for the indication “prevention of endometrial hyperplasia during estrogen HRT” (involving 514 women) were observed with the same frequency, except where indicated by footnotes (*, **).

Table 2. Adverse Reactions

* “Common” for the indication “prevention of endometrial hyperplasia during estrogen HRT”.

** “Very Common” for the indication “prevention of endometrial hyperplasia during estrogen HRT”.

*** This frequency is based on the results of a large prospective comparative non-interventional cohort study of women using IUDs, which demonstrated that breastfeeding at the time of insertion and insertion up to 36 weeks postpartum are independent risk factors for perforation (see the “Special Precautions” section). In clinical trials with the Mirena^® IUD, which did not include women during breastfeeding, cases of perforation were reported with “rare” frequency.

MedDRA terminology has been used in most cases to describe certain reactions, their synonyms, and related conditions.

In a separate study involving 362 women who used the Mirena^® IUD for more than 5 years, a comparable adverse reaction profile was demonstrated during the 6th year of use.

Additional Information

If a woman with an inserted Mirena^® IUD becomes pregnant, the relative risk of ectopic pregnancy increases.

The partner may feel the threads during sexual intercourse.

The risk of breast cancer with the use of the Mirena^® IUD for the indication “prevention of endometrial hyperplasia during estrogen HRT” is unknown. Cases of breast cancer have been reported (frequency not known, see the “Use with Caution” and “Special Precautions” sections).

The following ARs have been reported in connection with the insertion or removal procedure of the Mirena^® IUD: pain during the procedure, bleeding during the procedure, insertion-related vasovagal reaction accompanied by dizziness or fainting. The procedure may trigger a seizure in patients with epilepsy.

Infection

Cases of sepsis (including group A streptococcal sepsis) have been reported after IUD insertion (see the “Special Precautions” section).

Contraindications

• Pregnancy or suspected pregnancy;
• Acute or recurrent inflammatory diseases of the pelvic organs;
• Infections of the external and internal genital organs;
• Postpartum endometritis;
• Septic abortion within the last 3 months;
• Cervicitis;
• Diseases accompanied by increased susceptibility to infections;
• Cervical dysplasia;
• Diagnosed or suspected malignant neoplasms of the uterus or cervix;
• Diagnosed or suspected progestogen-dependent tumors, including breast cancer;
• Genital bleeding of unknown etiology;
• Congenital and acquired uterine anomalies, including fibroids leading to deformation of the uterine cavity;
• Acute liver diseases or liver tumors;
• Hypersensitivity to levonorgestrel or any of the excipients in the drug;
• Age over 65 years (studies in this patient group have not been conducted).

Use with Caution

For the following diseases/conditions/risk factors, the Mirena^® IUD should be used with caution after consultation with a specialist:

• Congenital heart defects or valvular heart diseases (due to the risk of developing septic endocarditis);
• Diabetes mellitus.

The advisability of removing the system should be discussed if any of the following diseases/conditions/risk factors are present or occur for the first time:

• Migraine, focal migraine with asymmetrical vision loss or other symptoms indicating transient cerebral ischemia;
• Unusually severe headache;
• Jaundice;
• Severe arterial hypertension;
• Severe circulatory disorders, including stroke and myocardial infarction.

Use in Pregnancy and Lactation

Pregnancy

The use of the Mirena^® IUD is contraindicated during pregnancy or suspected pregnancy.

Pregnancy in women who have the Mirena^® IUD inserted is an extremely rare occurrence. But if the IUD is expelled from the uterine cavity, the woman is no longer protected from pregnancy and should use other methods of contraception until consulting a physician.

During the use of the Mirena^® IUD, some women do not have menstrual bleeding. The absence of menstruation does not necessarily indicate pregnancy. If a woman has no menstrual periods and simultaneously has other signs of pregnancy (nausea, fatigue, breast tenderness), she should consult a physician for examination and a pregnancy test.

If pregnancy occurs in a woman while using the Mirena^® IUD, it is recommended to remove the IUD, as any intrauterine contraceptive left in situ increases the risk of spontaneous abortion, infection, or preterm labor. Removal of the Mirena^® IUD or sounding of the uterine cavity may lead to spontaneous abortion. Ectopic pregnancy should be ruled out.

If the intrauterine contraceptive cannot be removed carefully, the advisability of medical abortion should be discussed. If the woman wishes to continue the pregnancy and the IUD cannot be removed, the patient should be informed about the risks, in particular, the possible risk of septic abortion in the second trimester of pregnancy, postpartum purulent-septic diseases that may be complicated by sepsis, septic shock, and death, as well as the possible consequences of preterm birth for the child. In such cases, the pregnancy should be closely monitored. The woman should be advised to report to her physician any symptoms suggestive of pregnancy complications, particularly the appearance of cramping lower abdominal pain accompanied by fever.

There have been isolated cases of masculinization of the external genitalia of female fetuses following local exposure to levonorgestrel during pregnancy with the use of levonorgestrel-containing IUDs.

Breastfeeding Period

Breastfeeding a child while using the Mirena^® IUD is not contraindicated. Approximately 0.1% of the levonorgestrel dose may pass into the child’s body during breastfeeding. However, it is unlikely to pose a risk to the child at the doses released into the uterine cavity after insertion of the Mirena^® IUD.

It is considered that the use of the Mirena^® IUD 6 weeks after delivery does not have a harmful effect on the growth and development of the child. Progestogen-only therapy does not affect the quantity and quality of breast milk.

Fertility

After removal of the Mirena^® IUD, fertility is restored in women.

Use in Hepatic Impairment

Use is contraindicated in acute liver diseases, liver tumors.

Use in Renal Impairment

The Mirena^® IUD has not been studied in patients with renal function impairment.

Pediatric Use

The safety and efficacy of the Mirena^® IUD in adolescent girls under 18 years of age have not yet been established. There are no indications for the use of the Mirena^® IUD prior to menarche (establishment of the menstrual cycle).

Geriatric Use

Use is contraindicated in patients over 65 years of age.

Special Precautions

Before insertion of the Mirena^® IUD, pathological processes in the endometrium should be ruled out, since irregular bleeding/spotting is often observed during the first months of its use. Pathological processes in the endometrium should also be ruled out if bleeding occurs after the initiation of estrogen HRT in a woman who continues to use the Mirena^® IUD, previously inserted for contraception. Appropriate diagnostic measures should also be taken when irregular bleeding develops during long-term treatment.

The Mirena^® IUD is not used for postcoital contraception.

Due to the risk of developing bacterial endocarditis, the Mirena^® IUD should be used only under strict indications in the presence of current congenital or acquired heart defects or valvular defects.

Levonorgestrel in low doses may affect glucose tolerance, therefore plasma glucose levels should be regularly monitored in women with diabetes mellitus using the Mirena^® IUD. Typically, no adjustment of hypoglycemic drug doses is required.

Some manifestations of endometrial polyposis or cancer may be masked by irregular bleeding. In such cases, additional examination is necessary to clarify the diagnosis.

The Mirena^® IUD should not be considered as a first-choice method in the postmenopausal period in women with severe uterine atrophy.

Available data indicate that the use of the Mirena^® IUD does not increase the risk of developing breast cancer in postmenopausal women under 50 years of age. Due to limited data obtained during the study of the Mirena^® IUD for the indication “prevention of endometrial hyperplasia during estrogen HRT”, the risk of breast cancer with the use of the Mirena^® IUD for this indication cannot be confirmed or refuted.

Oligo- and Amenorrhea

Oligo- and amenorrhea in women of fertile age develop gradually, in approximately 57% and 16% of cases during the first year of Mirena^® IUD use, respectively. By the end of the 6th year of Mirena^® IUD use, oligo- and amenorrhea were observed in 31% and 24% of patients, respectively. If menstruation is absent for 6 weeks after the start of the last menstrual period, pregnancy should be ruled out. Repeated pregnancy tests in case of amenorrhea are not necessary if there are no other signs of pregnancy.

When the Mirena^® IUD is used in combination with continuous estrogen HRT, amenorrhea gradually develops in most women during the first year.

Pelvic Inflammatory Disease (PID)

The inserter tube helps protect the Mirena^® IUD from infection during insertion, and the Mirena^® IUD insertion device is specifically designed to minimize the risk of infection. PID in women using intrauterine contraception is often caused by sexually transmitted infections. Having multiple sexual partners or having a partner with multiple sexual partners has been identified as a risk factor for PID. PID can have serious consequences: it can impair reproductive function and increase the risk of ectopic pregnancy.

As with other gynecological or surgical procedures, severe infection or sepsis (including group A streptococcal sepsis) may occur after IUD insertion, although this happens extremely rarely.

In cases of recurrent endometritis or PID, as well as severe or acute infections resistant to treatment for several days, the Mirena^® IUD should be removed. If a woman experiences persistent lower abdominal pain, chills, fever, pain associated with sexual intercourse (dyspareunia), prolonged or heavy spotting/vaginal bleeding, or a change in vaginal discharge, she should consult a doctor immediately. Severe pain or fever occurring shortly after IUD insertion may indicate a severe infection that requires immediate treatment. Even in cases where only isolated symptoms suggest the possibility of infection, bacteriological testing and monitoring are indicated.

Expulsion

Uterine muscle contractions during menstruation can sometimes lead to displacement of the IUD or even its expulsion from the uterus, resulting in the cessation of the contraceptive effect. Possible signs of partial or complete expulsion of any IUD are bleeding and pain; however, expulsion of the Mirena^® IUD may also occur unnoticed. Since the Mirena^® IUD reduces menstrual blood loss, an increase in blood loss may indicate IUD expulsion.

The risk of expulsion is increased

• In women with a history of heavy menstrual bleeding;
• In women with a higher-than-normal BMI at the time of insertion; this risk gradually increases with increasing BMI.

The woman should be counseled about the possible signs of expulsion and instructed on how to check the threads of the Mirena^® IUD (see the subsection “Signs that the Mirena^® IUD is in place”). The woman should be advised to contact her healthcare provider if she cannot feel the threads and to avoid sexual intercourse or use barrier contraceptive methods (such as condoms) until the position of the Mirena^® IUD is confirmed.

Partial expulsion may reduce the effectiveness of the Mirena^® IUD.

A partially expelled Mirena^® IUD should be removed. A new system can be inserted at the time of removal of the previous IUD provided that pregnancy has been excluded.

Perforation and Penetration

Perforation or penetration of the uterine body or cervix by the IUD can occur mainly during insertion, although it may not be detected until some time after insertion and can reduce the effectiveness of the Mirena^® IUD. In these cases, the system should be removed. If diagnosis of perforation and IUD migration is delayed, complications such as adhesions, peritonitis, intestinal obstruction, intestinal perforation, abscesses, or erosions of adjacent internal organs may occur.

In a large prospective comparative non-interventional cohort study of women using IUDs (N=61,448 women) with a 1-year observation period, the perforation rate 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^® IUD study cohort and 1.1 (95% CI: 0.7-1.6) per 1000 insertions in the copper IUD study cohort.

When extending the observation period to 5 years in a subgroup of this study (N=39,009 women using the Mirena^® IUD or a copper intrauterine contraceptive), the perforation rate, detected at various times throughout the entire 5-year period, was 2.0 (95% CI: 1.6-2.5) per 1000 insertions.

The study demonstrated that both breastfeeding at the time of insertion and insertion within 36 weeks after delivery were associated with an increased risk of perforation (see Table 3). These risk factors were confirmed in the subgroup with a 5-year observation period. Both risk factors were independent of the type of IUD used.

Table 3. Perforation rate per 1000 insertions for the entire study cohort with a 1-year observation period, stratified by breastfeeding and time since delivery at insertion (parous women)

An increased risk of perforation during IUD insertion exists in women with a fixed malposition of the uterus (retroversion and retroflexion).

Ectopic Pregnancy

Women with a history of ectopic pregnancy, those who have undergone tubal surgery, or those with a pelvic infection are at higher risk of ectopic pregnancy. The possibility of ectopic pregnancy should be considered in case of lower abdominal pain, especially if it is combined with cessation of menstruation, or when a woman with amenorrhea starts bleeding. The rate of ectopic pregnancy in clinical studies with the Mirena^® IUD was approximately 0.1% per year. In a large prospective comparative non-interventional cohort study with a 1-year observation period, the rate of ectopic pregnancy with the Mirena^® IUD was 0.02%. The absolute risk of ectopic pregnancy in women using the Mirena^® IUD is low. However, if a woman with a Mirena^® IUD in place becomes pregnant, the relative likelihood of an ectopic pregnancy is higher.

Lost Threads

If the IUD removal threads cannot be found in the cervical area during a gynecological examination, pregnancy must be ruled out. The threads may have been retracted into the uterine cavity or the cervical canal and may become visible again after the next menstruation. If pregnancy is excluded, the location of the threads can usually be determined by careful probing with an appropriate instrument. If the threads cannot be found, perforation of the uterine wall or expulsion of the IUD from the uterine cavity is possible. Ultrasound can be performed to determine the correct position of the system. If ultrasound is unavailable or unsuccessful in locating the Mirena^® IUD, an X-ray examination should be performed.

Ovarian Cysts

Since the contraceptive effect of the Mirena^® IUD is mainly due to its local action, ovulatory cycles with follicle rupture are usually observed in women of fertile age. Sometimes follicular atresia is delayed, and follicle development may continue. Such enlarged follicles are clinically indistinguishable from ovarian cysts. Ovarian cysts have been reported as an adverse reaction in approximately 7% of women using the Mirena^® IUD. In most cases, these follicles do not cause any symptoms, although they are sometimes accompanied by lower abdominal pain or pain during sexual intercourse.

Ovarian cysts usually disappear spontaneously within two to three months of observation. If this does not happen, continued monitoring with ultrasound, as well as therapeutic and diagnostic measures, is recommended. In rare cases, surgical intervention may be necessary.

Use of Mirena^® IUD in combination with estrogen HRT

When using the Mirena^® IUD in combination with estrogens, the information provided in the prescribing information for the respective estrogen must be additionally considered.

Excipients contained in the Mirena^® IUD

The T-shaped body of the Mirena^® IUD contains barium sulfate, which becomes visible on X-ray examination.

It must be borne in mind that the Mirena^® IUD does not protect against HIV infection and other sexually transmitted diseases.

Effect on ability to drive and use machines

The Mirena^® IUD does not affect the ability to drive and use machines.

Additional information for patients

Regular check-ups

Your doctor should examine you 4-12 weeks after IUD insertion; thereafter, regular medical check-ups at least once a year are necessary.

Consult your doctor as soon as possible if

• You can no longer feel the threads in your vagina.
• You can feel the lower end of the system.
• You suspect you are pregnant.
• You experience persistent abdominal pain, fever, or notice a change in your usual vaginal discharge.
• You or your partner experience pain during sexual intercourse.
• You notice sudden changes in your menstrual cycle (for example, if your periods were scanty or absent and then you experience persistent bleeding or pain, or your periods become excessively heavy).
• You develop other clinical manifestations, such as migraine-type headache or severe recurrent headache, sudden visual disturbances, jaundice, increased blood pressure, or any other diseases and conditions listed in the “Contraindications” and “Use with caution” sections.

What to do if you want to become pregnant or have the Mirena^® IUD removed for other reasons

Your doctor can easily remove the IUD at any time, after which pregnancy becomes possible. Removal is usually painless. After removal of the Mirena^® IUD, reproductive function returns to normal.

When pregnancy is not desired, the Mirena^® IUD should be removed no later than the 7th day of the menstrual cycle (with a monthly cycle). If the Mirena^® IUD is removed after the 7th day of the cycle, barrier contraceptive methods (e.g., condoms) should be used for at least 7 days prior to its removal. If irregular periods or absence of periods are observed while using the Mirena^® IUD, barrier methods should be started 7 days before IUD removal and continued until menstruation resumes. A new IUD can also be inserted immediately after removal of the previous one; in this case, no additional contraceptive measures are required.

How long can the Mirena^® IUD be used

The Mirena^® IUD can be used for 6 years for contraception (to prevent pregnancy) and for 5 years for idiopathic menorrhagia (heavy menstrual bleeding), protection from endometrial hyperplasia (excessive growth of the uterine lining) during estrogen replacement therapy, after which it should be removed. A new Mirena^® IUD can be inserted immediately after removal of the previous one.

The Mirena^® IUD provides protection against pregnancy for 5 years, after which it should be removed. A new Mirena^® IUD can be inserted immediately after removal of the previous one.

Return of fertility (Can you get pregnant after stopping the use of the Mirena^® IUD)

Yes, you can. After the Mirena^® IUD is removed, it no longer affects your normal reproductive function. Pregnancy can occur during the first menstrual cycle after removal of the Mirena^® IUD.

Effect on the menstrual cycle (Can the Mirena^® IUD affect your menstrual cycle)

The Mirena^® IUD affects the menstrual cycle. Under its influence, periods may change and become “spotting”, become longer or shorter, involve heavier or lighter bleeding than usual, or stop altogether.

In the first 3-6 months after insertion of the Mirena^® IUD, many women experience frequent spotting or light bleeding in addition to their regular periods. In some cases, very heavy or prolonged bleeding is noted during this period. If you experience these symptoms, especially if they do not go away, inform your doctor.

It is most likely that with the use of the Mirena^® IUD, the number of bleeding days and the amount of blood lost will gradually decrease each month. Some women eventually find that their periods have stopped completely. Since the amount of blood lost during menstruation with the Mirena^® IUD usually decreases, most women experience an increase in hemoglobin levels in the blood.

After removal of the system, the menstrual cycle returns to normal.

Absence of periods (Is it normal not to have periods)

Yes, if you are using the Mirena^® IUD. If you notice the disappearance of periods after insertion of the Mirena^® IUD, this is due to the effect of the hormone on the uterine lining. The monthly thickening of the lining does not occur, therefore, its shedding during menstruation does not occur. This does not necessarily mean that you have reached menopause or that you are pregnant. The concentration of your own hormones in the blood plasma remains normal.

In fact, the absence of periods can be a great advantage for a woman’s comfort.

How can you tell if you are pregnant

Pregnancy in women using the Mirena^® IUD, even if they do not have periods, is unlikely.

If you have not had a period for 6 weeks and are concerned about it, take a pregnancy test. If the result is negative, there is no need for additional tests unless you have other signs of pregnancy, such as nausea, fatigue, or breast tenderness.

Can the Mirena^® IUD cause pain or discomfort

Some women experience pain (resembling menstrual cramps) in the first 2-3 weeks after IUD insertion. If you experience severe pain or if the pain continues for more than 3 weeks after insertion of the system, contact your doctor or the healthcare facility where you had the Mirena^® IUD inserted.

Does the Mirena^® IUD affect sexual intercourse

Neither you nor your partner should feel the IUD during sexual intercourse. Otherwise, sexual intercourse should be avoided until your doctor confirms that the system is in the correct position.

How much time should pass between insertion of the Mirena^® IUD and sexual intercourse

It is best, to allow your body to rest, to refrain from sexual intercourse for 24 hours after insertion of the Mirena^® IUD into the uterus. However, the Mirena^® IUD has a contraceptive effect from the moment of insertion.

Can tampons or menstrual cups be used

The use of sanitary pads is recommended. If you use tampons or menstrual cups, they should be changed very carefully so as not to pull on the threads of the Mirena^® IUD. If you think you may have pulled on the threads of the Mirena^® IUD (see the section “Consult your doctor as soon as possible if” for possible signs), avoid sexual intercourse or use barrier contraceptive methods (such as condoms) and consult a doctor.

What happens if the Mirena^® IUD spontaneously comes out of the uterine cavity

Very rarely, expulsion of the IUD from the uterine cavity may occur during menstruation. An unusual increase in blood loss during menstrual bleeding may mean that the Mirena^® IUD has been expelled through the vagina. Partial expulsion of the IUD from the uterine cavity into the vagina is also possible (you and your partner may notice this during sexual intercourse). When the Mirena^® IUD is completely or partially expelled from the uterus, its contraceptive effect ceases immediately.

Signs that the Mirena^® IUD is in place

You can check for yourself whether the threads of the Mirena^® IUD are in place after your period has ended. After your period has ended, gently insert a finger into your vagina and feel for the threads at the end, near the entrance to the uterus (the cervix).

Do not pull on the threads, as you may accidentally pull the Mirena^® IUD out of the uterus. If you cannot feel the threads, contact your doctor.

Overdose

Not applicable.

Drug Interactions

Effect of other medicinal products on the Mirena^® IUD

Interaction with medicinal products that induce or inhibit hepatic microsomal enzymes is possible, which may increase or decrease the clearance of sex hormones.

Substances that increase the clearance of levonorgestrel, for example: phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, as well as preparations containing St. John’s wort. The effect of these substances on the contraceptive efficacy of the Mirena^® IUD is unknown, but it is assumed to be not significant due to the local mechanism of action.

Substances with variable effects on the clearance of levonorgestrel: when used concomitantly with sex hormones, many HIV or hepatitis C virus protease inhibitors and non-nucleoside reverse transcriptase inhibitors can either increase or decrease the plasma concentration of the progestin.

Substances that decrease the clearance of levonorgestrel (enzyme inhibitors), for example: strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g., fluconazole, itraconazole, ketoconazole, voriconazole), verapamil, macrolide antibiotics (e.g., clarithromycin, erythromycin), diltiazem and grapefruit juice may increase plasma concentrations of the progestin.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life (before insertion) is 3 years. Do not use after the expiry date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.