Mirena intrauterine system 20 mcg/24 hours with delivery device #1

Instructions for Mirena intrauterine system 20 mcg/24 hours with insertion device No. 1

Composition

active ingredient: levonorgestrel;

1 intrauterine system contains levonorgestrel 52 mg (20 μg/24 h);

excipients: polydimethylsiloxane elastomer, polyethylene, barium sulfate, colloidal anhydrous silicon dioxide, iron oxide (E 172).

Dosage form

Intrauterine system with levonorgestrel.

Main physicochemical properties: intrauterine system with levonorgestrel and with inserter (introduction device).

Intrauterine drug delivery system (IUD) consisting of a hormone-elastomeric matrix reservoir placed on a T-shaped polyethylene housing. The reservoir core consists of 50% levonorgestrel and 50% polydimethylsiloxane elastomer, covered with a polydimethylsiloxane membrane. At one end of the T-shaped housing there is a loop, at the other end there are two white or almost white hangers. Two brown removal threads are attached to the loop. There should be no visually noticeable particles on the surface of the system.

The injection device consists of an injection tube, piston, flange, housing, and slider.

Pharmacotherapeutic group

Contraceptive for topical use.

Intrauterine contraceptive.

ATX code G02B A03.

Pharmacological properties

Pharmacodynamics

Levonorgestrel is a progestogen with antiestrogenic activity, widely used in gynecology as a progestogen component in oral contraceptives, in hormone replacement therapy or alone for contraception in progestogen-only pills and in subcutaneous implants. When using the Mirena IUD, the release of levonorgestrel occurs directly in the uterine cavity. This allows the use of very small doses, since the hormone is released directly into the target organ. Therefore, plasma concentrations of levonorgestrel are lower than with many other methods of contraception.

The Mirena system is characterized mainly by the local action of the progestogen in the uterine cavity. The high concentration of levonorgestrel in the endometrium reduces the expression of estrogen and progestogen receptors of the endometrium, which causes a pronounced antiproliferative effect, since the endometrium becomes insensitive to the action of estrogens. During the use of the Mirena system, morphological changes of the endometrium and a weak local reaction to a foreign body are observed. Thickening of the cervical mucus prevents the passage of sperm through the cervical canal. The local environment of the uterus and fallopian tubes inhibits the motility and function of sperm, preventing fertilization. In some women, ovulation is suppressed.

The contraceptive efficacy of the Mirena intrauterine system has been studied in 5 large clinical trials involving 3330 women. The contraceptive efficacy of the Mirena system when used for a period of more than 5 years was studied in 362 women in a clinical trial using the Mirena system, with 221 women completing the 8-year study. During the 6th to 8th year of use of the Mirena system, the Pearl Index was 0.28 [95% CI (0.03, 1.00)]. Information on the contraceptive efficacy of the Mirena system is summarized in Table 1.

Table 1. Cumulative failure rate (%) and Pearl index

* Kaplan–Meier method.

The failure rate also includes pregnancies resulting from unexpected expulsion and perforation. Similar contraceptive efficacy was observed in a large post-marketing study involving more than 17,000 women using the Mirena system. Since the Mirena system does not require daily dosing, the pregnancy rate with typical use is similar to that observed in controlled clinical trials (perfect use).

When analyzing the tolerability of the drug based on the number of people who continued to use it, the Mirena system (when used as a contraceptive method) and the copper intrauterine devices were found to be equally tolerable. After the first year of use, about 80% of women continued to use the system.

The pattern of menstruation is a direct result of the direct action of levonorgestrel on the endometrium and is not regulated by ovarian function. There is no clear difference in follicular development, ovulation, or estradiol and progesterone production in women with different menstrual patterns. During the initial phase of use, the suppression of endometrial proliferation may lead to increased spotting during the first months. Over time, the suppression of the endometrium leads to a reduction in the duration and volume of menstrual bleeding during the use of the Mirena system. Minor spotting often progresses to oligomenorrhea or amenorrhea. Even with amenorrhea, women using the Mirena system have normal ovarian function and estradiol levels are maintained.

The Mirena IUD was designed specifically for women who require long-term effective contraception. The Mirena system can also be successfully used in the treatment of idiopathic menorrhagia. In women with menorrhagia, menstrual blood loss was reduced by 62–94% during the first three months of use of the system and by 71–95% during the six months of use of the system. The use of the Mirena system has shown similar effectiveness in reducing menstrual blood loss over two years compared with endometrial ablation or resection. Treatment of menorrhagia caused by submucosal leiomyomas may be less effective. The reduction in menstruation increases hemoglobin levels in the blood. Mirena also relieves dysmenorrhea, as do oral contraceptives.

The efficacy of the Mirena system in the treatment of menorrhagia and in the local use of progestogen in conjunction with estrogen replacement therapy is due to the effect of levonorgestrel on the endometrium, which is to prevent endometrial proliferation. No cases of endometrial hyperplasia were reported during the 12-month study. Prevention of proliferation was equally effective when estrogen was administered orally, transdermally, or subcutaneously. The total level of levonorgestrel released by the Mirena system is sufficient to prevent endometrial proliferation for 5 years.

The efficacy of Mirena in preventing endometrial hyperplasia during long-term estrogen therapy was as high as with oral and transdermal estrogen. The incidence of hyperplasia during estrogen monotherapy is 20%. In clinical trials of Mirena in 634 perimenopausal and postmenopausal women, no cases of endometrial hyperplasia were reported during a follow-up period of 1 to 5 years.

Pharmacokinetics

Levonorgestrel is released into the uterine cavity and acts locally. The expected in vivo release rate of levonorgestrel for different time periods is presented in Table 2.

Table 2. Expected in vivo levonorgestrel release rate for Mirena IUD

Absorption: After insertion, levonorgestrel begins to be released into the uterine cavity immediately, as determined by serum concentrations. The released levonorgestrel is fully systemically available.

After insertion of the Mirena system, levonorgestrel can be detected in serum/plasma as early as 1 hour. The maximum concentration of 180 ng/L (coefficient of variation, CV 38.3%) is reached within 2 weeks after insertion. In line with the decrease in the release rate, the serum/plasma concentration of levonorgestrel (geometric mean) decreases steadily, as shown in Table 3.

Table 3. Total plasma levonorgestrel concentration

Distribution. The pharmacokinetics of levonorgestrel have been extensively studied and described in the literature. When administered orally, levonorgestrel is rapidly and completely absorbed, with an absolute bioavailability of about 90%. Levonorgestrel binds nonspecifically to serum albumin and specifically to sex steroid binding globulin (SSGB). Less than 2% of the total serum levonorgestrel concentration is represented as free steroid. Levonorgestrel binds with high affinity to SSGB. Accordingly, changes in serum SSGB concentration lead to an increase (at higher SSGB concentration) or a decrease (at lower SSGB concentration) in the total serum levonorgestrel concentration. SSGB concentration decreases by an average of 20% during the first two months after insertion of the Mirena system and remains stable thereafter, increasing slightly at the end of 8 years of use. For levonorgestrel, the mean volume of distribution is approximately 106 liters.

Body weight and serum LH concentrations influence systemic levonorgestrel concentrations, i.e. low body weight and/or high LH levels lead to increased levonorgestrel concentrations. In women of reproductive age with low body weight (37 to 55 kg), the average serum levonorgestrel concentration is approximately 1.5 times higher.

In postmenopausal women, when using the Mirena system in combination with non-oral estrogen therapy, the mean serum concentration of levonorgestrel decreases from
257 pg/ml after 12 months of treatment (25th to 75th percentile: 186 to 326 pg/ml) to 149 pg/ml (122 to 180 pg/ml) after 60 months. When the Mirena system is used in combination with oral estrogen therapy, the serum levonorgestrel concentration after 12 months increases to 478 pg/ml (341 to 655 pg/ml) due to the induction of the GHSS by oral estrogen therapy.

Biotransformation. Levonorgestrel is extensively metabolized. The most important metabolic pathway is reduction of the Δ4-3-oxo group and hydroxylation at positions 2α, 1β and 16β with subsequent conjugation. CYP3A4 is also involved in the oxidative metabolism of levonorgestrel. Available in vitro data indicate that this metabolic pathway is of lesser importance for levonorgestrel compared to reduction and conjugation.

Elimination. The total clearance of levonorgestrel from plasma is approximately 1 ml/min/kg. Only trace amounts of levonorgestrel are excreted unchanged. Metabolites are excreted in feces and urine in equal amounts. The half-life is approximately one day.

Linearity/nonlinearity

The pharmacokinetics of levonorgestrel depend on the concentration of the GHSS, which in turn is influenced by estrogens and androgens. A decrease in the level of GHSS leads to a decrease in the total serum concentration of levonorgestrel, which indicates nonlinear pharmacokinetics of levonorgestrel over time. Since the Mirena system has a predominantly local effect, no effect on its effectiveness is expected.

Indication

Contraception;

idiopathic menorrhagia;

hypermenorrhea;

dysmenorrhea;

local progestogen therapy during estrogen replacement therapy.

Contraindication

- Pregnancy or suspected pregnancy;

- progestogen-dependent tumors, such as breast cancer;

- acute or recurrent pelvic inflammatory disease;

- cervicitis;

- infectious disease of the lower genital tract;

- postpartum endometritis;

- infected miscarriage or abortion within the last 3 months;

- conditions associated with increased susceptibility to infectious diseases;

- cervical dysplasia;

- confirmed or suspected malignant tumors of the cervix or uterus;

- uterine bleeding, the cause of which is not clear;

- congenital or acquired pathology of the uterus, including leiomyoma, in case of deformation of the uterine cavity;

- acute liver disease or liver tumors;

- hypersensitivity to the active substance or to the excipients of the drug.

Interaction with other medicinal products and other types of interactions

Interactions are possible with simultaneous use with drugs that induce liver enzymes and may lead to increased clearance of sex hormones.

Active substances that increase the clearance of levonorgestrel, for example: phenytoin, barbiturates, primidone, carbamazepine, rifampicin and possibly oxcarbazepine, topiromate, felbamate, griseofulvin and herbal remedies containing St. John's wort extract (Hypericum perforatum).

The effect of these drugs on the contraceptive efficacy of the Mirena system is unknown, but is believed to be minor due to the predominantly local mechanism of action of the drug.

Active substances that reduce the clearance of levonorgestrel (enzyme inhibitors): Concomitant use of strong and moderate CYP3A4 inhibitors, such as azole antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice may increase the plasma concentration of the progestin.

Special safety measures.

Instructions for use

The Mirena system should be inserted by a physician under aseptic conditions.

The Mirena system is sold in a sterile package that should be opened immediately before insertion. It cannot be resterilized or reused. For single use only.

Aseptic precautions should be observed when handling the unpackaged system. If the protective layer of the packaging has been damaged, the unused intrauterine system should be disposed of as medical waste.

Do not administer after the expiry date. For the time of administration, see the section “Method of administration and dosage”.

Application features

If you have any of the following conditions or diseases, Mirena should only be used after consulting a qualified healthcare professional. If these symptoms occur for the first time, removal of the system should be considered:

migraine, focal migraine accompanied by asymmetric visual disturbances or other symptoms suggestive of transient cerebral ischemia;

extremely severe headache;

jaundice;

significant increase in blood pressure;

severe cardiovascular diseases, such as stroke or myocardial infarction;

acute venous thromboembolism.

If symptoms suggestive of retinal thrombosis occur, such as partial or complete loss of vision of unknown cause, proptosis or diplopia, optic disc swelling, or retinal vascular lesions, appropriate diagnostic and therapeutic measures should be taken immediately.

There is no consensus on the possible role of varicose veins and superficial thrombophlebitis in the development of thromboembolism. The Mirena system should be used with caution in women with congenital heart disease or valvular heart disease if there is a risk of developing infective endocarditis.

Low doses of levonorgestrel may affect glucose tolerance, so blood glucose levels should be monitored in diabetic patients using Mirena. However, there is usually no need to change the therapeutic regimen in diabetic women using Mirena.

Irregular bleeding may mask certain symptoms and signs of the presence of polyps or endometrial cancer, in which case diagnostic testing should be considered.

The Mirena system is not the method of first choice for postmenopausal women with severe uterine atrophy.

When using the Mirena system simultaneously with estrogen as part of hormone replacement therapy, the safety data of estrogens should also be taken into account.

Medical examination/consultation.

Before insertion, the woman should be informed about the effectiveness, risks (including the signs of risks described in the instructions for medical use of the medicinal product) and side effects of using the Mirena system. A physical examination of the patient should be performed, including the pelvic organs, breasts, and cytological examination of a cervical smear if a smear has not been taken within the last three months. Pregnancy and sexually transmitted diseases should be excluded, and if necessary, genital tract infections should be treated. The location of the uterus and the size of the uterine cavity should be determined. It is important to place the Mirena system in the fundal area of the uterus to ensure uniform exposure of the progestogen to the entire surface of the endometrium, prevent expulsion and achieve maximum effectiveness. Therefore, the instructions for inserting the system should be carefully followed (see section "Method of administration and dosage"). Since the technique of inserting this system is different from that of other intrauterine contraceptives, special attention should be paid to mastering the technique of correct installation of the system. Insertion and removal of the system may cause brief pain and bleeding. The procedure may cause dizziness as a vasovagal reaction or seizure in epileptic patients. If insertion-related complications and/or severe pain are anticipated, a system with a smaller diameter insertion tube should be considered.

The woman should be re-examined 4–12 weeks after insertion of the system, and then annually or more frequently as medically indicated.

The Mirena system cannot be used as a postcoital contraceptive.

Irregular bleeding/spotting is common during the first months of use, so it is recommended to rule out endometrial pathology before Mirena is inserted. If a woman continues to use Mirena as hormone replacement therapy when contraception is no longer required, endometrial pathology should be ruled out if abnormal bleeding occurs after estrogen replacement therapy is started. If irregular bleeding develops during prolonged use of the system, appropriate diagnostic measures should also be taken.

57% of women of reproductive age gradually develop oligomenorrhea and 16% develop amenorrhea during the first year of use. By the end of the eighth year of Mirena use, oligomenorrhea and amenorrhea were observed in 26% and 34% of women, respectively. If a woman does not have a new menstruation six weeks after her last menstruation, pregnancy should be excluded and the position of the system checked. If there are no other symptoms of pregnancy, there is no need to perform a second pregnancy test in women with amenorrhea.

Due to the pronounced local effect of levonorgestrel on the endometrium, the latter does not respond to estrogens, and, therefore, endometrial proliferation does not occur. The duration and intensity of menstrual bleeding is reduced. When comparing women with different menstrual bleeding patterns, no clear difference was found between follicular development, ovulation, or estradiol or progesterone production. During the first three and six months of use of the system, the intensity of menstrual bleeding in women with menorrhagia decreased by 62–94% and 71–95%, respectively. As a result of the reduction in menstrual bleeding, hemoglobin levels increase.

When local progestogen therapy is used in combination with estrogen therapy, most women gradually develop amenorrhea during the first year. Irregular menstrual bleeding and spotting were quite common during the first three months of system use.

Infectious diseases of the pelvic organs.

The insertion tube prevents contamination of the system with microorganisms during insertion, and the insertion device is also designed to minimize the risk of infectious diseases. Based on experience with copper-containing intrauterine systems, the rate of pelvic inflammatory disease is highest during the first month of use and decreases thereafter. The risk of pelvic inflammatory disease is highest in young women and increases if the woman or her partner has multiple sexual partners. Pelvic inflammatory disease can have serious consequences, affect reproductive function, and increase the risk of ectopic pregnancy. As with other gynecological or surgical procedures, severe infections or sepsis (including sepsis caused by group A streptococcus) may occur, although the risk of these complications is extremely low.

If a woman experiences recurrence of endometritis or pelvic inflammatory disease, acute inflammation that does not respond to treatment within several days, the Mirena system should be removed (see section "Contraindications"). The results of some studies suggest that the incidence of pelvic inflammatory disease is lower among Mirena users than among patients who used copper-containing intrauterine systems.

It is necessary to conduct bacteriological studies and monitor the patient if there are even mild symptoms of an infectious disease.

Expulsion.

In clinical trials of Mirena for contraception, the expulsion rate was low (< 4% of insertions) and was in the same range as other IUDs or intrauterine devices. The system may spontaneously fall out of the uterine cavity without the woman noticing, resulting in reduced contraceptive efficacy. Symptoms of partial or complete expulsion of the Mirena intrauterine system may include bleeding and pain. Since Mirena helps to reduce the amount of menstrual discharge, increased menstrual flow may be a sign of expulsion.

The risk of expulsion is increased in:

- women with a history of heavy menstrual bleeding (including women using the Mirena system for the treatment of heavy uterine bleeding);

- women with a BMI above normal at the time of system installation; this risk gradually increases with increasing BMI.

Women should be counseled about possible signs of expulsion and how to check for the presence of Mirena threads and advised to seek medical attention if the threads cannot be felt. Barrier contraceptives (e.g. condoms) should be used until the location of Mirena is confirmed.

Partial expulsion of the Mirena system may reduce its effectiveness.

A partially displaced Mirena should be removed. A new Mirena can then be inserted. A new system can be inserted immediately after removal, provided that pregnancy is excluded.

Perforation.

In a prospective, comparative, non-interventional cohort study of IUD users (N = 61,448 women), the perforation rate during a 1-year follow-up period was 1.3 (95% confidence interval: 1.1–1.6) per 1000 insertions in the entire cohort; 1.4 (95% confidence interval: 1.1–1.8) per 1000 insertions in the Mirena IUD group; and 1.1 (95% confidence interval: 0.7–1.6) per 1000 insertions in the copper-containing IUD cohort.

The data suggest that both insertion during breastfeeding and insertion before 36 weeks postpartum are associated with an increased risk of perforation (see Table 4). Both risk factors were independent of the type of IUD inserted.

Table 4. Perforation rates per 1000 injections in a 1-year cohort study, stratified by breastfeeding status at the time of injection and time of injection after delivery

When the follow-up period was extended to 5 years in a subgroup of this study (n = 39,009 women using Mirena or copper-containing IUDs; for 73% of these women, data were available for the entire follow-up period), the rate of perforations detected at any time during the 5-year period was 2.0 (95% CI: 1.6–2.5) per 1000 insertions. Insertion during breastfeeding and within 36 weeks postpartum were confirmed as risk factors also in the 5-year follow-up subgroup.

The risk of perforation may be increased in women with a fixed uterine bend.

A post-insertion re-examination should be performed according to the information provided in the Medical Examination/Consultation section, which may be adapted as clinically indicated in women with risk factors for perforation.

Breast cancer.

A meta-analysis of 54 epidemiological studies suggests a small increased relative risk (RR = 1.24) of breast cancer in women using combined oral contraceptives (COCs), mainly those containing a combination of estrogen and progestogen. The risk gradually disappears within 10 years after stopping COC use. Since breast cancer is rare in women under 40 years of age, the number of cases of this disease in current or recent COC users is small compared with the overall risk of breast cancer. It is likely that the risk of breast cancer in users of progestogen-only oral contraceptives is similar to that in users of COCs. However, the conclusions for progestogen-only products are based on data from much smaller populations of women and are therefore less conclusive than those for COCs. These studies do not provide evidence of a causal relationship. The observed increased risk may be due to the earlier diagnosis of breast cancer in users of oral contraceptives, the biological action of such contraceptives, or a combination of these two factors. Breast cancer diagnosed in women who have ever used COCs tends to be less clinically significant than breast cancer in women who have never used COCs.

The risk of breast cancer is increased in postmenopausal women who use systemic hormone replacement therapy (pills or products applied to the skin). The risk is higher in women who use a combination of estrogen and progestogen than in those who use estrogen-only products. It is also important to carefully read the information about the estrogen-containing product used in the therapy.

Ectopic pregnancy.

The possibility of ectopic pregnancy should be considered in the presence of lower abdominal pain, especially in the absence of menstruation, or if bleeding occurs in a woman who has been amenorrhoeic. Women with a history of previous ectopic pregnancies, tubal surgery, or pelvic infections are at increased risk for ectopic pregnancy.

The absolute risk of ectopic pregnancy in women using Mirena is lower because the overall probability of pregnancy is lower in women using Mirena than in women not using any contraceptive method. In a prospective, non-interventional cohort study with a 1-year follow-up period, the pregnancy rate in women using Mirena was 0.02%. In clinical trials, the absolute rate of ectopic pregnancy in women using Mirena was approximately 0.1% per year. This rate is lower than in women not using any contraceptives (0.3–0.5% per year). However, if a woman with Mirena becomes pregnant, the relative risk of ectopic pregnancy is increased.

If the removal threads are not visible in the cervix during examination, pregnancy should be ruled out. The threads may have entered the uterus or cervix and may reappear during the next menstrual period. If pregnancy has been ruled out, the threads can be removed from the cervical canal with a suitable instrument. If the threads cannot be found, perforation or expulsion should be considered. Ultrasound can be used to confirm correct placement of the system. If ultrasound is not available or if ultrasound is not satisfactory, X-rays can be used to determine the location of the Mirena system.

Ovarian cysts

Because the contraceptive effect of the Mirena system is primarily due to the local action of the progestin, ovulatory cycles with ruptured follicles usually proceed normally in women of reproductive age. Occasionally, follicular atresia is delayed and follicular development may continue. Such enlarged follicles are clinically indistinguishable from ovarian cysts. Ovarian cysts have been diagnosed in approximately 7% of women using the Mirena system. Most such follicles are asymptomatic, although some may present with pelvic pain or dyspareunia.

In most cases, ovarian cysts resolve spontaneously within 2–3 months of observation. If this does not occur, regular ultrasound examinations or other diagnostic/therapeutic procedures are recommended. In rare cases, surgical intervention may be necessary.

Mental disorders

Depressed mood and depression may occur with hormonal contraceptive use (see section 4.8). Depression can be a serious condition and is a risk factor for suicidal behaviour and suicide. Women should be advised to seek medical advice if they experience mood changes or symptoms of depression, including early in the course of treatment.

Precautions during removal

Using excessive force or sharp instruments during removal may cause the system to break (see section 4.2). Therefore, after removal, the Mirena system should be inspected to ensure that it has been completely removed.

Use during pregnancy or breastfeeding

Pregnancy

The use of the Mirena system is contraindicated during pregnancy or if pregnancy is suspected (see section "Contraindications").

If a woman becomes pregnant with Mirena in place, the system should be removed as soon as possible, as any intrauterine contraceptive left in the uterus during pregnancy increases the risk of miscarriage and premature birth. Removal of Mirena may result in spontaneous abortion. If a woman wishes to continue the pregnancy and is unable to remove the system, she should be informed of the risk to the child and the possible consequences of premature birth. The course of such a pregnancy requires careful monitoring. An ectopic pregnancy should be excluded. The doctor should advise the woman to inform him of any symptoms that may be associated with complications of pregnancy, such as cramping abdominal pain with fever.

In addition, an increased risk of virilizing effects in the female fetus due to intrauterine exposure to levonorgestrel cannot be excluded. Isolated cases of masculinization of the external genitalia of the female fetus have been reported following topical exposure to levonorgestrel during pregnancy with a hormonal IUD in the uterus.

Lactation

The daily dose and plasma concentration of levonorgestrel are lower with Mirena than with many other hormonal contraceptive methods, but levonorgestrel has been detected in breast milk. About 0.1% of the levonorgestrel dose is excreted in the breast milk. Hormonal contraceptives are not recommended as first-line contraceptives during lactation, but progestogen-only methods are the first-line contraceptives after non-hormonal methods. No harmful effects on the growth and development of the child have been observed when the system is used six weeks postpartum. Progestogen-only methods have shown no effect on the cycle.