Expiration date: 02/2025

The composition and form of issue:

Intrauterine therapeutic system contains:

levonorgestrel 52 mg

excipients: polydimethylsiloxane elastomer — 52 mg 

vacuum paper plastic packing 1 PCs in a box 1 pack.

Description pharmaceutical form:

Therapeutic intrauterine system (ius) placed in the tube of the conductor. The system consists of a white or almost white hormone-elastomer core, placed on a T-shaped housing and covered with an opaque membrane that regulates the release of levonorgestrel. T-shaped housing is provided with a loop on one end and two shoulders on the other. Attached to the loop of the thread to remove the system. System Explorer is free from visible impurities.

Pharmacokinetics:

Absorption. After the introduction of the Mirena in the uterus begins to immediately release levonorgestrel.

High local drug exposure in the uterine cavity, is necessary for the local effects of Mirena on the endometrium, provides a high concentration gradient in the direction from the endometrium to the myometrium (the concentration of levonorgestrel in the endometrium is greater than its concentration in the myometrium more than 100-fold) and low concentrations of levonorgestrel in serum (concentration of levonorgestrel in the endometrium higher than the concentration in the serum of more than 1000 times).

The rate of release of levonorgestrel in the uterine cavity in vivo is initially approximately 20 µg/day, and in 5 years be reduced to 10 mg/day.

Distribution. Levonorgestrel is associated with nonspecific serum albumin, and a specific — globulin, linking sex hormones (SHBG). About 1-2% of the circulating levonorgestrel is present as free steroid, while 42-62% specifically associated with SHBG. During the application of Mirena the concentration of SHBG is reduced. Accordingly, the fraction associated with SHBG, during the use of Mirena is reduced and the free fraction increases. Average apparent Vd levonorgestrel is 106 L.

After insertion Mirena levonorgestrel detected in blood serum an hour later. Cmax achieved within 2 weeks after insertion of Mirena. In accordance with the declining release rate, the median concentration of levonorgestrel in serum from women of reproductive age with a body weight above 55 kg is reduced from 206 PG/ml (25-75 th percentiles: 151-264 PG/ml) determined at 6 months to 194 PG/ml (146-266 PG/ml) after 12 months and to 131 PG/ml (113-161 PG/ml) in 60 months.

It was shown that body weight and the concentration of SHBG in serum affects systemic concentration was levonogestrel, i.e. at low body weight and/or high levels of SHBG, the concentration of levonorgestrel is higher. In women of reproductive age with low body mass (37-55 kg) median concentration of levonorgestrel in serum of about 1.5 times higher.

In women in postmenopausal women, using a Mirena in conjunction with the estrogen therapy is neironalnuu, the median concentration of levonorgestrel in serum is reduced from 257 PG/ml (25-75 th percentiles: 186-326 PG/ml) determined after 12 months, to 149 (122-180 PG/ml) in 60 months. When using Mirena concurrently with oral estrogen therapy is the concentration of levonorgestrel in serum, determined after 12 months increases to about 478 PG/ml (25-75 th percentiles: 341-655 PG/ml), due to the induction of the synthesis of SHBG oral administration of estrogens.

Biotransformation. Levonorgestrel is largely metabolized. The main metabolites in plasma are the unconjugated and conjugated forms of 3&alpha, 5&beta-tetrahydrolevonorgestrel. Based on the results of studies in vitro and in vivo, the main isoenzyme involved in the metabolism of levonorgestrel is CYP3A4. In the metabolism of levonorgestrel can participate isoenzymes CYP2E1, CYP2C9 and CYP2C19, but to a lesser degree.

Elimination. Total clearance of levonorgestrel from plasma is approximately 1 ml/min/kg unchanged levonorgestrel is excreted only in trace amounts. Metabolites are excreted via the bowel and kidney excretion ratio, approximately equal to 1.77. T1/2 the terminal phase, mainly represented by metabolites amounts to about a day.

Description pharmacological action:

Mirena intrauterine system (ius), levonorgestrel releasing, it has mainly local progestogenic effect. Gestagen (levonorgestrel) is released directly into the uterine cavity, which allows to use it in very low daily dose. High concentrations of levonorgestrel in the endometrium reduce the sensitivity of its progesterone, estrogen receptors, making the endometrium insensitive to estradiol and exerting a strong antiproliferative effect. When using Mirena observed morphological changes of the endometrium and a weak local reaction to the presence in the uterus of a foreign body. Thickening of the mucous membrane of the cervical canal prevents the penetration of sperm into the uterus, Mirena prevents fertilization due to inhibition of mobility and function of sperm in the uterus and fallopian tubes. In some women occurs and inhibition of ovulation.

Prior to the use of Mirena has no effect on fertility. Approximately 80% of women wishing to have a baby, pregnancy occurs within 12 months after the removal of the Navy.

In the first months of use of Mirena due to inhibition of the process of endometrial proliferation may be the initial gain spotting bleeding. Following this, a marked suppression of the endometrium leads to a decrease in the duration and volume of menstrual bleeding in women who use Mirena. Scanty bleeding often transformirovalsya in oligo - or amenorrhea. The function of the ovaries and estradiol levels in the blood remain normal. Mirena may be used for the treatment of idiopathic menorrhagia, ie menorrhagia in the absence of genital diseases (such as cancer of the endometrium, metastatic lesions of the uterus, submucosal or large interstitial site of uterine fibroids, leading to deformation of uterine cavity, adenomyosis, endometrial hyperplasia, endometritis) and extragenital diseases and conditions, accompanied by severe anticoagulation (e.g. von Willebrand's disease, severe thrombocytopenia), symptoms is menorrhagia. By the end of the third month after the installation of Mirena in women with menorrhagia, the amount of menstrual bleeding is reduced by 88%. If menorrhagia caused by submucosal fibroids, the treatment effect is less pronounced. Reduction of menstrual blood loss reduces the risk of iron deficiency anemia. Mirena can also reduce the severity of dysmenorrhea.

The efficacy of Mirena in preventing endometrial hyperplasia during continuous estrogen therapy was equally high as oral and transdermal use of estrogen.

Indications:

• contraception
  
• idiopathic menorrhagia
  
• prevention of endometrial hyperplasia during of estrogen replacement therapy.
  

Contraindications:

• hypersensitivity to the drug
  
• pregnancy or suspicion on it
  
• existing or recurrent inflammatory diseases of pelvic organs
  
• infections of the lower urinary tract
  
• postpartum endometritis
  
• septic abortion in the last 3 months
  
• cervicitis
  
• the disease is accompanied by increased susceptibility to infections
  
• cervical dysplasia
  
• malignant neoplasms of the uterus or cervix
  
• progestagens.obesity tumors, including breast cancer
  
• pathological uterine bleeding of unknown etiology
  
• congenital or acquired uterine abnormalities, including fibroids, leading to deformation of uterine cavity
  
• acute disease or a liver tumor.
  

WITH CAUTION

After the consultation with the specialist:

• migraine, focal migraine with asymmetrical visual loss or other symptoms indicating transient cerebral ischemia
  
• unusually severe headache
  
• jaundice
  
• severe hypertension
  
• severe circulatory disorders, including stroke and myocardial infarction.
  

You should discuss the advisability of removal of the system with or the first occurrence of any of the following conditions.

Application of pregnancy and breast-feeding:

Pregnancy. The Mirena cannot be used in pregnancy or suspected it. If pregnancy occurs in a woman during Mirena use, it is recommended to remove the IUD, since any intrauterine contraceptive left in situ, increases the risk of spontaneous abortion and premature birth. Removal of Mirena or probing of the uterus may result in spontaneous abortion. If you care to remove intrauterine impossible, you should discuss the appropriateness of abortion. If a woman wants to keep the pregnancy and the IUD cannot be removed, you should inform the patient about the risks and possible consequences of preterm birth for the baby. In such cases pregnancy should be carefully monitored. It is necessary to exclude ectopic pregnancy. She should explain that she should report any symptoms that suggest a complication of pregnancy, in particular colicky abdominal pain accompanied by fever.

For intrauterine applications, and the local actions of the hormone you need to take into account the possibility of virilizing effects on the fetus. Due to the high contraceptive efficacy of Mirena clinical experience related to pregnancy outcomes in its application, is limited. However, the woman should be informed that for today of the certificate of birth defects caused by Mirena use in cases where continuation of pregnancy until the birth without the removal of the Navy, no.

Lactation. About 0.1% of the dose of levonorgestrel may enter the body of the newborn in the process of breastfeeding. However, it is unlikely to represent a risk to the child when doses released by Mirena, located in the cavity of the uterus.

It is believed that the use of Mirena in 6 weeks after delivery no adverse effects on growth and development of the child. Monotherapy with progestin has no effect on the quantity and quality of breast milk. It was reported about rare cases, uterine bleeding in women using the Mirena, during lactation.

Side effects:

Side effects often develop in the first months after insertion of Mirena in the uterus with prolonged use, they gradually disappear.

Very common side effects (seen in more than 10% of women using the Mirena) are uterine/vaginal bleeding, spotting, oligo - amenorrhea and benign ovarian cysts. The average number of days where the observed spotting in women of childbearing age is gradually reduced from nine to four days per month during the first six months after the Navy. The number of women with prolonged (more than eight days) bleeding reduced from 20 to 3% in the first 3 months of use of Mirena. In clinical studies, it was found that in the first year of Mirena use and 17% of women had amenorrhea of at least 3 months. When Mirena is used in combination with estrogen substitution therapy, in the first months of treatment the majority of women in peri - and postmenopausal period observed spotting and irregular bleeding. In the future, their frequency decreases, and about 40% receiving this therapy in women in the last 3 months of the first year of treatment the bleeding generally disappear. The changing nature of bleeding is more common in perimenopausal period than in postmenopausal. The detection rate of benign ovarian cysts depends on the diagnostic method. According to clinical trials enlarged follicles have been diagnosed in 12% of women who used Mirena. In most cases, the increase in follicles of asymptomatic and disappeared within 3 months. The table shows side effects, classified by organs and systems according to MedDRA. The frequency corresponds to the data of clinical trials.

Table

Organ and system	The degree of frequency of development of side effects
	Often — &ge1/100, <1/10	Rarely — &ge1/1000, <1/100	Very rarely — &ge1/10000, <1/1000
Mental disorders	Reduced mood, nervousness, decreased libido	Mood changes
Violations from nervous system	Headache	Migraine
Gastrointestinal disorders	Abdominal pain, nausea	Bloating
Violations from skin and hypodermic tissues	Acne	Alopecia, rash, hirsutism, itching, eczema	Rash, urticaria
Violations of the musculoskeletal system	Back pain
Violations of the reproductive system and mammary glands	Pain in the pelvis, dysmenorrhea, vaginal discharge, vulvovaginitis, breast tension, breast tenderness	Inflammatory diseases of small pelvis organs, endometritis, cervicitis/the result of the study, including Papanicolaou smear corresponds to a class II	Perforation of the uterus
Metabolic disorders	The increase in body weight
From the body as a whole		Swelling
General disorders and pathological conditions in the installation of Mirena	Expulse VMS

Cm. also "Use with caution" and "Special instructions".

For the description of certain reactions, their synonyms and related conditions, in most cases, terminology used, corresponding to MedDRA.

If a woman with an installed Mirena pregnancy, the relative risk of ectopic pregnancy increases. In addition, reported cases of breast cancer (frequency not known).

Drug interactions:

The metabolism of progestins may be enhanced by concomitant use of substances that are inducers of enzymes, especially cytochrome P450 isoenzymes involved in the metabolism of drugs such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and means for treating infections (e.g. rifampicin, rifabutin, nevirapine, efavirenz). The impact of these drugs on the efficacy of Mirena is not known, but I believe that it is not essential, since Mirena has a mainly local effect.

Method of application and dose:

Intrauterine. Mirena is inserted into the uterus and remains effective for five years. The rate of release of levonorgestrel in vivo at the beginning is about 20 g/day and reduced in five years to about 10 mg/day. The average release rate of levonorgestrel is about 14 microgram/day for up to 5 years. The Mirena can be used in women receiving hormone replacement therapy in combination with oral or transdermal preparations of estrogen that does not contain progestins.

When installed correctly, the Mirena conducted in accordance with the instruction for medical use, the Pearl index (indicator, reflecting the number of pregnancies in 100 women using a contraceptive during the year) is about 0.2% for 1 year. The cumulative indicator of the number of pregnancies in 100 women using a contraceptive for 5 years is 0.7%.

Instructions for use of VMS and handling

Mirena is supplied in a sterile package which is opened only immediately before installing the intrauterine system. It is necessary to observe the rules of asepsis when handling the exposed system. If the sterility of the package seems broken, the Navy should be destroyed as medical waste. You should also contact and remote from the uterus, the IUD, because it contains the remains of hormone.

Installation, removal and replacement of intrauterine system

Install Mirena need only a doctor who has experience with the Navy or well trained to perform this procedure.

Before installation of Mirena the woman should be informed about the effectiveness, risks and side effects of this IUD. It is necessary to conduct General and gynecological examination, including examination of the pelvic organs and mammary glands, as well as smear from your cervix. Should exclude pregnancy and sexually transmitted diseases, and genital infections must be treated and cured. Determine the position of the uterus and its cavity. Especially important is the correct location of Mirena in the bottom of the uterus that ensures a uniform effect of progestogen on the endometrium, prevents expulsio Navy and creates the conditions for its maximum efficiency. Therefore, you should carefully comply with instructions for installing the Mirena. Since the equipment setup in the uterus different Navy different, special attention should be paid to practicing the correct technique of installation of a particular system.

The woman should be re-evaluated after 4-12 weeks after installation and then 1 time per year or more frequently when clinically indicated.

In women of childbearing age Mirena should be set into the uterine cavity within seven days from the onset of menstruation. Mirena can be replaced by a new Navy any day of the menstrual cycle. The CPA also can be installed immediately after abortion in the first trimester of pregnancy.

Postpartum installation of VMS should be done when there will be involution of the uterus, but not earlier than 6 weeks after giving birth. Long subinvolution is necessary to exclude postpartum endometritis and to postpone the decision on the introduction of Mirena prior to the completion of involution. In case of difficulties with the installation of VMS and/or very severe pain or bleeding during or after the procedure should be to immediately conduct a physical examination and ultrasonography (us) to exclude perforation.

To protect the endometrium during estrogen substitution therapy in women with amenorrhea Mirena can be fitted at any time in women with preserved menstrual the installation produced in the last days of menstruation or withdrawal bleeding.

You should not apply the Mirena for emergency contraception.

Before installation of Mirena should exclude pathological processes in the endometrium, since in the first months of its application are often marked by irregular bleeding/spotting. You should also exclude pathological processes in the endometrium in the event of bleeding after beginning estrogenovmi substitution therapy in women, which continues to use Mirena, previously established for contraception. Appropriate diagnostic measures should also be taken when irregular bleeding develops during prolonged treatment.

The Mirena is removed by careful pulling the strings, captured with forceps. If threads are not visible, and the system is in the uterine cavity, it can be removed with a traction hook for removing the IUD. This may require expansion of the cervical canal.

The system must be removed within 5 years after installation. If a woman wants to continue using the same method, the new system can be installed immediately after removing the previous one.

If necessary, further contraception in women of childbearing age IUD removal should be performed during menstruation, provided that the menstrual cycle is saved. If the system is removed mid-cycle and the woman in the previous week had sexual intercourse, she is at risk to become pregnant, except in those cases where the new system was installed immediately after removing the old one.

Installation and removal of VMS may be accompanied by pain and bleeding. The procedure can cause fainting due to a vasovagal reaction or seizure in patients with epilepsy.

After removal of Mirena should check the system for integrity. Difficulties related to IUD removal were observed isolated cases of slippage hormone-elastomer core on the horizontal shoulders of the T-shaped housing, with the result that they were hiding inside the core. Once the integrity of the CPA is confirmed, further intervention, this situation is not required. The limiters on the horizontal arms usually warn the complete separation of the core from the T-shaped body.

Overdose:

Not marked.

Special instructions:

The results of some recent studies show that women taking contraceptives containing only progestogen may have a small increased risk of venous thrombosis but these results are not statistically significant. However, at the onset of symptoms the thrombosis should immediately take appropriate diagnostic and therapeutic measures.

So far not installed, is there a connection between varicose veins or superficial thrombophlebitis with the occurrence of venous thromboembolism. The Mirena should be cautiously used in women with congenital or acquired valvular heart defects, bearing in mind the risk of septic endocarditis. When you install or uninstall Navy these patients antibiotics should be prescribed to prevent.

Levonorgestrel in low doses can affect glucose tolerance, and blood levels should be regularly checked in women with diabetes and using a Mirena. However, as a rule, there is no need to change therapeutic appointments women with diabetes who apply Mirena. Some of the manifestations of polyposis or endometrial cancer may be masked irregular bleeding. In such cases, an additional examination to clarify the diagnosis.

Mirena does not apply to methods of first choice for young women who have never ex-pregnant women, nor for women in postmenopausal period with atrophy of the uterus.

Monotherapy with estrogen the incidence of endometrial hyperplasia can reach 20%. In a clinical study of the use of the Mirena (201 female perimenopausal and 259 postmenopausal women) during the 5-year observation period in the group of women who were in menopause, and cases of endometrial hyperplasia were observed.

Oligo - and amenorrhea. Oligo - and amenorrhea in women of childbearing age develops gradually in about 20% of cases of use of Mirena. If menses are absent for 6 weeks after the start of the last menstrual period should be deleted pregnancy. Repeat pregnancy tests when amenorrhea is not required, unless there are no other signs of pregnancy.

The Mirena when used in combination with a permanent replacement estrogen therapy, most women gradually developed amenorrhea during the first year.