Mirena, intrauterine therapy system (coil) 20 mcg/24 h

Mirena^®, a levonorgestrel-releasing IUD, has a predominantly local gestagenic effect. The gestagen (levonorgestrel) is released directly into the uterine cavity, allowing it to be used at an extremely low daily dose.

High concentrations of levonorgestrel in the endometrium help reduce the sensitivity of its estrogen and progesterone receptors, making the endometrium immune to estradiol and having a strong antiproliferative effect.

When using Mirena^® the morphological changes of endometrium and weak local reaction to the presence of a foreign body in the uterus are observed. An increase in the viscosity of the cervical secretion prevents the penetration of sperm into the uterus. Mirena prevents fertilization by inhibiting sperm motility and function in the uterus and fallopian tubes. In some women there is also a suppression of ovulation.

Pre-use of Mirena® has no effect on fertility. Approximately 80% of women who wish to have a baby become pregnant within 12 months after removal of the IUD.

In the first months of Mirena use, there may be an initial increase in a vaginal discharge of mucus due to inhibition of endometrial proliferation. Subsequent marked suppression of endometrial proliferation leads to a reduction in the duration and volume of menstrual bleeding in women using Mirena®. Scanty bleeding often transforms into oligo- or amenorrhea.

In this case, ovarian function and plasma estradiol concentrations remain normal.

The Mirena drug^® may be used to treat idiopathic menorrhagia, i.e. menorrhagia in the absence of endometrial hyperplastic processes (endometrial cancer, metastatic uterine lesions, submucosal or large interstitial myomatous nodules leading to a uterine cavity deformity, adenomyosis), endometritis, extragenital diseases and conditions accompanied by marked hypocoagulation (e.g. Willebrand disease, severe thrombocytopenia), which are symptoms of menorrhagia. After 3 months of Mirena use the menstrual blood loss in women with menorrhagia decreased by 62-94% and by 71-95% after 6 months of use.

When using Mirena^® for 2 years its effectiveness (decrease of menstrual bleeding) is comparable to surgical methods of treatment (endometrial ablation or resection).

A less favorable response to treatment is possible in menorrhagia due to submycotic uterine myoma. Reducing menstrual blood loss reduces the risk of iron deficiency anemia. Mirena ^® reduces symptoms of dysmenorrhea.

The efficacy of Mirena^® in preventing endometrial hyperplasia during ongoing estrogen therapy was equally high with both oral and percutaneous estrogen administration.

Pharmacokinetics

Absorption. After administration of Mirena^® levonorgestrel is immediately released into the uterine cavity, as evidenced by measurements of its plasma concentrations. The high local uterine exposure required for the local effects of Mirena^® on the endometrium provides a high concentration gradient from endometrium to myometrium (the concentration of levonorgestrel in the endometrium exceeds its concentration in 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).

The rate of levonorgestrel release into the uterine cavity in vivo is initially approximately 20 mcg/d and decreases to 10 mcg/d after 5 years.

Distribution. Levonorgestrel binds nonspecifically to plasma albumin and specifically to hSPH. About 1-2% of circulating levonorgestrel is present as a free steroid, whereas 42-62% is specifically bound to hGDP. During the use of Mirena^®, the concentration of hGH is decreased. Accordingly, the hGH-bound fraction decreases during Mirena^® and the free fraction increases. The average apparent V_d of levonorgestrel is about 106L.

After administration of Mirena^® levonorgestrel is detectable in plasma one hour later.C_max is reached 2 weeks after administration of Mirena^®. Consistent with the decreasing rate of release, the median plasma concentration of levonorgestrel in women of reproductive age with a body weight greater than 55 kg decreases from 206 pg/ml (25-75th percentile: 151-264 pg/ml) determined after 6 months to 194 pg/ml (146-266 pg/ml) after 12 months and to 131 pg/ml (113-161 pg/ml) after 60 months.

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

In postmenopausal women using Mirena^® simultaneously with intravaginal or transdermal estrogen administration, the median plasma levonorgestrel concentration decreases from 257 pg/mL (25-75th percentile: 186-326 pg/mL) determined after 12 months to 149 pg/mL (122-180 pg/mL) after 60 months.

When Mirena ^® is used concomitantly with oral estrogen administration, plasma levonorgestrel concentrations determined after 12 months increase to approximately 478 pg/mL (25th-75th percentile: 341-655 pg/mL) due to induction of hCG synthesis.

Biotransformation. Levonorgestrel is largely metabolized. The main metabolites in the blood plasma are unconjugated and conjugated forms of 3α, 5β-tetrahydrolevonorgestrel.

Based on in vitro and in vivo studies, the main isoenzyme involved in the metabolism of levonorgestrel is CYP3A4. The isoenzymes CYP2E1, CYP2C19 and CYP2C9 may also be involved in levonorgestrel metabolism, but to a lesser extent.

Elimination. Total blood plasma clearance of levonorgestrel is approximately 1 ml/min/kg. Unchanged levonorgestrel is excreted only in trace amounts. Metabolites are excreted through the intestine and the kidneys with an excretion rate of approximately 1.77.T_1/2 in the terminal phase, represented mainly by metabolites, is about one day.

Linearity/nonlinearity. The pharmacokinetics of levonorgestrel depend on the concentration of hGH, which, in turn, is influenced by estrogens and androgens. With Mirena^®, a decrease of approximately 30% in mean hGHG concentrations was observed, which was accompanied by a decrease in plasma levonorgestrel concentrations.

This indicates that levonorgestrel pharmacokinetics is non-linear over time. Given the predominantly local action of Mirena^®, the effect of changes in systemic levonorgestrel concentrations on the efficacy of Mirena^® is unlikely.

Indications

Active ingredient

Composition

Active ingredient:

levonorgestrel 52 mg;

Associates:

Polydimethylsiloxane elastomer – 52 mg

How to take, the dosage

Intrauterine. Mirena® is injected into the uterine cavity and remains effective for five years. The levonorgestrel release rate in vivo is about 20 mcg/day at the start and decreases to about 10 mcg/day after five years. The average levonorgestrel release rate is approximately 14 mcg/d for up to five years.

Mirena® can be used in women receiving hormone replacement therapy in combination with oral or transdermal oestrogen preparations not containing gestagens.

If the Mirena® is properly inserted according to the instructions for medical use, the Perl Index (a measure of the number of pregnancies in 100 women using the contraceptive in a year) is approximately 0.2% for 1 year. The cumulative rate, reflecting the number of pregnancies in 100 women using the contraceptive over 5 years, is 0.7%.

Instrument use and handling instructions

The Mirena® product comes in a sterile package that is only opened just before insertion of the IUD. It is important to be aseptic when handling the opened system. If the sterility of the package appears to be compromised, the IUD should be disposed of as medical waste. The IUD removed from the uterus should also be handled, as it contains hormone residues.

The insertion, removal, and replacement of the IUD

The insertion of Mirena®

Interaction

The metabolism of gestagens may be enhanced with 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 agents to treat infections (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

The effect of these drugs on the effectiveness of Mirena® is not known, but it is thought to be minor because Mirena® has mainly local effects.

Special Instructions

Before inserting Mirena®, pathological processes in the endometrium must be excluded, since irregular bleeding/major bleeding occurs frequently during the first months of use. Also, pathological processes in the endometrium must be excluded if bleeding occurs after the start of oestrogen replacement therapy in a woman who continues to use Mirena®, previously established for contraception. Appropriate diagnostic measures should also be taken when irregular bleeding develops during long-term treatment.

Mirena® is not used for post-coital contraception.

Mirena should be used with caution in women with congenital or acquired valvular heart disease, given the risk of septic endocarditis. If an IUD is inserted or removed, these patients should be given antibiotics to prevent this.

Levonorgestrel at low doses may affect glucose tolerance, so blood glucose levels should be checked regularly in diabetic women using Mirena®. As a rule, correction of the dose of hypoglycemic drugs is not required.

Some manifestations of polyposis or endometrial cancer may be masked by irregular bleeding. In these cases, further examinations are necessary to clarify the diagnosis.

Mirena is not the drug of first choice for young women who have never been pregnant or for postmenopausal women who have severe uterine atrophy.

The available evidence suggests that Mirena® does not increase the risk of breast cancer in postmenopausal women under the age of 50. Because of the limited data from the Mirena trial for the indication “prevention of endometrial hyperplasia with estrogen replacement therapy,” the risk of breast cancer with Mirena® for this indication cannot be confirmed or refuted.

Oligo- and amenorrhea. Oligo- and amenorrhea develop gradually in women of fertile age, in about 57% and 16% of cases by the end of the first year of Mirena®. If menstruation is absent for 6 weeks after the start of the last menstrual period, pregnancy should be ruled out. Repeated pregnancy tests for amenorrhea are not necessary if there are no other signs of pregnancy.

When Mirena® is used in combination with continuous estrogen replacement therapy, most women gradually develop amenorrhea within the first year.

Pelvic inflammatory disease (PID). The guide tube helps protect Mirena® from infection during insertion, and the Mirena® insertion device is specially designed to minimize the risk of infection.

IUD patients who use IUDs often refer to sexually transmitted diseases. Having multiple sexual partners has been found to be a risk factor for STIs. IUDs can have serious consequences: they can impair fertility and increase the risk of ectopic pregnancy.

As with other gynecological or surgical procedures, severe infection or sepsis (including group A streptococcal sepsis) can develop after IUD placement, although this is extremely rare. Mirena® should be removed if recurrent endometritis or VOMT or if severe or acute infections are resistant to treatment for several days. If a woman has persistent lower abdominal pain, chills, fever, pain associated with sexual intercourse (dyspareunia), prolonged or heavy bleeding/bleeding from the vagina, change in the nature of the vaginal discharge, consult a doctor immediately.

Severe pain or fever that occurs shortly after insertion of the IUD may indicate a serious infection that must be treated immediately. Even in cases where only isolated symptoms suggest the possibility of infection, bacteriological testing and monitoring are indicated.

Expulsion. Possible signs of partial or complete expulsion of any IUD are bleeding and pain. Contractions of the uterine muscles during menstruation sometimes cause the IUD to move or even push it out of the uterus, resulting in the cessation of contraceptive action. Partial expulsion may reduce the effectiveness of Mirena®. Because Mirena reduces menstrual blood loss, an increase in blood loss may indicate IUD expulsion. A woman is advised to check the threads with her fingers, for example while taking a shower. If a woman finds signs of IUD dislocation or prolapse or does not feel the threads, she should avoid intercourse or use other methods of contraception and see her doctor as soon as possible.

If the IUD is not correctly positioned in the uterine cavity, it must be removed. At the same time, a new system may be installed.

You should explain to the woman how to check the Mirena® threads.

Perforation and penetration. Perforation or penetration of the body or cervix of the IUD is rare, mostly during insertion, and may decrease the effectiveness of Mirena®. In these cases, the system should be removed. Complications such as adhesions, peritonitis, intestinal obstruction, intestinal perforation, abscesses or erosions of adjacent internal organs may occur if the diagnosis of perforation and IUD migration is delayed. The risk of uterine perforation is increased in women who are breastfeeding. There may be an increased risk of perforation if an IUD is inserted after delivery and in women with a fixed uterine curvature.

Ectopic pregnancy. Women with a history of ectopic (ectopic) pregnancy, who have had fallopian tube surgery or a pelvic organ infection are at higher risk of ectopic pregnancy. The possibility of an ectopic pregnancy should be considered if there is lower abdominal pain, especially if it is combined with cessation of menstruation, or when a woman with amenorrhea begins to bleed. The rate of ectopic pregnancy with Mirena® is approximately 0.1% per year. The absolute risk of ectopic pregnancy in women using Mirena is low. However, if a woman with Mirena® installed becomes pregnant, the relative likelihood of an ectopic pregnancy is higher.

Loss of filaments. If the IUD removal threads cannot be found in the cervical area on gynecological examination, pregnancy must be ruled out. Threads may be retracted into the uterine cavity or cervical canal and become visible again after another menstrual period. If pregnancy is ruled out, the location of the threads can usually be identified by careful probing with an appropriate instrument. If the threads cannot be found, the IUD may have expelled from the uterine cavity. An ultrasound scan may be used to determine if the system is properly located. If this is not available or is unsuccessful, an x-ray may be used to determine the location of the Mirena®.

Ovarian cysts. Since the contraceptive effect of Mirena® is mainly due to its local action, ovulatory cycles with ruptured follicles are commonly observed in women of fertile age. Sometimes the atresia of follicles is delayed and their development may continue. Such enlarged follicles cannot be clinically distinguished from ovarian cysts. Ovarian cysts have been reported as an adverse reaction in approximately 7% of women who have used Mirena®. In most cases, these follicles do not cause any symptoms, although they are sometimes accompanied by lower abdominal pain or pain during intercourse. As a rule, ovarian cysts disappear on their own during 2-3 months of follow-up. If this does not happen, it is recommended to continue monitoring with ultrasound, as well as therapeutic and diagnostic measures. In rare cases it is necessary to resort to surgical intervention.

The use of Mirena® in combination with estrogen replacement therapy. If Mirena® is used in combination with oestrogens, the information in the instructions for use for the oestrogen in question must be consulted in addition.

The excipients contained in Mirena®. The T-base of Mirena ® contains barium sulfate, which becomes visible on x-ray examination.

Please note that Mirena® does not protect against HIV or other sexually transmitted diseases.

Patient Additional Information

Patient regular checkups. The doctor must examine the patient 4-12 weeks after insertion of the IUD and regular check-ups at least once a year thereafter are necessary.

You should consult your doctor as soon as possible in the following cases:

– the patient can no longer feel the threads in her vagina;

– the patient can feel the lower end of the system;

– the patient suspects she is pregnant;

– The patient has persistent abdominal pain, fever, or has noticed a change in the usual amount of vaginal discharge. – The patient experienced a sudden change in her menstrual cycle (such as little or no menstruation followed by persistent bleeding or pain or overly heavy periods). – The patient has had other medical problems, such as migraine-type headaches or severe recurrent headaches, sudden visual disturbances, jaundice, high blood pressure, or any of the other diseases or conditions listed under Contraindications and Cautions.

What to do if the patient wants to get pregnant or remove the Mirena® for other reasons. The doctor can easily remove the IUD at any time, after which pregnancy becomes possible. Removal is usually painless. After removal, Mirena® fertility function is restored.

When pregnancy is not desired, the Mirena® must be removed no later than the 7th day of the menstrual cycle. If Mirena® is removed later than day 7 of the menstrual cycle, use a barrier method of contraception (such as a condom) for at least 7 days before removal. If menstruation is not present with Mirena, barrier contraception should be started 7 days before IUD removal and continued until menstruation resumes. It is also possible to insert a new IUD immediately after removing the previous one; in this case, no additional birth control measures are needed.

How long Mirena® can be used. Mirena® provides protection against pregnancy for 5 years, after which it must be removed. A new IUD can be inserted after the old one has been removed.

Resumption of fertility (can you get pregnant after stopping Mirena®). Once Mirena® is removed, it no longer has any effect on normal fertility. Pregnancy can occur within the 1st menstrual cycle after removal of Mirena®.

Impacts on the menstrual cycle (Can Mirena® affect the menstrual cycle).The Mirena drug affects the menstrual cycle. Mirena may cause changes in menstrual cycle, such as menstrual spotting, longer or shorter periods, more or less bleeding than usual, or absence of bleeding altogether. During the first three to six months after insertion of Mirena, many women will have frequent spotting or light bleeding in addition to their normal menstrual periods. In some cases, very heavy or prolonged bleeding occurs during this period. If you find these symptoms, especially if they persist, you should tell your doctor. It is most likely that the number of days of bleeding and the amount of blood lost will gradually decrease with each month of Mirena use. Some women find over time that their periods stop completely. Because the amount of blood lost with menstruation with Mirena ® usually decreases, most women see an increase in their hemoglobin levels.

The menstrual cycle normalizes after removal of the system.

The absence of menstruation. When you use Mirena® it is normal not to have menstruation. If after Mirena® is inserted, the patient has noticed disappearance of menstruations, it is because of the influence of the hormone on uterine mucosa. There is no monthly thickening of the mucous membrane, hence there is no rejection during menstruation. This does not necessarily mean that the patient has reached menopause or is pregnant. The plasma concentration of your own hormones remains normal. In fact, the absence of menstruation can be a great benefit to a woman’s comfort.

How you can tell if you are pregnant. Pregnancy in women using Mirena®, even if they do not menstruate, is unlikely. If you have not had your periods for 6 weeks and are worried about this, you should do a pregnancy test. If the result is negative, no additional tests are necessary, unless there are other signs of pregnancy, such as nausea, fatigue, or sore breasts.

If Mirena can cause pain or discomfort. Some women experience pain (similar to menstrual pain) in the first 2-3 weeks after IUD insertion. If you have severe pain or if it continues for more than 3 weeks after insertion you should talk to your doctor or the Mirena® facility.

If Mirena has any effect on sexual intercourse. Neither the patient nor her partner should feel the IUD during intercourse. Otherwise, intercourse should be avoided until the physician is satisfied that the system is in the correct position.

What time should pass between insertion of the Mirena® product and intercourse. It is best to abstain from sexual intercourse for 24 hours after insertion of Mirena® in the uterus to give the body a rest. However, Mirena® has its contraceptive effect from the moment of insertion.

If tampons can be used. The use of sanitary pads is recommended. If the patient uses tampons, however, they must be changed very carefully so that the Mirena ® threads do not pull out.

What happens if the Mirena product® spontaneously comes out of the uterine cavity. Very rarely during menstruation, expulsion of the IUD from the uterine cavity may occur. An unusual increase in bleeding during menstrual bleeding may mean that the Mirena ® has fallen through the vagina. Partial expulsion of the IUD from the uterine cavity to the vagina is also possible (the patient and her partner may notice this during intercourse). If all or part of the Mirena ® escapes from the uterus, its contraceptive effect immediately ceases.

What are the signs that the Mirena® is in place? The patient can check for herself to see if the Mirena ® sutures are in place after her menstruation is over. After your period is over, gently insert your finger into your vagina and feel for the threads at the end of the vagina, near the entrance of the uterus (cervix). Do not pull the threads as you may accidentally pull the Mirena® from the uterus. If the patient is unable to feel the threads, you should see your doctor.

The effect on the ability to drive vehicles and machinery. Not observed.

Contraindications

The following conditions should be used with caution and only after consultation with a healthcare professional. You should discuss the appropriateness of removing the system in the presence or first occurrence of any of the following conditions:

Side effects

Immune system disorders: frequency unknown – hypersensitivity to the drug or drug components, including rash, urticaria and angioedema.

Psychiatric disorders: often – depressed mood, depression.

Nervous system disorders: very often – headache; often – migraine.

The digestive system: very often – abdominal pain/pelvic pain; often – nausea.

Skin and subcutaneous tissue: often – acne, hirsutism; infrequently – alopecia, itching, eczema.

Muscular system disorders: often – back pain.

Reproductive system and mammary gland disorders: very often – changes in the volume of blood loss, including increased and decreased intensity of bleeding, mastic bloody discharge, oligomenorrhea, amenorrhea, vulvovaginitis, discharge from the genital tract; often – pelvic organ infections, ovarian cysts, dysmenorrhea, breast pain, breast engorgement, IUD expulsion (complete or partial); rarely – uterine perforation (including penetration).

Cardiovascular system: frequency unknown – increase in BP.

Pregnancy use

Pregnancy. The use of Mirena® is contraindicated if pregnancy is suspected or suspected.

Pregnancy in women with Mirena® is extremely rare. But if the IUD has fallen out of the uterine cavity, the woman is no longer protected from pregnancy and must use other contraceptive methods until she consults her doctor.

When using Mirena® some women do not have menstrual bleeding. Lack of menstruation is not necessarily a sign of pregnancy. If a woman has no periods and at the same time there are other signs of pregnancy (nausea, fatigue, pain in the breasts), it is necessary to see a doctor for an examination and pregnancy test.

If a woman becomes pregnant while using Mirena®, removal of the IUD is recommended, as any intrauterine contraceptive left in situ increases the risk of spontaneous abortion and premature birth. Removal of Mirena® or uterine probing may result in spontaneous abortion.

If careful removal of the intrauterine contraceptive is not possible, a medical abortion should be discussed.

If a woman wants to continue a pregnancy and the IUD cannot be removed, the patient should be informed of the risks, particularly the possible risk of septic abortion in the second trimester of pregnancy, postpartum septicemia, which can be complicated by sepsis, septic shock and death, and the possible effects of premature birth on the baby. In such cases, the course of the pregnancy should be closely monitored.

Ectopic pregnancy should be ruled out. It should be explained to the woman that she should report all symptoms suggestive of a complicated pregnancy, such as cramping pain in the lower abdomen, bleeding or bloody discharge from the vagina, and an increase in body temperature.

The hormone in Mirena ® is released into the uterine cavity. This means that the fetus is exposed to relatively high local concentrations of the hormone, although the hormone enters the fetus in small amounts through the blood and placenta.

Because of the intrauterine use and local action of the hormone, the possibility of virilizing effects on the fetus must be taken into account. Because of the high contraceptive efficacy of Mirena®, clinical experience regarding pregnancy outcomes with its use is limited.

Yet women should be advised that there is currently no evidence of birth defects caused by the use of Mirena® in cases of continuing pregnancy to delivery without removal of the IUD.

Breastfeeding period. Breast-feeding a baby with Mirena® is not contraindicated. About 0.1% of the levonorgestrel dose may be absorbed by the baby during breastfeeding. However, it is unlikely to pose a risk to the baby at the doses released into the uterine cavity after Mirena® placement.

The use of Mirena® 6 weeks after delivery is not thought to have harmful effects on the growth and development of the baby. Gestagen monotherapy has no effect on the quantity or quality of breast milk. Rare cases of uterine bleeding have been reported in women using Mirena® during the lactation period.

After removal of Mirena®, women regain fertility.

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