Jaydess intrauterine system with levonorgestrel 13.5 mg blister No. 1

Instructions for use Jaydess intrauterine system with levonorgestrel 13.5 mg blister No. 1

Composition

active ingredient: levonorgestrel;

1 intrauterine system contains levonorgestrel 13.5 mg;

excipients: polydimethylsiloxane elastomer core;

silicon-filled polydimethylsiloxane elastomer; polyethylene; barium sulfate; iron oxide (E 172); silver (E 174).

Dosage form

Intrauterine system with levonorgestrel.

Main physicochemical properties: intrauterine system with a silver ring, without visible damage. The color of the reservoir with the active substance is whitish or pale yellow.

Pharmacotherapeutic group

Drugs affecting the genitourinary system and sex hormones. Contraceptive for local use. Intrauterine contraceptives. Plastic intrauterine contraceptives with progestogens.

ATX code G02B A03.

Pharmacological properties

Pharmacodynamics

The Jaydess® system has a predominantly local progestogenic effect on the uterine cavity.

High concentrations of levonorgestrel in the endometrium suppress endometrial estrogen synthesis and progesterone receptors. The endometrium becomes relatively insensitive to circulating estradiol, and a significant antiproliferative effect is noted. Morphological changes in the endometrium and a weak foreign body reaction were observed when using the Jaydess® system. Thickening of cervical mucus prevents the passage of sperm through the cervical canal. The local microenvironment of the uterus and fallopian tubes inhibits sperm motility and function, preventing fertilization. In clinical studies of the Jaydess® system, ovulation was observed in the majority of women studied from the corresponding subgroup. Signs of ovulation were noted in 34 of 35 women during the first year, in 26 of 27 women during the second year, and in all 26 women during the third year.

Clinical efficacy and safety

The contraceptive efficacy of the Jaydess® system was evaluated in a clinical study involving 1432 women aged 18–35 years, including 556 (38.8%) nulliparous women, of whom 465 (83.6%) had no pregnancies. At 1 year, the Pearl Index was 0.41 (95% confidence interval 0.13–0.96), and at 3 years, the Pearl Index was 0.33 (95% confidence interval 0.16–0.60). The contraceptive failure rate at 1 year was approximately 0.4%, and the cumulative failure rate was approximately 0.9% at 3 years. This failure rate also includes pregnancies resulting from undetected expulsion and perforation. The use of the levonorgestrel-containing system does not affect a woman’s subsequent fertility. Based on data from the use of IUDs with a higher dose of levonorgestrel, approximately 80% of women who wanted to become pregnant conceived within the first 12 months after removal of the system.

The safety profile of Jaydess® IUD, as determined in a study of 304 adolescents, was comparable to that in adult women. The same efficacy is expected in adolescents under 18 years of age as in women 18 years of age and older.

When using the Jaydess® system, changes in the nature of menstruation are a consequence of the direct effect of levonorgestrel on the endometrium and are independent of the ovarian cycle. In women with different bleeding patterns, there is no clear difference between follicular development, ovulation and the synthesis of estradiol and progesterone. During the suppression of endometrial proliferation during the first months of use, more intense spotting may be observed. Later, during the use of the Jaydess® system, strong suppression of the endometrium leads to a decrease in the duration and volume of menstrual bleeding. Such weak bleeding often develops into oligomenorrhea or amenorrhea. Ovarian function remains normal, and an appropriate level of estradiol is maintained, even if a woman has amenorrhea.

Preclinical safety data

Data from relevant studies on pharmacological safety, pharmacokinetics, toxicity, including genotoxicity and carcinogenic potential, do not indicate the existence of any specific risk for the human body.

Pharmacokinetics

Levonorgestrel is released into the uterine cavity and acts locally. The in vivo release curve is characterized by a sharp initial decrease followed by a gradual slowdown, resulting in little change after the first year of system use and by the end of the intended third year of system use. The determined in vivo drug release rates at different time points are presented in Table 1.

Table 1. In vivo drug release rates based on ex vivo residual data.

Absorption. Based on serum concentration measurements, it was determined that levonorgestrel begins to be released into the uterine cavity immediately after insertion of the Jaydess® system. More than 90% of the released levonorgestrel is systemically available. Maximum serum levonorgestrel concentrations are reached within the first two weeks after insertion of the Jaydess® system. Seven days after insertion, the mean levonorgestrel concentration was 162 pg/mL (5th percentile: 102 pg/mL - 95th percentile: 249 pg/mL). Thereafter, serum levonorgestrel concentrations decrease over time, reaching 59 pg/mL (5th percentile: 36 pg/mL - 95th percentile: 92 pg/mL) after 3 years. When using an IUD with levonorgestrel, the high local concentration of the drug in the uterine cavity leads to a significant concentration gradient between the endometrium and myometrium (difference in endometrium-myometrium concentrations > 100 times) and to low levonorgestrel concentrations in serum (difference in endometrium-serum concentrations > 1000 times).

Distribution. Levonorgestrel binds nonspecifically to serum 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. Accordingly, changes in serum SHBG concentration lead to an increase (at higher SHBG concentration) or a decrease (at lower SHBG concentration) in the total serum levonorgestrel concentration. Within one month after insertion of the Jaydess® system, SHBG concentration decreases by an average of 15% and remains stable for 3 years of use. The mean apparent volume of distribution of levonorgestrel is approximately 106 L.

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 followed by conjugation. CYP3A4 is the main enzyme 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 plasma clearance of levonorgestrel is approximately 1.0 ml/min/kg. Only trace amounts of unchanged levonorgestrel are excreted. Metabolites are excreted in urine and feces with an elimination ratio of approximately 1.

The half-life is about 1 day.

Linearity/non-linearity. The pharmacokinetics of levonorgestrel depend on the concentration of GH, which in turn is influenced by estrogens and androgens. A decrease in GH leads to an overall decrease in serum levonorgestrel concentrations, indicating a nonlinear kinetics of the decline in levonorgestrel concentrations over time. Since the Jaydess® system has a predominantly local effect, no effect on its efficacy is expected.

Pediatric Patients: In a one-year Phase III study in postmenarcheal adolescent girls (mean age 16.2 years; range 12 to 18 years), pharmacokinetic analysis of data from 283 study participants showed that the expected serum concentrations of levonorgestrel were slightly higher (approximately 10%) in adolescents compared to adult women. This correlates with the overall lower body weight in adolescents. The expected range for adolescents is within the range expected for adults and shows a high degree of similarity.

No differences in the pharmacokinetics of levonorgestrel are expected in adolescent and adult women after insertion of the Jaydess® IUD.

Ethnic differences. A three-year phase III study of the Jaydess® system was conducted in the Asia-Pacific region (93% Asian, 7% other ethnicities). Comparison of the pharmacokinetic characteristics of levonorgestrel in women of Mongoloid race in this study with those in women of Caucasian race in another phase III study showed no clinically significant differences in systemic distribution and other pharmacokinetic parameters. In addition, the daily rate of levonorgestrel release from the Jaydess® system was similar in both populations.

No differences in the pharmacokinetics of levonorgestrel are expected between women of Mongoloid and Caucasian race after insertion of the Jaydess® system.

Indication

Contraception for three years.

Contraindication

Pregnancy.

Acute or recurrent pelvic inflammatory disease or conditions associated with an increased risk of pelvic infection.

Acute cervicitis or vaginitis.

Postpartum endometritis or infected abortion within the last three months.

Cervical intraepithelial neoplasia until complete recovery.

Malignant tumors of the cervix or uterus.

Progestogen-dependent tumors, including breast cancer.

Pathological uterine bleeding, the cause of which is not clear.

Congenital or acquired uterine pathologies, including leiomyomas, which may interfere with the insertion and/or retention of an intrauterine system (for example, if they deform the uterine cavity).

Acute liver disease or liver tumors.

Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other types of interactions

Note: To identify potential interactions, consult the Summary of Product Characteristics of the concomitantly administered medicinal product.

Effects of other drugs on Jaydess® IUD

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 preparations containing St. John's wort.

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

Active substances with variable effects on levonorgestrel clearance

When used concomitantly with sex hormones, a large number of HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors may increase or decrease progestin plasma concentrations.

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.

Magnetic resonance imaging (MRI)

A nonclinical study demonstrated that a safe MRI procedure is possible for a patient after insertion of the Jaydess® system under the following conditions: a static magnetic field of 3-T or less, a maximum spatial magnetic field gradient of 720-Gauss/cm or less. Under these conditions, the maximum temperature increase at the Jaydess® system site during a 15-minute procedure was 1.8° C. The quality of the MRI scan may be slightly lower if the study site is in the same location or relatively close to the Jaydess® system site.

Application features

Jaydess® should be used with caution after consultation with a specialist. Removal of the system should be considered if any of the following conditions are present or if these conditions occur for the first time:

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

extremely severe headache;

jaundice;

significant increase in blood pressure;

severe cardiovascular disease, such as stroke or myocardial infarction.

Low doses of levonorgestrel may affect glucose tolerance, so diabetic patients using the Jaydess® system should monitor their blood glucose levels. However, there is usually no need to change the therapeutic regimen for diabetic women using levonorgestrel-releasing IUDs.

Medical examination/consultation

Before using the drug, the woman should be informed about the benefits and risks of using the Jaydess® system, including the signs and symptoms of perforation and the risk of ectopic pregnancy (see below). A physical examination of the patient, including the pelvic organs and breasts, should be performed. Cervical cytology should be performed as necessary according to the physician's judgment. Pregnancy and sexually transmitted diseases should be excluded. Sexually transmitted diseases should be treated before insertion of the IUD. The location of the uterus and the size of the uterine cavity should be determined. It is especially important to place the Jaydess® system in the fundal area to achieve maximum effectiveness and reduce the risk of expulsion. The instructions for insertion of the system should be carefully followed.

Special attention should be paid to learning and mastering the technique of proper system installation.

Insertion and removal of the system may cause pain and bleeding. The procedure may cause a vasovagal reaction (e.g. dizziness or seizures in patients with epilepsy).

The woman should undergo a re-examination 4-6 weeks after insertion of the system to check the location of the threads and the correct position of the system. In the future, scheduled visits to the doctor are recommended once a year or more often if medically indicated.

The Jaydess® system is not intended for use as a means of postcoital contraception.

The use of the Jaydess® system for the treatment of heavy menstrual bleeding or for protection against endometrial hyperplasia during estrogen replacement therapy has not been studied. Therefore, the system is not recommended for use in these conditions.

Ectopic pregnancy

Women with a history of ectopic pregnancy, tubal surgery, or pelvic infection are at increased risk of 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 with amenorrhea.

Because an ectopic pregnancy may affect future fertility, the benefits and risks of using the Jaydess® system should be carefully considered, particularly for women who have not yet given birth.

Use in nulliparous women: The Jaydess® system is not a first-line contraceptive method for nulliparous women, as clinical experience with the system in this group of women is limited.

Effect on menstrual bleeding pattern

The effect on menstrual bleeding intensity is expected in most patients using the Jaydess® system and is considered to be a result of the direct action of levonorgestrel on the endometrium and may not correlate with ovarian activity.

In the first months of use, irregular bleeding/spotting is often observed. Over time, strong suppression of endometrial activity leads to a decrease in the duration and volume of menstrual bleeding. Minor spotting often transforms into oligomenorrhea or amenorrhea.

Clinical evidence suggests that infrequent bleeding and/or amenorrhea may develop gradually. By the end of the third year, approximately 22.3% and 11.6% of women using the IUD experience infrequent bleeding and/or amenorrhea, respectively. If a woman has not had a new menstrual period within 6 weeks of her last menstrual period, the possibility of pregnancy should be considered. In the absence of other symptoms of pregnancy, there is no need to repeat a pregnancy test in amenorrheal women unless other signs of pregnancy appear.

If bleeding increases and/or becomes more irregular over time, appropriate diagnostic measures should be considered, as irregular bleeding may be a symptom of endometrial polyps, hyperplasia, or cancer. Heavy bleeding may indicate an undetected expulsion of the IUD.

Pelvic Infectious Diseases

The Jaydess® system and insertion tube are sterile, but they may be vectors for the transfer of microorganisms to the upper genital tract due to bacterial contamination during insertion. Pelvic inflammatory disease has been reported with the use of any IUD or intrauterine device. Clinical studies have shown that pelvic inflammatory disease (PID) is most common early in the use of the Jaydess® system, which is consistent with data from copper IUDs. The risk of PID is highest during the first three weeks after insertion, after which the risk of infection decreases.

Before starting Jaydess®, patients should be evaluated for risk factors for pelvic inflammatory disease (e.g., multiple sexual partners, sexually transmitted infections, history of pelvic inflammatory disease). Pelvic inflammatory disease, such as PID, can have serious consequences, affect fertility, and increase the risk of ectopic pregnancy.

As with other gynecological or surgical procedures, the development of severe infections or sepsis (including sepsis caused by group A streptococcus) is possible with the insertion of an intrauterine device, although the likelihood of such complications is extremely low.

If a woman experiences recurrence of endometritis or pelvic inflammatory disease or acute inflammation that is severe or does not respond to treatment within several days, the Jaydess® system should be removed.

Bacteriological studies should be performed, and careful monitoring of the patient's condition is recommended in the presence of even individual symptoms of infection.

Expulsion

In clinical trials, the rate of expulsion (spontaneous expulsion) of the Jaydess® system was low (< 4% of insertions) and was in the same range as with other IUDs or intrauterine devices. Symptoms of partial or complete expulsion of the Jaydess® system may include pain and bleeding. However, the system may fall out of the uterine cavity without the woman noticing, resulting in loss of contraceptive protection. Since the Jaydess® system 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;

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 Jaydess® threads, and advised to seek medical attention if threads cannot be felt. Barrier contraceptives (e.g. condoms) should be used until the location of Jaydess® has been confirmed.

A partially displaced Jaydess® system should be removed. A new system may be inserted immediately after removal, provided that pregnancy is excluded.

Perforation

In rare cases, most often during insertion, an intrauterine contraceptive device may cause perforation or puncture of the uterine corpus or cervix, although this may remain undetected for some time, which may reduce the contraceptive efficacy of the Jaydess® system. If there is difficulty in inserting the system and/or unusual pain or bleeding during or after insertion, appropriate measures should be taken immediately, such as a gynecological examination and ultrasound, to exclude the possibility of perforation of the uterine wall. Such a system should be removed. Surgical intervention may be necessary.

In a prospective, comparative, non-interventional cohort study of users of other intrauterine devices (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 for other levonorgestrel-containing IUDs in the cohort; and 1.1 (95% confidence interval: 0.7–1.6) per 1000 insertions for copper-containing IUDs.

The data suggest that both insertion during breastfeeding and insertion before 36 weeks postpartum are associated with an increased risk of perforation (see Table 2). Both risk factors were independent of the type of IUD inserted.

Table 2. Perforation rate per 1000 insertions in the cohort of women participating in the study during 1 year of follow-up, by presence of breastfeeding at the time of insertion and time of insertion after childbirth.

When the follow-up period was extended to 5 years in the subgroup of this study (n = 39,009 women using another LNG-IUD or copper-containing IUDs; for 73% of these women, data were available for the entire 5-year 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 for perforation 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 recommendations outlined in the Medical Examination/Consultation section, which may be adapted as clinically indicated for women with risk factors for perforation.

Missing threads

If the removal threads are not visually identifiable in the cervix at the next examination, expulsion or the possibility of pregnancy should be ruled out. The threads may have become lodged in the uterus or cervical canal and then reappeared during the next menstruation. If pregnancy is ruled out, the location of the threads can be determined by careful probing of the cervical canal with an appropriate instrument. If the threads cannot be found, perforation or expulsion should be considered. Ultrasound may be performed to determine the location of the system. If ultrasound is not possible or does not give the desired results, X-rays may be used to determine the location of the Jaydess® system.

Ovarian cysts/enlarged ovarian follicles

Because the contraceptive effect of the Jaydess® system is mainly achieved through local action in the uterus, there is generally no change in ovulation, in particular regular follicular maturation, release of the egg (oocyte) as a result of rupture of a mature follicle, and follicular atresia in women of reproductive age. Sometimes follicular atresia is delayed and follicular development may continue. Such enlarged follicles are clinically indistinguishable from ovarian cysts and have been diagnosed in approximately 13.2% of women using the Jaydess® system. Most such follicles are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia.

In most cases, enlarged follicles resolve spontaneously within two to three months of observation. If the follicles do not resolve, continuous ultrasound monitoring or other diagnostic/therapeutic procedures are recommended. In rare cases, surgical intervention may be necessary.

Mental disorders

Depressed mood and depression are well-known side effects that can occur with hormonal contraceptives (see section "Adverse reactions"). Depression can be a serious condition and is a well-known risk factor for suicidal behavior and suicide. Women should be advised to seek medical advice if they experience mood changes and symptoms of depression, including shortly after starting the drug.

Use during pregnancy or breastfeeding

Pregnancy. The use of the Jaydess® system in pregnant women is contraindicated (see Contraindications).

If a woman becomes pregnant with Jaydess® inserted, an ectopic pregnancy should be ruled out and the system removed as soon as possible, since any intrauterine contraceptive device left in the uterus during pregnancy increases the risk of miscarriage and premature birth. Removal of the Jaydess® system or probing of the uterus may also result in spontaneous abortion. The possibility of an ectopic pregnancy should be ruled out. If the woman wishes to continue the pregnancy and removal of the system is not possible, she should be informed of the risk and possible consequences of premature birth and premature birth. The course of such a pregnancy requires careful monitoring. The woman should inform her doctor of any symptoms that may be associated with complications of pregnancy, for example, cramping abdominal pain with fever.

In addition, an increased risk of virilization in the female fetus due to intrauterine exposure to levonorgestrel cannot be excluded. There have been isolated cases of masculinization of the external genitalia of the female fetus after topical exposure to levonorgestrel during pregnancy that occurred with a levonorgestrel-releasing IUD inserted.

Lactation. In general, no harmful effects on the growth and development of the child have been observed when using a progestogen-only product six weeks after delivery. Levonorgestrel IUDs do not affect the quantity or quality of breast milk. Progestogens are excreted in small amounts (about 0.1% of levonorgestrel) in breast milk.

Fertility: The use of a levonorgestrel IUD does not affect future fertility. After removal of the IUD, fertility in women is restored (see section "Pharmacodynamics").

Ability to influence reaction speed when driving vehicles or other mechanisms

The Jaydess® system does not affect the ability to drive or operate other machinery.

Method of administration and doses

The Jaydess® intrauterine system is inserted into the uterine cavity and is effective for three years.

Introduction

It is recommended that the Jaydess® system be inserted only by a physician who is experienced in IUD insertion and/or has been trained in Jaydess® system insertion.

Before insertion, the patient should be carefully examined to identify any contraindications to IUD insertion. Pregnancy should be excluded before insertion. The possibility of ovulation and conception should be considered before using this medicinal product. The Jaydess® system is not intended for use as a postcoital contraceptive (see Contraindications and Medical Examination/Consultation in the Special Precautions for Use section).

Table 3. Timing of Jaydess® system insertion in women of reproductive age.

If there is difficulty in inserting the system and/or unusual pain or bleeding during or after insertion, the possibility of perforation should be considered and appropriate measures taken, such as physical examination and ultrasound.

The Jaydess® system can be distinguished from other IUDs by the visualization of the silver ring on ultrasound and the brown removal threads. The T-shaped body of the Jaydess® system contains barium sulfate, which is visualized by X-ray.

Delete/replace

The Jaydess® system is removed by gently pulling on the threads with surgical forceps. If the threads are not visible and the system is in the uterine cavity, it can be removed using narrow surgical forceps. This may require cervical dilation or surgery. After removal, the Jaydess® system should be inspected to ensure that it is not damaged.

The system should be removed no later than the end of the three-year period.

Continuing contraceptive protection after removal

If the patient wishes to continue using this method, the new system can be inserted immediately after the previous system is removed.

If the patient does not wish to use the same method of contraception, but pregnancy is not desired, the system should be removed within 7 days of the start of menstruation, provided that the woman has a regular menstrual cycle. If the system is removed at any other time or if the woman does not have regular menstruation and the woman has had sexual intercourse within the week before removal of the system, there is a risk of pregnancy. To ensure contraceptive effect, a barrier method of contraception (condoms) should be started at least 7 days before removal. After removal, a new method of contraception should be started immediately (the instructions for using the new method of contraception must be followed).

Additional information regarding use in specific patient groups

Elderly patients. The Jaydess® system has not been studied in women over the age of 65. There is no indication for the Jaydess® system in postmenopausal women.

Patients with hepatic impairment. The Jaydess® system has not been studied in women with hepatic impairment. The Jaydess® system is contraindicated in women with acute liver disease or liver tumors (see Contraindications).

Patients with renal impairment: The use of the Jaydess® system in women with renal impairment has not been studied.

Method of application

The Jaydess® system is intended for aseptic administration by a physician.

The Jaydess® system is supplied in a sterile package that should not be opened until the system is installed. Do not sterilize. For single use only. If the protective layer of the sterile package is torn or damaged, the system cannot be used. Do not use after the expiration date printed on the package.

Any unused product or waste material should be disposed of in accordance with local requirements.

The Jaydess® system comes with a patient card enclosed in a cardboard box. Complete the patient card and give it to the patient after insertion of the system.

Preparation for introduction

Examine the patient for contraindications to Jaydess® insertion (see Contraindications and Medical Examination/Consultation in the Precautions section).

Insert a speculum, examine the cervix, and then thoroughly clean the cervix and vagina with an appropriate antiseptic solution.

If necessary, use the help of an assistant.

Grasp the anterior lip of the cervix with a pair of claw forceps or other forceps to hold the uterus in place. If the uterus is bent, it may be more appropriate to grasp the posterior lip of the cervix with the forceps.