What Is a Levonorgestrel Intrauterine System?

The levonorgestrel intrauterine birth control system is indicated for idiopathic multiple menstrual periods, that is, multiple periods caused by non-organic lesions.

The levonorgestrel intrauterine birth control system is indicated for idiopathic multiple menstrual periods, that is, multiple periods caused by non-organic lesions.

Drug Name

Levonorgestrel intrauterine birth control system

Drug type

prescription

Use classification

Progestins

Components of Levonorgestrel Intrauterine System

The main component of this system is levonorgestrel.
Chemical name: D (-)-17-ethynyl-17-hydroxy-18-methylestrone-4-en-3-one Molecular formula: C ₂₁ H ₂₈ O ₂
Molecular weight: 312.4

Levonorgestrel intrauterine birth control system traits

Intrauterine drug delivery system (IUS).
The system has a white to off-white tubular drug core, an opaque membrane covering it, and is supported on the longitudinal arm of a T-shaped body. There is a small ring on one end of the T-shaped longitudinal arm and two horizontal arms on the other end. Take out the tail wire on the small ring. The trailing arm of the system is placed in a placement tube at the top of the placer. The system should be free of visible foreign objects.

Levonorgestrel Intrauterine System Indications

Contraceptive idiopathic menstruation, that is, menstruation caused by non-organic lesions.

Levonorgestrel Intrauterine Birth Control System Specifications

Contains levonorgestrel 52mg / piece (20 micrograms / 24 hours).

Dosage and dosage of Levonorgestrel IUD

The levonorgestrel intrauterine birth control system is placed in the uterine cavity and is effective for 5 years.
The in vivo dissolution rate was about 20 g / 24h at the beginning and decreased to about 10 g / 24h after 5 years. The average dissolution rate of levonorgestrel over a 5-year period is approximately 14 g / 24 h.
The correct placement of the levonorgestrel intrauterine birth control system according to the placement instructions has a failure rate of about 0.2% in one year and a cumulative failure rate of about 0.7% in five years.
· Place and remove / replace women of childbearing age. The levonorgestrel intrauterine system must be placed in the uterine cavity within 7 days of menstruation. The replacement of the levonorgestrel IUD can be performed at any time during the cycle.
The system can also be placed immediately after an abortion in early pregnancy.
Postpartum placement should be postponed until the uterus is completely restored, and the earliest should not be earlier than 6 weeks after delivery. If the uterine recovery time is flat and pushed back, you should consider waiting until 12 weeks postpartum: if there is difficulty in placement and / or abnormal pain or bleeding during or after placement, physical examination and ultrasound should be performed immediately to exclude uterine perforation.
It is recommended that the system be operated only by doctors and health professionals who have experience with placement and / or have been sufficiently trained in the placement of the system.
The tail wire of the levonorgestrel intrauterine birth control system can be clamped with forceps and gently pulled out. If the tail wire is not visible and the system is in the uterine cavity, it can be removed using a thin holding forceps. This may require dilation of the cervical canal.
The system should be removed after 5 years. If the user wants to continue using the same method, he can put in a new system while taking it out.
If women of childbearing age do not wish to conceive, as long as there is still a menstrual cycle, removal should be performed during the menstrual period. If the system is removed in the middle of the menstrual cycle and a woman has sex within a week after removal, she is at risk of pregnancy unless a new system is placed immediately after removal.
After removing the levonorgestrel intrauterine birth control system, check for completeness. When removal is difficult, there have been individual reports of the hormone cannula sliding over the cross arm and hiding the cross arm in the cannula. In this case, as long as the integrity of the system can be ensured, no further access to the uterine cavity is required. Nodules on the transverse arm usually prevent the hormone cannula from falling off the T-body.
· Usage / Handling Instructions Levonorgestrel IUD is supplied in sterile packaging and must not be opened before placement.
Opened products must be handled aseptically. If the system's sealed, sterile packaging is damaged, it should be discarded.

Adverse effects of levonorgestrel intrauterine birth control system

Adverse reactions are more common in the first few months after placement, and gradually decrease with prolonged use. In addition to the adverse reactions listed in [Precautions], users of this system have also reported the following adverse reactions.
Very common adverse reactions (greater than 10% of users) include uterine / vaginal bleeding (including drip bleeding), less menstruation, amenorrhea, and benign ovarian cysts.
During the first 6 months of use, women of childbearing age gradually reduced the average number of days of monthly bleeding from 9 to 4 days. In the first 3 months of use, the percentage of women with prolonged bleeding (more than 8 days) decreased from 20% to 3%. In clinical studies using the first year, 17% of women had amenorrhea for at least 3 months.
The incidence of benign ovarian cysts varies according to the method of diagnosis. In clinical trials, about 12% of subjects using the levonorgestrel intrauterine system were diagnosed with enlarged follicles, but most were asymptomatic Disappeared within 3 months.

The most appropriate MedDRA term is used to describe a response, its synonym or related situation.
If women with this system have a pregnancy with a device, the relative risk of ectopic pregnancy increases.
In addition, there have been reports of breast cancer cases (the incidence is unknown, see [Notes]).

Intrauterine contraceptive system of levonorgestrel is contraindicated

· Known or suspected pregnancy;
· Currently suffering from pelvic inflammatory disease or recurrence of pelvic inflammatory disease;
· Lower reproductive tract infections;
· Postpartum endometritis;
· Infectious abortion in the past 3 months;
Cervicitis;
· Cervical dysplasia;
· Malignant lesions of the uterus or cervix;
Progestin-dependent tumors;
· Unexplained abnormal uterine bleeding;
Congenital or acquired uterine abnormalities, including fibroids that deform the uterine cavity;
Increased susceptibility to infections;
· Acute liver disease or liver tumor;
Allergic to system components.

Precautions for levonorgestrel intrauterine birth control system

The levonorgestrel intrauterine birth control system can be used with caution after consulting an expert. If any of the following conditions exist or appear for the first time during use, you should consider removing the system.
Migraine, focal migraine with asymmetric visual loss or other symptoms suggesting temporary cerebral ischemia;
Particularly severe headaches;
·jaundice;
Significantly increased blood pressure;
Severe arterial diseases such as stroke or myocardial infarction;
Affirmative or suspected sex hormone-dependent tumors.
Some recent epidemiological studies have shown a slight increase in the risk of venous thromboembolism among women using a single progestin contraceptive, but the results have not been statistically significant. However, if symptoms or signs of thrombosis occur, appropriate diagnostic and treatment measures should be taken immediately. Symptoms of venous or arterial thrombosis include: unilateral leg pain and / or swelling; sudden severe chest pain, whether or not it radiates to the left arm; sudden shortness of breath; sudden cough; any abnormal, severe, persistent headache Sudden partial or full vision loss; diplopia; ambiguity or aphasia; dizziness; prostration with or without local convulsions: sudden weakness or very obvious numbness affecting one or a part of the body; dyskinesia; acute abdomen. There are symptoms or signs of retinal thrombosis, including: unexplained partial or full vision loss, exophthalmos or diplopia, papillary edema, or retinal vascular disease.
The possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism is inconclusive.
The levonorgestrel intrauterine system can be used with caution in women with congenital heart disease or valvular heart disease at risk for infective endocarditis. These patients should be given prophylactic antibiotics when placing or removing IUS.
Low doses of levonorgestrel may affect glucose tolerance, so women with diabetes should monitor blood glucose levels when using the levonorgestrel intrauterine system. However, in general, there is no need to adjust the treatment plan for diabetic patients using this system.
Irregular bleeding may mask some symptoms and signs of endometrial polyps or cancer, and diagnostic measures should be considered in these cases.
The levonorgestrel intrauterine birth control system is not the method of choice for young unborn women, nor is it suitable for postmenopausal women with severe uterine atrophy.
A meta-analysis of 54 epidemiological studies revealed that women who are currently using compound oral contraceptives (COCs), primarily estrogen and progestin preparations, have a slightly increased relative risk of being diagnosed with breast cancer (RR = 1.24). Within 10 years after stopping COC use, the increased risk gradually disappeared. Because breast cancer rarely occurs in women under 40 years of age, the number of breast cancer diagnoses that are being used and recently used by COC is small compared to the overall risk of breast cancer. The risk of being diagnosed with breast cancer among users of single progestin contraceptives is similar to the risk associated with the use of COC. However, for a single progestin formulation, the evidence is less conclusive than that of COCs because it uses far fewer people than COCs. These studies did not provide causal evidence. The increased risk observed may be due to earlier diagnosis of breast cancer for oral contraceptive (OC) users, the biological effects of OCs, or both. Compared with those who have never used OC, breast cancer in those who have used OC is often clinically staged earlier.
· Before medical examination / consultation, women must be informed about the effects, dangers and adverse effects of the levonorgestrel intrauterine system. Physical examination should be performed, including pelvic examination, breast examination and cervical smear. Pregnancy and sexually transmitted diseases should be excluded, and reproductive tract infections must be completely treated. The location of the uterus and the size of the uterine cavity should be determined. In order to ensure that the endometrium is evenly exposed to progesterone, prevent shedding and achieve the best results, the benchmark positioning of the intrauterine birth control system is particularly important. Therefore, carefully follow the placement instructions. Because this system placement technique is different from other IUDs, special attention should be paid to training in proper placement techniques. There may be some pain and bleeding during placement and removal. Surgery may cause syncope due to vasovagal reactions, or seizures in patients with epilepsy.
Women must be followed up for 4-12 weeks after placement, and then once a year thereafter, or the number of follow-up examinations can be increased if clinically needed.
The levonorgestrel intrauterine birth control system is not suitable as a contraceptive method after intercourse.
Because irregular bleeding / drip bleeding is common during the first few months of treatment, it is recommended that endometrial lesions be excluded before placing the levonorgestrel intrauterine system. If irregular bleeding occurs during prolonged placement, appropriate diagnostic measures should be taken.
Menopause / menorrhea of women of childbearing age, about 20% of users gradually develop menopause and / or amenorrhea. The possibility of pregnancy should be considered if menopause has been stopped for 6 weeks since the beginning of the last menstrual period. It is not necessary to repeat the pregnancy test for amenorrhea users unless there are other signs of pregnancy.
· Pelvic infection placement tube helps prevent levonorgestrel intrauterine contraception system from microbial contamination during placement, and the design of the levonorgestrel intrauterine system placement device minimizes the risk of infection. When using copper-containing IUDs, the incidence of pelvic infection was highest in the first month after placement and gradually decreased afterwards. Some studies suggest that levonorgestrel users have lower pelvic infection rates than those with copper-containing IUDs. Known risk factors for pelvic infectious diseases are multiple sexual partners. Pelvic infections can have serious consequences that can impair fertility and increase the risk of ectopic pregnancy.
If a woman has relapsed endometritis or a pelvic infection, or a severe acute infection, or does not improve after a few days of treatment, the levonorgestrel intrauterine system must be removed.
When infection is possible, bacteriological examination and monitoring are recommended even if the symptoms are not indicated.
· Symptoms of any or all of the IUS shedding include bleeding or pain. However, sometimes the system may be excreted from the uterine cavity without being noticed by the woman, resulting in loss of contraceptive protection. Partial shedding may reduce the effectiveness of the levonorgestrel intrauterine birth control system. Because the levonorgestrel intrauterine birth control system reduces the amount of menstrual bleeding, if the amount of menstrual bleeding increases, it may indicate shedding.
The displaced levonorgestrel intrauterine system must be removed. A new system can be placed at the same time.
Women should be instructed how to check the tail wire of the levonorgestrel intrauterine system.
· Perforation of the uterine body or cervix by perforated intrauterine contraception devices is extremely rare, usually occurs when placed, and may reduce the efficacy of levonorgestrel intrauterine contraception system. In this case, the system must be removed. The risk of perforation of the uterus may increase in postpartum (see [Usage and Administration]), breastfeeding women, and women in the posterior uterus.
Women with a history of ectopic pregnancy, tubal surgery, or pelvic infection have a higher risk of ectopic pregnancy. The possibility of ectopic pregnancy should be considered if lower abdominal pain occurs-especially in women with menstrual periods or if menopause begins to bleed. The ectopic pregnancy rate for users of levonorgestrel intrauterine system is about 0.1% of women-years. This rate is lower than the estimated ectopic pregnancy rate for women who have not used any method of contraception (0.3-0.5% per year). The absolute risk of ectopic pregnancy among users of this system is low. However, the relative likelihood of ectopic pregnancy will increase when women with this system have a pregnancy with a device.
If tail wire loss is not seen at the cervix during follow-up examination, pregnancy must be excluded. The tail wire may be drawn into the uterus or cervical canal, and may reappear during the next menstrual period. If pregnancy is excluded, a light probe using a suitable device can usually determine the location of the tail wire. If not found, the system may have been drained. Ultrasound diagnostics can be used to determine the correct location of the system. If there is no ultrasound or the ultrasound is not clear, X-rays can be used to locate the levonorgestrel intrauterine system.
Delayed follicular atresia Because the contraceptive effect of the levonorgestrel intrauterine contraception system depends mainly on local effects, women of childbearing age often experience follicular rupture during the ovulation cycle. Sometimes follicular atresia is delayed and follicle production continues. Clinically, these enlarged follicles cannot be distinguished from ovarian cysts. Approximately 12% of women using the levonorgestrel intrauterine system are diagnosed with enlarged follicles. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain or sexual intercourse.
For most cases, enlarged follicles disappear spontaneously during the observation period of 2-3 months. If it does not disappear, ultrasound monitoring should be continued and other diagnostic / treatment measures recommended. Rare cases may require surgery.
If any adverse events and / or adverse reactions occur while using this system, please consult your doctor.
Please tell your doctor about using other medicines at the same time.
· The impact on driving and machine operation capabilities is unknown.

Levonorgestrel IUD for pregnant and lactating women

· Pregnancy levonorgestrel intrauterine birth control system cannot be used in the case of pregnancy or suspicious pregnancy. If a woman is pregnant during the use of levonorgestrel IUD, it is recommended to remove the levonorgestrel IUD, as any IUD indwelling the uterine cavity may increase the risk of miscarriage and preterm birth. Taking out the levonorgestrel intrauterine birth control system or exploring the uterine cavity may cause spontaneous abortion. If you cannot easily remove the IUD, consider terminating the pregnancy. If a woman wishes to continue the pregnancy and the system cannot be removed, the woman should be informed of these dangers and possible outcomes of premature delivery. Such pregnancy processes must be closely monitored. Ectopic pregnancy should be excluded. Women should be instructed to report all symptoms suggestive of pregnancy complications, such as spastic abdominal pain with fever.
Because of intrauterine administration and local hormonal exposure, the potential for virilization of the fetus must be considered. Due to the high effectiveness of levonorgestrel intrauterine contraception, clinical experience with pregnancy outcomes with levonorgestrel is limited, but women should be informed that to date, no levonorgestrel has been used Evidence of birth defects caused by the progesterone intrauterine birth system occurring when the system continues in place while pregnancy continues to term.
· Breastfeeding about 0.1% of levonorgestrel is transferred to the baby through breast milk, but the dose released by the levonorgestrel intrauterine birth system placed in the uterine cavity is unlikely to cause harm to the baby.
No harmful effects of levonorgestrel intrauterine birth control system on infant growth were observed after 6 weeks postpartum. No single progestin approach was observed to affect the quantity or quality of milk. Uterine bleeding has rarely been reported in lactating women using the levonorgestrel intrauterine system.

Levonorgestrel IUD for Children

Not applicable.

Levonorgestrel Intrauterine Birth Control System

Not applicable.

Drug Interactions with Levonorgestrel Intrauterine System

Progesterone metabolism may be increased by concurrent use of substances known to induce drug metabolism enzymes, especially cytochrome P450 enzymes, such as anticonvulsants (e.g., phenobarbital, phenytoin, carbamazepine) and anti-convulsants Infective drugs (such as rifampicin, rifabutin, nevirapine, efavirenz). The effect of these drugs on the contraceptive effectiveness of the levonorgestrel intrauterine birth control system is not clear, but because its mechanism of action is local, it is not considered to have a large impact.
Compatibility contraindications are not applicable.

Levonorgestrel IUD overdose

Not applicable.

Clinical trial of levonorgestrel intrauterine birth control system

The contraceptive effectiveness of levonorgestrel intrauterine contraception system was studied in 3330 women in 5 major clinical trials. The one-year failure index (Pearl Index) is about 0.2%, and the five-year cumulative failure rate is about 0.7%. The failure rate also includes pregnancy and perforation due to no excretion of levonorgestrel intrauterine system. Similar contraceptive effects were also observed in a large post-marketing study of levonorgestrel intrauterine birth control systems used by more than 17,000 women. Since the levonorgestrel intrauterine birth control system does not require daily intake by the user, the pregnancy rate for "typical use" is similar to that of a controlled clinical study ("perfect use").
The use of levonorgestrel intrauterine birth control system does not affect future fertility. About 80% of women who wish to conceive will conceive within 12 months of removing the system.

Levonorgestrel intrauterine birth control system pharmacology and toxicology

[u] Pharmacodynamic properties [/ u]
Levonorgestrel is an anti-estrogen-active progesterone that has multiple uses in gynecology: for example, as a progestogen component in oral contraceptives and hormone replacement therapy, or as a sole contraceptive containing Hormonal contraceptives and subcutaneous implants. Levonorgestrel can also be administered intrauterinely via an intrauterine release system. In this way, since the hormone is released directly into the target organ, very low daily doses can be used.
The levonorgestrel intrauterine birth control system mainly plays a local progestin effect in the uterine cavity. The high levonorgestrel concentration in the endometrium down-regulates the endometrial estrogen and progesterone receptors, making the endometrium insensitive to estradiol in the blood circulation, thereby exerting a strong endometrial antagonistic effect. During the use of levonorgestrel intrauterine birth control system, morphological changes of the intima and weak local foreign body reaction can be observed. The thickening of the cervical mucus prevents sperm from passing through the cervical canal. The local internal environment of the uterus and fallopian tubes inhibits the movement and function of sperm and prevents fertilization. In some women, ovulation is also suppressed.
The type of menstruation is the result of levonorgestrel acting directly on the endometrium and does not reflect the ovarian cycle. Women with different types of bleeding did not have a clear difference in follicular development, ovulation or estradiol and progesterone production. In the fight against endometrial hyperplasia, there is an increased likelihood of spotting bleeding during the first few months of use. Then, during the use of levonorgestrel intrauterine birth control system, due to the strong inhibitory effect on the endometrium, the duration and amount of menstrual bleeding were reduced. Reduced menstrual blood volume often develops as less menstruation or amenorrhea. Even if amenorrhea occurs in users of the levonorgestrel intrauterine system, ovarian function is normal and estradiol levels remain unchanged.
The levonorgestrel intrauterine birth control system can be effectively used for the treatment of idiopathic menstruation. Women with more menstrual periods reduced their menstrual blood loss by 88% within 3 months of using the levonorgestrel intrauterine system. For menstruation caused by submucosal fibroids, the effect may not be good. Reduced bleeding increases the concentration of hemoglobin. Levonorgestrel intrauterine birth control system can also relieve dysmenorrhea.
During continuous oral or transdermal estrogen treatment, the application of levonorgestrel intrauterine birth control system can also achieve the same effect to prevent intimal hyperplasia. The rate of hyperplasia observed under estrogen alone can reach 20%. In a clinical study of 201 perimenopausal women and 259 postmenopausal women using the levonorgestrel intrauterine birth control system, after five years of observation, no endometrial hyperplasia was reported in the postmenopausal group.
[u] Preclinical safety information [/ u]
Based on the research of safety pharmacology, toxicity, genotoxicity and carcinogenic potential of levonorgestrel, the results of preclinical safety evaluation show that it is not particularly harmful to humans. Levonorgestrel is a well-known progestin with anti-estrogen activity. A large amount of data has been elucidated on the safety after systemic administration. A study of levonorgestrel administered to monkeys for 12 months confirmed its local pharmacological effects and good local tolerability without signs of systemic toxicity. No embryo toxicity was observed after intra-uterine administration of levonorgestrel in rabbits. Elastomer composition of the hormone reservoir of this system, polyethylene material and the safety evaluation of the elastomer and the combination of levonorgestrel, and the evaluation of the in vitro and in vivo genetic toxicology test system based on the two standards The biocompatibility tests of rats, guinea pigs, rabbits and in vitro detection systems did not show that the system was biocompatible.

Pharmacokinetics of levonorgestrel intrauterine birth control system

Absorption < br Levonorgestrel is released immediately after implantation of the intrauterine birth control system. The rate of levonorgestrel release in vivo in the uterine cavity was initially about 20 g / 24h, and it decreased to 10 g / 24h after 5 years.
Distribution < br Levonorgestrel binds specifically to serum albumin and specifically to SHBG. About 1-2% of levonorgestrel in circulation is present as free steroids, and 42-62% specifically bind to SHBG. During the use of levonorgestrel intrauterine birth control system, the SHBG concentration will decrease. Accordingly, the proportion of SHBG binding decreases during use, while the proportion of free form increases. The average apparent volume of levonorgestrel was about 106L.
After the levonorgestrel intrauterine birth control system is inserted, levonorgestrel can be detected in the serum. Due to the decrease in release rate, the median serum concentration of levonorgestrel in women of childbearing age over 55 kg weighed from 206 pg / ml at 6 months (25th to 75th percentile: 151pg / ml to 264pg / ml) decreased to 194 pg / ml (146 pg / ml to 266 pg / ml) at 12 months and to 131 pg / ml (113 pg / ml to 161 pg / ml) at 60 months.
Biotransformation br Levonorgestrel is extensively metabolized. The main metabolite in the plasma is unbound and bound 3, 5-tetrahydrolevonorgestrel. According to in vitro and in vivo studies, CYP3A4 is the main enzyme involved in levonorgestrel metabolism; CYP2E1, CYP2C19, and CYP2C9 may also be involved, but to a lesser extent.
Elimination < br The total clearance of levonorgestrel from plasma is approximately 1.0 ml / min / kg. Only trace amounts of levonorgestrel were excreted as prototypes. Metabolites are excreted via feces and urine, and their excretion ratio is approximately equal to one. The excretion half-life depends mainly on metabolites, about 1 day.

Storage of Levonorgestrel Intrauterine System

This system should be stored at 15-30 , avoiding direct sunlight and humidity.

Packaging of levonorgestrel intrauterine birth control system

· Placer:
A set of IUDs with a placer is packaged in a thermoformed blister pack with a peelable lid.
Packaging specifications: 1 placer / box

Validity of levonorgestrel intrauterine birth control system

36 months

Levonorgestrel Intrauterine Birth Control System Implementation Standard

Import drug registration standard JX20070121 ^[1]