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Noncontraceptive Use of the Levonorgestrel-Releasing Intrauterine System
07.10.05n

Policy

MEDICALLY NECESSARY

Insertion and use of the 52-mg levonorgestrel-releasing intrauterine system (LNG-IUS) (Mirena®, Liletta®) for noncontraceptive use is considered medically necessary and, therefore, covered for any of the following:
  • As an alternative to hysterectomy in an individual who meets all of the following: 
    • Has excessive or irregular bleeding that necessitates an alteration in lifestyle, defined as one of the following:
      • Idiopathic menorrhagia: excessively heavy, regular menses in the absence of intracavitary pathology or coagulopathy
      • Menometrorrhagia (i.e., irregular and heavy uterine bleeding, abnormal uterine bleeding): bleeding that is excessive in amount, is prolonged in duration, and may occur at regular or irregular intervals
    • Attempted prior treatment with standard medical therapies (i.e., oral contraceptives, oral progesterone) has failed, was medically contraindicated, or was not tolerated by the individual 
    • All of the following have been ruled out:
      • Endometrial and cervical pathology 
      • A coagulopathy problem 
      • The use of medications or supplements that could promote bleeding 
      • Any other pertinent medical conditions that could cause bleeding (e.g., thyroid disease)
  • As an alternative delivery system to protect against endometrial intraepithelial neoplasia (endometrial hyperplasia) in women who are under 65 years of age and currently receiving menopausal estrogen therapy who meet both of the following:
    • Attempted prior treatment with standard medical therapies (i.e., oral contraceptives, oral progesterone) has failed, was medically contraindicated, or was not tolerated by the individual.
    • All of the following have been ruled out:
      • Endometrial and cervical pathology
      • A coagulopathy problem
      • The use of medications or supplements that could promote bleeding
      • Any other pertinent medical conditions that could cause bleeding (e.g., thyroid disease)​
  • As second-line treatment for endometriosis after attempted prior treatment with standard medical therapies (i.e., combined hormonal contraceptives [CHC], progestins [e.g., dienogest]) who meet all of the following: 
    • Have surgically or histologically confirmed diagnosis of stage I to IV endometriosis according to the revised American Society for Reproductive Medicine (ASRM) classification
    • A history of dysmenorrhea or chronic pelvic pain lasting more than 6 months
    • Moderate to severe pain (e.g., visual analogue scale [VAS] score of 4 or more)​
​ All other uses for the LNG-IUS (Mirena​, Liletta) are considered a benefit contract exclusion and, therefore, not covered or eligible for reimbursement, unless the individual has a contraceptive benefit.

EXPERIMENTAL/INVESTIGATIONAL

Insertion and use of the 13.5-mg LNG-IUS (Skyla®) for noncontraceptive use is considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

Insertion and use of the 19.5-mg LNG-IUS (Kyleena®) for noncontraceptive use is considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

ABSOLUTE CONTRAINDICATIONS

LNG-IUS (Mirena​, Liletta) for noncontraceptive use is considered not medically necessary and, therefore, not covered for individuals with any of the following absolute contraindications:
  • Pregnancy or suspicion of pregnancy
  • Congenital or acquired uterine anomaly, including fibroids that distort the uterine cavity
  • Acute pelvic inflammatory disease or a history of pelvic inflammatory disease unless there has been a subsequent intrauterine pregnancy
  • Postpartum endometritis or infected abortion in the past three months
  • Known or suspected uterine or cervical neoplasia or unresolved, abnormal Pap smear
  • Genital bleeding of unknown etiology (which has been appropriately evaluated)
  • Untreated acute cervicitis or vaginitis, including bacterial vaginosis or other lower genital tract infection until infection is controlled
  • Acute liver disease or liver tumor (benign or malignant)
  • Conditions associated with increased susceptibility to pelvic infections
  • A previously inserted intrauterine device (IUD) that has not been removed
  • Hypersensitivity to any component of this product
  • Known or suspected carcinoma of the breast
REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.

Guidelines

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, the levonorgestrel-releasing intrauterine system (LNG-IUS) (Mirena) for noncontraceptive use is covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met.

However, when LNG-IUS (Mirena) for noncontraceptive use is given to an individual who has any of the absolute contraindications listed in the policy, it is considered not medically necessary and, therefore, not covered.

Services that are identified in this policy as experimental/investigational are not eligible for coverage or reimbursement by the Company.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

MIRENA
Mirena, an LNG-IUS containing 52 mg of levonorgestrel, was approved by the FDA on December 6, 2000, for intrauterine contraception for up to 5 years. Supplemental approvals for LNG-IUS (Mirena) have since been issued by the FDA.

SKYLA
Skyla, an LNG-IUS containing 13.5 mg of levonorgestrel, was approved by the FDA on January 9, 2013, for the prevention of pregnancy for up to 3 years.

Skyla has not been approved by the FDA for noncontraceptive use.

LILETTA
Liletta, an LNG-IUS containing 52 mg of levonorgestrel, was approved by the FDA on February 26, 2015, for the prevention of pregnancy for up to 3 years. Supplemental approvals for LNG-IUS (Liletta) have since been issued by the FDA.

KYLEENA
Kyleena, an LNG-IUS containing 19.5 mg of levonorgestrel, was approved by the FDA on September 16, 2016, for the prevention of pregnancy for up to 5 years.

Kyleena has not been approved by the FDA for noncontraceptive use.

Description

LEVONORGESTREL-RELEASING INTRAUTERINE SYSTEM

CONTRACEPTIVE AND NONCONTRACEPTIVE USE: MIRENA, LILETTA
An intrauterine device (IUD) is a birth control device that is inserted into the uterus. An intrauterine system (IUS) is an IUD that slowly releases a hormone. Mirena and Liletta are both a LNG-releasing intrauterine system (LNG-IUS). Levonorgestrel (LNG) is released into the uterine cavity through the intrauterine delivery system. Initially, LNG is released at a rate of approximately 20 µg/day. Although the rate decreases progressively over the years, the hormone levels from the device remain high enough to make it an effective contraceptive. The insertion of the LNG-IUS is a simple office procedure.

Mirena, an LNG-IUS containing 52 mg of LNG, was approved in 2000 by the US Food and Drug Administration (FDA) for the indication of intrauterine contraception for up to 5 years. The use of Mirena for this indication was increased to 6 years on August 20, 2020; 7 years on August 11, 2021; and 8 years on August 12, 2022.

Mirena consists of a T-shaped polyethylene frame (T-body) with a steroid reservoir (hormone elastomer core) around the vertical stem. The reservoir consists of a white or almost white cylinder, made of a mixture of LNG and silicone (polydimethylsiloxane), containing a total of 52 mg LNG. Initially, LNG is released at a rate of approximately 21 µg/day after 24 days; this rate is reduced to about 11 µg/day after 5 years, and 7 µ​g/day after 8 years. 

On October 1, 2009, the FDA approved Mirena to treat heavy menstrual bleeding in women who choose to use intrauterine contraception as their method of pregnancy prevention for up to 5 years. 

Liletta, an LNG-IUS containing 52 mg of LNG, was approved by the FDA on February 26, 2015, for the prevention of pregnancy for up to 3 years. It received FDA approval on October 28, 2019, for the prevention of pregnancy for up to 6 years. The use of Liletta for this indication was increased to 4 years on August 3, 2017; 5 years on October 15, 2018; 6 years on October 25, 2019; and 8 years on November 10, 2022.

Liletta contains 52 mg of LNG. Initially, LNG is released at a rate of approximately 20 µg/day. This rate decreases progressively to approximately 8.6 µ/day after 6 years, and approximately 6.5 µg/day after 8 years. Liletta must be removed or replaced by the end of the eighth year.

On June 29, 2023, the FDA approved Liletta to treat heavy menstrual bleeding in women who choose to use intrauterine contraception as their method of pregnancy prevention for up to 5 years.

​CONTRACEPTIVE USE: SKYLA, KYLEENA
Skyla, an LNG-IUS containing 13.5 mg of LNG, was approved by the FDA on January 9, 2013, for the prevention of pregnancy for up to 3 years. Skyla consists of a T-shaped polyethylene frame with a steroid reservoir containing 13.5 mg of LNG, a type of progestin. The release rate of LNG is 14 µg/day after 24 days and declines to 5 µg/day after 3 years; Skyla must be removed or replaced after 3 years.

Kyleena, an LNG-IUS containing 19.5 mg of LNG, was approved by the FDA on September 16, 2016, for the prevention of pregnancy for up to 5 years. Kyleena contains 19.5 mg of LNG. Initially, LNG is released at a rate of 17.5 µg/day after 24 days. This rate decreases progressively to approximately 9.8 µg/day at 1 year, and 7.4 µg/day after 5 years after insertion. Kyleena must be removed or replaced after 5 years.

ABNORMAL UTERINE BLEEDING
Abnormal uterine bleeding is defined as bleeding that occurs between menstrual periods or excessive menstrual bleeding. Any significant change in a female individual’s menstrual pattern or amount of bleeding should be investigated. Abnormal uterine bleeding can be developmental or endocrinologic in nature; it can also be caused by factors such as acquired anatomic lesions (e.g., fibroids or polyps), congenital or acquired coagulopathy, infections, pregnancy, or cancer.

Menorrhagia is defined as menstrual bleeding that is excessive in both amount and duration; it occurs at regular intervals. When excessive menstrual bleeding occurs at irregular intervals, it is referred to as menometrorrhagia. For some women, the only way to treat excessive menstrual bleeding is a hysterectomy.

Any female individual who has excessive menstrual bleeding should have a thorough evaluation (history and physical) after the possibility of a pregnancy has been eliminated. Based on the findings of the history and examination, the appropriate diagnostic tests should be ordered. These may include pelvic ultrasonography, endometrial biopsy, and serum lab tests (e.g.​​, thyroid-stimulating hormone [TSH], complete blood count [CBC]).

POSTMENOPAUSAL ENDOMETRIAL INTRAEPITHELIAL NEOPLASIA (ENDOMETRIAL HYPERPLASIA)
Endometrial intraepithelial neoplasia (endometrial hyperplasia; AH) occurs when the endometrium (the lining of the uterus) does not shed and becomes too thick. If the lining does not shed, the cells can become abnormal and lead to cancer. Endometrial intraepithelial neoplasia (EH) is most often caused by excess estrogen without progesterone. Estrogen replacement therapy is prescribed to relieve symptoms of menopause and slow bone loss after menopause. Progestins keep the lining of the uterus from growing too thick. Progestins can be administered in many ways, including the LNG-IUS. The use of the LNG-IUS to prevent postmenopausal endometrial intraepithelial neoplasia (EH) represents an off-label indication.

MECHANISM OF ACTION
The LNG-IUS is used to control heavy menstrual bleeding and prevent postmenopausal endometrial intraepithelial neoplasia (EH)​ because of the local progestogenic effects in the uterine cavity. Specifically, the higher local levels of LNG lead to thinning of the uterine lining by altering the connective tissue of the lining, reducing the size of the glands, and decreasing cell division. These effects may cause vaginal bleeding in menopausal women like a menstrual period.

COMPLICATIONS
The most common side effects of the device include irregular bleeding and other hormonal side effects such as breast tenderness, mood changes, ovarian cysts, headaches/migraines, and acne. Other potential disadvantages can include abdominal pain, infection, and difficulty with insertion. Also, there have been reports to the FDA regarding device migration and potential for perforation of surrounding organs and tissue.

CLINICAL RESEARCH FINDINGS
Mirena

Several randomized controlled trials (RCTs) were performed to address the noncontraceptive use of the 52-mg LNG-IUS (Mirena) with other treatments. These studies included comparison with norethindrone (a progestogen found in some oral contraceptive pills and a mainstay of oral therapy for menorrhagia as norethindrone acetate, marketed as Aygestin) and transcervical resection of the endometrium (TCRE) for women with menorrhagia. Meta-analysis revealed that the LNG-IUS can be significantly more effective than oral cyclical norethindrone as a treatment for heavy menstrual bleeding. The LNG-IUS was also compared with TCRE or endometrial ablation. Although the use of the LNG-IUS resulted in a smaller mean reduction of menstrual blood loss at 1 year, the rates of patient satisfaction at 1 year were similar in both groups.

A randomized study that took place between October 1, 1994, and October 6, 2002, involved 236 women with an average age of 43 years who had menorrhagia. Participants were randomly assigned to treatments of either the LNG-IUS (Mirena) (n=119) or a hysterectomy (n=117). Health-related quality of life (HRQL) and other measures of psychosocial well-being (i.e., anxiety, depression, sexual function) and costs were monitored. After 5 years, outcomes for 232 women (99 percent) were analyzed. There were 50 women from the LNG-IUS group who eventually underwent a hysterectomy. There remained no substantial difference in quality of life and psychosocial well-being between the groups.

Another trial that compared endometrial ablation to the LNG-IUS (Mirena) revealed a blood loss reduction of 79 percent in the group using the LNG-IUS, versus 89 percent in the group that underwent endometrial ablation.

Additional studies involving women with a diagnosis of idiopathic menorrhagia (defined as excessively heavy, regular menses in the absence of intracavitary pathology or coagulopathy) revealed that the LNG-IUS (Mirena) appears to significantly reduce menstrual blood loss.

In addition to treating menorrhagia, the 52-mg LNG-IUS (20 µg/day) dosage has been found comparable to systemic progesterone use in the prevention of endometrial proliferation in perimenopausal and postmenopausal women receiving menopausal estrogen therapy.

The ACOG supports the use of LNG-IUS (Mirena) for treating menorrhagia and for women receiving menopausal estrogen therapy who may use the device to provide protection against hyperplasia and malignancy.

In a 2010 RCT investigating treatment methods for idiopathic heavy menstrual bleeding, 165 women were randomly assigned to use either a LNG-IUS​ (n=82) or medroxyprogesterone acetate (MPA) (n=83) to determine which provides the greater absolute and relative decrease in menstrual blood loss. A screening phase of two to three cycles was conducted to determine baseline blood loss; blood loss of 80 mL or more in at least two cycles was confirmed prior to randomization. Participants underwent six cycles of treatment with either therapy. Intention-to-treat analysis found that the LNG intrauterine system users had significantly greater reduction in absolute blood loss than MPA users by the end of the study. LNG users experienced a much larger percentage decrease in percentage blood loss than those treated with MPA (−70.8 percent vs −21.5 percent, P<0.001). The LNG-IUS performed better than the FDA-approved medications available at that time with respect to reducing "abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology."

In 2014, a large multisite RCT was conducted to determine if Mirena is as safe and effective a therapeutic option as oral MPA for low- and medium-risk endometrial hyperplasia (AH). This Norwegian RCT examined the primary outcomes of normalization of endometrium or persistence of hyperplasia in 170 women via three treatment arms: Mirena for 6 months; oral MPA 10 mg for 10 d​ays per cycle for 6 months; and continuous oral MPA 10 mg daily for 6 months. Examination of endometrial biopsy by light microscopy confirmed EH; all investigators and pathologists were blinded to the treatment groups. Analysis was completed according to intention-to-treat assignment; results showed regression of hyperplasia for 100 percent of Mirena users, 96 percent of continuous oral users, and only 69 percent for cyclic oral users; effect of treatment was highly significant in all three groups. Women presenting with simple, complex, and atypical hyperplasia using this LNG intrauterine system had histologically normal endometrial cells by the end of the 6-month period. These findings indicated that Mirena is at least as good as continuous oral MPA use for the treatment of endometrial intraepithelial neoplasia (endometrial hyperplasia).

In a subsequent study published in 2016, the same research team followed up with women who were randomly assigned (6 months of Mirena, daily oral MPA, or 10 days/cycle MPA) for 24 months posttherapeutic intervention, to measure histological relapse of endometrial intraepithelial neoplasia (endometrial hyperplasia). They were curious to learn if treatment with a LNG-IUS (Mirena) resulted in fewer relapses than with oral progestogen therapy, as well as the time to relapse. They found that histological relapse, defined as regression from normal, healthy endometrium back to hyperplastic state, occurred in 41 percent (55/135). Using Kaplan-Meier estimation, they found that the time to relapse and overall rate of relapse was similar across the three study groups (P=0.66). Although multivariate regression analyses revealed that relapse was significantly predicted by menopause status and estrogen level, there is clearly an elevated level of risk of relapsing to non-atypical EH within 24 months of ending progestogen therapy. Authors suggest that continued therapy (as well as EH surveillance) may be the path to pursue for long-lasting EH control in populations unsuited to surgical intervention.

A prospective observational study published in 2018 provides additional support for the use of the 52 mg LNG-IUS (Mirena) for women suffering from idiopathic abnormal uterine bleeding. A sample of 106 parous women were followed forward in time 24 months after the insertion of the Mirena intrauterine system. The authors found statistically significant histological uterine changes during the study period, including decrease in irregular proliferative endometrium, atypical hyperplasia, and secretory endometrium (P<0.001 for each pre-/posttreatment comparison), and increase in decidual stroma, desquamated endometrium, and endometrial atrophy (P<0.001). Hematocrit and concentration of hemoglobin increased statistically during the follow-up period. This study contributes to the body of evidence indicating that use of the LNG-IUS Mirena decreases level of abnormal bleeding and that this is a relatively long-term effect.

Liletta

 

The safety and efficacy of Liletta was evaluated in a multicenter, open label, randomized, parallel assignment, phase 3 clinical trial enrolling 1910 nulliparous and parous women (Eisenberg et al. [2015]; NCT00995150). Participants were randomly assigned 4:1 to receive either Liletta (n=1751) or Mirena (n=159). The primary outcome measure was the rate of pregnancy up to 10 years. Secondary outcome measures included adverse events up to 10 years, LNG levels, and fertility rates 1 year after the removal of the IUD. Of the participants randomly assigned to Liletta, 37 were unable or failed to have the IUD placed (98.7 percent placement). Of the remaining participants, 1412 completed 1 year. By year 3, 383 participants remained. Two pregnancies occurred in year 1 and four pregnancies occurred in year 2. The pregnancy rate through 3 years was 0.55 with no pregnancies occurring in participants aged between 36 and 45 years. The ectopic pregnancy rate through 3 years was 0.12 per 100-women years. Uterine perforation occurred in three participants. Expulsion of the IUD occurred in 62 participants and occurred less frequently in nulliparous participants, with most expulsions occurring in the first year. There were 10 reported pelvic infections that resolved with outpatient antibiotics. Of 661 participants who were followed to assess for spontaneous return of menses, 94.6 percent returned after 2 months and 97.3 percent within 3 months after IUD discontinuation. Of 68 participants followed for fertility, 70.6 percent conceived spontaneously within 6 months and 86.8 percent within 12 months. Teal et al. (2019) reported on the 5-year results of the study. It was reported that 495 participants completed 5 years and 176 entered the seventh year of IUD use. A total of nine pregnancies occurred, with 6 of them being ectopic. Sixty-five expulsions occurred. Thirty-nine individuals discontinued treatment due to bleeding symptoms. Fourteen participants were diagnoses with a pelvic infection.  

 

The efficacy of Liletta as a treatment for heavy menstrual bleeding was evaluated in a multicenter, open label, single-group assignment, phase 3 clinical trial enrolling 105 participants. The primary outcome measure was end of treatment blood loss of less than 80 mL and 50 percent or less than baseline at 6 months. Baseline blood loss ranged from 73 to 520 mL (median 143 mL). All participants were able to have the IUD placed successfully. Treatment success occurred in 81.8 percent of the 99 participants remaining at the end of the study. Of these, 15 reported no bleeding or spotting and 23 reported spotting only. Within three cycles, the median blood loss had decreased more than 90 percent in the study participants. By the end of the study, the overall efficacy was reported to be 80 percent. Nine participants experienced spontaneous expulsions with four undergoing reinsertion. Six participants discontinued treatment due to bleeding or cramping.


In summary, there is sufficient evidence supporting the use of a 52-mg LNG-IUS (Mirena) as a treatment option for idiopathic menorrhagia, and as a protection against endometrial intraepithelial neoplasia (endometrial hyperplasia) in women who are receiving menopausal estrogen therapy. Currently, there are no studies supporting off-label use of the 13.5 mg or the 52 mg LNG-IUS with 3-year approvals for contraception only. Additional research is recommended for the use of the LNG-IUS for the indications of dysmenorrhea, uterine fibroids, or endometrioid uterine adenocarcinoma, or as adjuvant therapy with tamoxifen to prevent endometrial carcinoma, a known side effect of tamoxifen therapy.​

References

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Margatho D, Carvalho NM, Bahamondes L. Endometriosis-associated pain scores and biomarkers in users of the etonogestrel-releasing subdermal implant or the 52-mg levonorgestrel-releasing intrauterine system for up to 24 months. Eur J Contracept Reprod Health Care. 2020;25(2):133-140.

Marjoribanks J, Lethaby A, Farquhar C. Surgery versus medical therapy for heavy menstrual bleeding. Cochrane Database Syst Rev. 2016;(1):CD003855.

Medicines 360. Press release: FDA approves Medicine360's Liletta® (levonorgestrel-releasing intrauterine system) 52 mg to prevent pregnancy for up to six years, the longest approved duration of use of any hormonal IUDs. 10/28/2019. Available at: https://www.medicines360.org/2019/10/28/fda-approves-medicines360s-liletta/. Accessed on October 12, 2023.

Merative Micromedex® DRUGDEX® (electronic version). Levonorgestrel. [Micromedex Web site]. Merative L.P., Ann Arbor, Michigan, USA. 09/14/2023. Available at: https://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed October 12, 2023.

Mittermeier T, Farrant C, Wise MR. Levonorgestrel-releasing intrauterine system for endometrial hyperplasia. Cochrane Database Syst Rev. 2020;(9):CD012658.

Monthly Prescribing Reference. (MPR). Liletta approved for pregnancy prevention for up to 6 years. 10/28/2019. Available at: https://www.empr.com/home/news/liletta-approved-for-pregnancy-prevention-for-up-to-6-years/. Accessed on October 12, 2023.

Orbo A, Vereide AB, Arnes M, et al. Levonorgestrel-impregnated intrauterine device as treatment for endometrial hyperplasia: a national multicentre randomised trial. BJOG. 2014;121(4):477-486.

Orbo A, Arnes M, Vereides AB, Straume B. Relapse risk of endometrial hyperplasia after treatment with the levonorgestrel-implanted intrauterine system or oral progestogens. BJOG. 2016;123(9):1512-1519.

Rodriguez MB, Lethaby A, Jordan V. Progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev. 2020;(6):CD002126.

Romero SA, Young K, Hickey M, Su HI. Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen.  Cochrane Database Syst Rev. 2020;(12):CD007245.

Sangkomkamhang US, Lumbiganon P, Laopaiboon M, Mol BWJ. Progestogens or progestogen-releasing intrauterine systems for uterine fibroids. Cochrane Database Syst Rev. 2013;(2):CD008994.

Sangkomkamhang US, Lumbiganon P, Pattanittum P. Progestogens or progestogen-releasing intrauterine systems for uterine fibroids (other than preoperative medical therapy). Cochrane Database Syst Rev. 2020;(11):CD008994.

Silva-Filho AL, Pereira Fde AN, de Souza SS, et al. Five-year follow-up of levonorgestrel-releasing intrauterine system versus thermal balloon ablation for the treatment of heavy menstrual bleeding: a randomized controlled trial. Contraception. 2013;87(4):409-415.

Somboonporn W, Panna S, Temtanakitpaisan T, et al. Effects of the levonorgestrel-releasing intrauterine system plus estrogen therapy in perimenopausal and postmenopausal women: systematic review and meta-analysis. Menopause. 2011;18(10):1060-1066.

Song SY, Park M, Lee GW, et al. Efficacy of levonorgestrel releasing intrauterine system as a postoperative maintenance therapy of endometriosis: a meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2018;231:85-92.

Teal SB, Turok DK, Chen BA, et al. Five-year contraceptive efficacy and safety of a levonorgestrel 52-mg intrauterine system. Obstet Gynecol. 2019;133(1):63-70.

Theodoridis TD, Zepiridis L, Zafrakas M, et al. Levonorgestrel-releasing intrauterine system vs. endometrial thermal ablation for menorrhagia. Hormones (Athens). 2009;8(1):60-64.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Levonorgestrel-releasing intrauterine system (Kyleena®). Prescribing information. [FDA Web site]. 05/04/2023. Available at https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed October 12, 2023.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Levonorgestrel-releasing intrauterine system (Liletta®). Prescribing information. [FDA Web site]. 06/29/2023. Available at https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed October 12, 2023.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Levonorgestrel-releasing intrauterine system (Mirena®). Prescribing information. [FDA Web site]. 08/12/2022. Available at https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed October 12, 2023.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Levonorgestrel-releasing intrauterine system (Skyla®). Prescribing information. [FDA Web site]. 05/04/2023. Available at https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed October 12, 2023.

Coding

CPT Procedure Code Number(s)
58300, 58301
ICD - 10 Procedure Code Number(s)
N/A
ICD - 10 Diagnosis Code Number(s)
MEDICALLY NECESSARY

THE FOLLOWING CODES ARE MEDICALLY NECESSARY WHEN REPORTED WITH THE INSERTION (58300) OF THE LEVONORGESTREL-RELEASING INTRAUTERINE SYSTEM (MIRENA®, LILETA®​) (J7297, J7298, S4981):
N80.00Endometriosis of the uterus, unspecified
N80.01Superficial endometriosis of the uterus
N80.02Deep endometriosis of the uterus
N80.03Adenomyosis of the uterus
N80.101Endometriosis of right ovary, unspecified depth
N80.102Endometriosis of left ovary, unspecified depth
N80.103Endometriosis of bilateral ovaries, unspecified depth
N80.109Endometriosis of o​​vary, unspecified side, unspecified depth
N80.111Superficial endometriosis of right ovary
N80.112Superficial endometriosis of left ovary
N80.113Superficial endometriosis of bilateral ovaries
N80.119Superficial endometriosis of ovary, unspecified ovary
N80.12Deep endometriosis of ovary
N80.121Deep endometriosis of right ovary
N80.122Deep endometriosis of left ovary
N80.123Deep endometriosis of bilateral ovaries
N80.129Deep endometriosis of ovary, unspecified ovary
N80.201Endometriosis of right fallopian tube, unspecified depth
N80.202Endometriosis of left fallopian tube, unspecified depth
N80.203Endometriosis of bilateral fallopian tubes, unspecified depth
N80.209Endometriosis of unspecified fallopian tube, unspecified depth
N80.211Superficial endometriosis of right fallopian tube
N80.212Superficial endometriosis of left fallopian tube
N80.213Superficial endometriosis of bilateral fallopian tubes
N80.219Superficial endometriosis of unspecified fallopian tube
N80.22Deep endometriosis of the fallopian tube
N80.221Deep endometriosis of right fallopian tube
N80.222Deep endometriosis of left fallopian tube
N80.223Deep endometriosis of bilateral fallopian tubes
N80.229Deep endometriosis of unspecified fallopian tube
N80.30Endometriosis of pelvic peritoneum, unspecified
N80.311Superficial endometriosis of the anterior cul-de-sac
N80.312Deep endometriosis of the anterior cul-de-sac
N80.319Endometriosis of the anterior cul-de-sac, unspecified depth
N80.321Superficial endometriosis of the posterior cul-de-sac
N80.322Deep endometriosis of the posterior cul-de-sac
N80.329Endometriosis of the posterior cul-de-sac, unspecified depth
N80.331Superficial endometriosis of the right pelvic sidewall
N80.332Superficial endometriosis of the left pelvic sidewall
N80.333Superficial endometriosis of bilateral pelvic sidewall
N80.339Superficial endometriosis of pelvic sidewall, unspecified side
N80.341Deep endometriosis of the right pelvic sidewall
N80.342Deep endometriosis of the left pelvic sidewall
N80.343Deep endometriosis of the bilateral pelvic sidewall
N80.349Deep endometriosis of the pelvic sidewall, unspecified side
N80.351Endometriosis of the right pelvic sidewall, unspecified depth
N80.352Endometriosis of the left pelvic sidewall, unspecified depth
N80.353Endometriosis of bilateral pelvic sidewall, unspecified depth
N80.359Endometriosis of pelvic sidewall, unspecified side, unspecified depth
N80.361Superficial endometriosis of the right pelvic brim
N80.362Superficial endometriosis of the left pelvic brim
N80.363Superficial endometriosis of bilateral pelvic brim
N80.369Superficial endometriosis of the pelvic brim, unspecified side
N80.371Deep endometriosis of the right pelvic brim
N80.372Deep endometriosis of the left pelvic brim
N80.373Deep endometriosis of bilateral pelvic brim
N80.379Deep endometriosis of the pelvic brim, unspecified side
N80.381Endometriosis of the right pelvic brim, unspecified depth
N80.382Endometriosis of the left pelvic brim, unspecified depth
N80.383Endometriosis of bilateral pelvic brim, unspecified depth
N80.389Endometriosis of the pelvic brim, unspecified side, unspecified depth
N80.391Superficial endometriosis of the pelvic peritoneum, other specified sites
N80.392Deep endometriosis of the pelvic peritoneum, other specified sites
N80.399Endometriosis of the pelvic peritoneum, other specified sites, unspecified depth
N80.3A1Superficial endometriosis of the right uterosacral ligament
N80.3A2Superficial endometriosis of the left uterosacral ligament
N80.3A3Superficial endometriosis of the bilateral uterosacral ligament(s)
N80.3A9Superficial endometriosis of the uterosacral ligament(s), unspecified side
N80.3B1Deep endometriosis of the right uterosacral ligament
N80.3B2Deep endometriosis of the left uterosacral ligament
N80.3B3Deep endometriosis of bilateral uterosacral ligament(s)
N80.3B9Deep endometriosis of the uterosacral ligament(s), unspecified side
N80.3C1Endometriosis of the right uterosacral ligament, unspecified depth
N80.3C2Endometriosis of the left uterosacral ligament, unspecified depth
N80.3C3Endometriosis of bilateral uterosacral ligament(s), unspecified depth
N80.3C9Endometriosis of the uterosacral ligament(s), unspecified side, unspecified depth
N80.40Endometriosis of rectovaginal septum, unspecified involvement of vagina
N80.41Endometriosis of rectovaginal septum without involvement of vagina
N80.42Endometriosis of rectovaginal septum with involvement of vagina
N80.50Endometriosis of intestine, unspecified
N80.511Superficial endometriosis of the rectum
N80.512Deep endometriosis of the rectum
N80.519Endometriosis of the rectum, unspecified depth
N80.521Superficial endometriosis of the sigmoid colon
N80.522Deep endometriosis of the sigmoid colon
N80.529Endometriosis of the sigmoid colon, unspecified depth
N80.531Superficial endometriosis of the cecum
N80.532Deep endometriosis of the cecum
N80.539Endometriosis of the cecum, unspecified depth
N80.541Superficial endometriosis of the appendix
N80.542Deep endometriosis of the appendix
N80.549Endometriosis of the appendix, unspecified depth
N80.551Superficial endometriosis of other parts of the colon
N80.552Deep endometriosis of other parts of the colon
N80.559Endometriosis of other parts of the colon, unspecified depth
N80.561Superficial endometriosis of the small intestine
N80.562Deep endometriosis of the small intestine
N80.569Endometriosis of the small intestine, unspecified depth
N80.6Endometriosis in cutaneous scar
N80.8Other endometriosis
N80.9Endometriosis, unspecified
N92.0Excessive and frequent menstruation with regular cycle
N92.1Excessive and frequent menstruation with irregular cycle
N92.2Excessive menstruation at puberty
N92.4Excessive bleeding in the premenopausal period
Z79.890 Hormone replacement therapy

HCPCS Level II Code Number(s)
MEDICALLY NECESSARY
J7297Levonorgestrel-releasing intrauterine contraceptive system (Liletta), 52 mg
J7298Levonorgestrel-releasing intrauterine contraceptive system (Mirena), 52 mg
S4981Insertion of levonorgestrel-releasing intrauterine system

 EXPERIMENTAL/INVESTIGATIONAL FOR NON-CONTRACEPTIVE USE
J7296Levonorgestrel-releasing intrauterine contraceptive system, (Kyleena), 19.5 mg
J7301Levonorgestrel-releasing intrauterine contraceptive system (Skyla), 13.5 mg​

Revenue Code Number(s)
N/A

​

Coding and Billing Requirements

Policy History

Revisions From 07.10.05n:
01/02/2024
This version of the policy will become effective 01/02/2024.

The following policy criteria have been added to this policy:
  • The noncontraceptive use of a levonorgestrel-releasing intrauterine system (LNG-IUS) (Liletta) for the treatment of heavy menstrual bleeding for up to 5 years in individuals who chose intrauterine contraception as their method of contraception
  • LNG-IUS (Liletta)​ as an alternative delivery system to protect against endometrial intraepithelial neoplasia (endometrial hyperplasia) in women who are under 65 years of age and currently receiving menopausal estrogen therapy
  • The use of LNG-IUS (Mirena, Liletta) as second-line treatment for endometriosis
The following section was removed from the policy:
Discussion of indications for removal of the LNG-IUS

The following ICD-10 codes have been ​added to this policy:

N80.00, N80.01, N80.02, N80.03, N80.101, N80.102, N80.103, N80.109, N80.111, N80.112, N80.113, N80.119, N80.12, N80.121, N80.122, N80.123, N80.129, N80.201, N80.202, N80.203, N80.209, N80.211, N80.212, N80.213, N80.219, N80.22, N80.221, N80.222, N80.223, N80.229, N80.30, N80.311, N80.312, N80.319, N80.321, N80.322, N80.329, N80.331, N80.332, N80.333, N80.339, N80.341, N80.342, N80.343, N80.349, N80.351, N80.352, N80.353, N80.359, N80.361, N80.362, N80.363, N80.369, N80.371, N80.372, N80.373, N80.379, N80.381, N80.382, N80.383, N80.389, N80.391, N80.392, N80.399, N80.3A1, N80.3A2, N80.3A3, N80.3A9, N80.3B1, N80.3B2, N80.3B3, N80.3B9, N80.3C1, N80.3C2, N80.3C3, N80.3C9, N80.40, N80.41, N80.42, N80.50, N80.511, N80.512, N80.519, N80.521, N80.522, N80.529, N80.531, N80.532, N80.539, N80.541, N80.542, N80.549, N80.551, N80.552, N80.559, N80.561, N80.562, N80.569, N80.6, N80.8, N80.9​

The following ICD-10 codes have been removed from this policy:

T83.31XA, T83.31XD, T83.31XS, T83.32XA, T83.32XD, T83.32XS, T83.39XA, T83.39XD, T83.39XS, T83.69XA, T83.69XD, T83.69XS, T83.79XA, T83.79XD, T83.79XS, T83.81XA, T83.81XD, T83.81XS, T83.82XA, T83.82XD, T83.82XS, T83.83XA, T83.83XD, T83.83XS, T83.84XA, T83.84XD, T83.84XS, T83.86XA, T83.86XD, T83.86XS, T83.89XA, T83.89XD, T83.89XS, T83.9XXA, and Z33.1​

Revisions From 07.10.05m:
​06/15/2022

​The policy has been reviewed and reissued to communicate the Company's continuing position on Noncontraceptive Use of the Levonorgestrel-Releasing Intrauterine System. ​
​03/24/2021
​The policy has been reviewed and reissued to communicate the Company's continuing position on Noncontraceptive Use of the Levonorgestrel-Releasing Intrauterine System. 
04/20/2020This version of the policy will become effective 04/06/2020. The intent of this policy remains unchanged, but the policy has been updated to reflect updated duration of use for Liletta®. The following ICD-10 diagnosis codes were added to the policy:

T83.79XA Other specified complications due to other genitourinary prosthetic materials, initial encounter

T83.79XD Other specified complications due to other genitourinary prosthetic materials, subsequent encounter

T83.79XS Other specified complications due to other genitourinary prosthetic materials, sequela

Revisions From 07.10.05l:
07/01/2019This version of the policy will become effective 01/01/2020. The intent of this policy remains unchanged, but the policy has been updated to add further clinical research information.

The following ICD-10 CM code has been added to this policy: N92.2 Excessive menstruation at puberty (Medically Necessary).

Revisions From 07.10.05k:
02/15/2018This policy has undergone a routine review, and no revisions have been made.

Effective 10/05/2017 this policy has been updated to the new policy template format.
1/2/2024
1/8/2024
07.10.05
Medical Policy Bulletin
Commercial
No
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