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| Leuprolide Acetate (e.g., Lupron Depot; Fensolvi) for Non-Oncologic Indications | |
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| Description: |
Leuprolide acetate is a long-acting Gonadotropin-releasing hormone agonist (GnRHa). That is widely used for the treatment of hormone-dependent conditions in men, women, and pediatric individual. The chronic administration of GnRHa leads to downregulation of GnRH receptors in the pituitary gland, which results in complete suppression of luteinizing hormone, follicle-stimulating hormone, and gonadal steroids after an initial stimulatory phase (hormonal flare). A single monthly injection of Leuprolide results in an initial stimulation followed by prolonged suppression of pituitary gonadotropins.
Regulatory Status
Leuprolide acetate
(e.g., Fensolvi) was approved by the U.S. Food and Drug Administration (FDA) on May 5, 2020, for the treatment of pediatric individuals with central precocious puberty.
Leuprolide acetate for depot suspension [e.g., Lupron Depot] has non-oncologic approvals for:
Coding
See CPT/HCPCS Code section below.
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Policy/ Coverage: |
Notice of Material Amendment Policy Revision:
Effective October 11, 2025, criteria of this coverage policy have been revised. Please see details of coverage below.
Please see policy #1997128 for Leuprolide acetate (Oncologic) indications.
Effective June 1, 2026
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Leuprolide acetate for depot/injectable suspension (e.g., Lupron Depot; Fensolvi)
meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following non-oncologic indications:
Labeled Indications:
ENDOMETRIOSIS
STANDARD REVIEW:
UTERINE FIBROIDS
STANDARD REVIEW:
CENTRAL PRECOCIOUS PUBERTY
INITIAL APPROVAL:
AUTHORIZATION RENEWAL:
Off-label Indications:
INITIAL APPROVAL:
AUTHORIZATION RENEWAL:
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
Leuprolide acetate for depot/injectable suspension (e.g., Lupron Depot; Fensolvi), for any indication or circumstance not described above, does not meet member benefit certificate
Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.
For members with contracts without Primary Coverage Criteria, Leuprolide acetate for depot/injectable suspension (e.g., Lupron Depot; Fensolvi), for any indication or circumstance not described above, is considered
not Medically Necessary and is not covered or is
investigational. Not Medically Necessary or
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
DOSAGE AND ADMINISTRATION
For FDA labeled indications,
Leuprolide acetate for depot/injectable suspension (e.g., Lupron Depot; Fensolvi) must be dosed in accordance with the indication specific recommended dose per FDA label unless otherwise specified in the dosage and administration section.
For off-label indications, authorizations will not exceed the maximum FDA labeled dose and frequency across all the FDA labeled indications unless higher dose is allowed for the specific indication in the dosage and administration section.
Leuprolide acetate for depot/injectable suspension [e.g., Lupron Depot] – Intramuscular inj
Leuprolide acetate for depot suspension (e.g., Lupron Depot-Ped)
Leuprolide acetate for injectable suspension (e.g., Fensolvi)
Endometriosis
Leuprolide acetate for depot suspension (e.g., Lupron Depot)
Uterine Fibroids
Leuprolide acetate for depot suspension (e.g., Lupron Depot)
CPP
Leuprolide acetate for injectable suspension for subcutaneous use (e.g., Fensolvi)
Leuprolide acetate for depot suspension (e.g., Lupron Depot-Ped)-Intramuscular administration with dosing based on body weight.
Body weight Once Monthly Recommended Dosage
less than or equal to 25 kg 7.5 mg
greater than 25 kg up to 37.5 kg 11.25 mg
greater than 37.5 kg 15 mg
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Effective October 11, 2025 to May 31, 2026
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Leuprolide acetate for depot/injectable suspension (e.g., Lupron Depot; Fensolvi)
meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following non-oncologic indications:
For FDA labeled indications,
Leuprolide acetate for depot/injectable suspension (e.g., Lupron Depot; Fensolvi) must be dosed in accordance with the indication specific recommended dose per FDA label unless otherwise specified in the dosage and administration section.
For off-label indications, authorizations will not exceed the maximum FDA labeled dose and frequency across all the FDA labeled indications unless higher dose is allowed for the specific indication in the dosage and administration section.
Labeled Indications:
ENDOMETRIOSIS
STANDARD REVIEW for up to 12 months:
UTERINE FIBROIDS
STANDARD REVIEW for up to 3 months:
CENTRAL PRECOCIOUS PUBERTY
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
CONTINUED APPROVAL for up to 12 months:
Off-label Indications:
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
CONTINUED APPROVAL for up to 12 months:
Dosage and Administration
Dosing per FDA Guidelines unless otherwise specified below.
Leuprolide acetate for depot/injectable suspension [e.g., Lupron Depot] – Intramuscular inj
Leuprolide acetate for depot suspension (e.g., Lupron Depot-Ped)
Leuprolide acetate for injectable suspension (e.g., Fensolvi)
Endometriosis
Leuprolide acetate for depot suspension (e.g., Lupron Depot)
Uterine Fibroids
Leuprolide acetate for depot suspension (e.g., Lupron Depot)
CPP
Leuprolide acetate for injectable suspension for subcutaneous use (e.g., Fensolvi)
Leuprolide acetate for depot suspension (e.g., Lupron Depot-Ped)-Intramuscular administration with dosing based on body weight.
Body weight Once Monthly Recommended Dosage
less than or equal to 25 kg 7.5 mg
greater than 25 kg up to 37.5 kg 11.25 mg
greater than 37.5 kg 15 mg
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Leuprolide acetate for depot/injectable suspension (e.g., Lupron Depot; Fensolvi), for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, leuprolide acetate for depot/injectable suspension (e.g., Lupron Depot; Fensolvi), for any indication or circumstance not described above, is considered
investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective June 2025 to October 10, 2025
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Leuprolide acetate for depot/injectable suspension (e.g., Lupron Depot; Fensolvi)
meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following non-oncologic indications:
For FDA labeled indications,
Leuprolide acetate for depot/injectable suspension (e.g., Lupron Depot; Fensolvi) must be dosed in accordance with the indication specific recommended dose per FDA label unless otherwise specified in the dosage and administration section.
For off-label indications, authorizations will not exceed the maximum FDA labeled dose and frequency across all the FDA labeled indications unless higher dose is allowed for the specific indication in the dosage and administration section.
Labeled Indications:
ENDOMETRIOSIS
STANDARD REVIEW for up to 12 months:
UTERINE FIBROIDS
STANDARD REVIEW for up to 3 months:
CENTRAL PRECOCIOUS PUBERTY
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
CONTINUED APPROVAL for up to 12 months:
Off-label Indications:
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
CONTINUED APPROVAL for up to 12 months:
Dosage and Administration
Dosing per FDA Guidelines unless otherwise specified below.
Leuprolide acetate for depot/injectable suspension [e.g., Lupron Depot] – Intramuscular inj
Leuprolide acetate for depot suspension (e.g., Lupron Depot-Ped)
Leuprolide acetate for injectable suspension (e.g., Fensolvi)
Endometriosis
Leuprolide acetate for depot suspension (e.g., Lupron Depot)
Uterine Fibroids
Leuprolide acetate for depot suspension (e.g., Lupron Depot)
CPP
Leuprolide acetate for injectable suspension for subcutaneous use (e.g., Fensolvi)
Leuprolide acetate for depot suspension (e.g., Lupron Depot-Ped)-Intramuscular administration with dosing based on body weight.
Body weight Once Monthly Recommended Dosage
less than or equal to 25 kg 7.5 mg
greater than 25 kg up to 37.5 kg 11.25 mg
greater than 37.5 kg 15 mg
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Leuprolide acetate for depot/injectable suspension (e.g., Lupron Depot; Fensolvi), for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, leuprolide acetate for depot/injectable suspension (e.g., Lupron Depot; Fensolvi), for any indication or circumstance not described above, is considered
investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective February 12, 2025 to May 2025
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Leuprolide acetate for depot/injectable suspension (e.g., Lupron Depot; Fensolvi)
meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following non-oncologic indications:
Labeled Indications:
For labeled indications, all products must be dosed in accordance with the label unless otherwise specified.
For off-label indications, authorizations will not exceed 15 mg monthly OR maximum recommended doses as outlined in dosage and administration section unless medical literature supports a higher dose.
ENDOMETRIOSIS
STANDARD REVIEW for up to 12 months:
UTERINE FIBROIDS
STANDARD REVIEW for up to 3
months:
CENTRAL PRECOCIOUS PUBERTY
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
CONTINUED APPROVAL for up to 12 months:
Off-label Indications:
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
CONTINUED APPROVAL for up to 12 months:
Dosage and Administration
Dosing per Guidelines where applicable. For off-label indications, authorizations will not exceed 15 mg per month OR maximum recommended doses as outlined below unless medical literature supports a higher dose.
Leuprolide acetate for depot/injectable suspension [e.g., Lupron Depot] – Intramuscular inj
Leuprolide acetate for depot suspension (e.g., Lupron Depot-Ped)
Leuprolide acetate for injectable suspension (e.g., Fensolvi)
Endometriosis
Leuprolide acetate for depot suspension (e.g., Lupron Depot)
Uterine Fibroids
Leuprolide acetate for depot suspension (e.g., Lupron Depot)
CPP
Leuprolide acetate for injectable suspension for subcutaneous use (e.g., Fensolvi)
Leuprolide acetate for depot suspension (e.g., Lupron Depot-Ped)-Intramuscular administration with dosing based on body weight.
Body weight Once Monthly Recommended Dosage
< less than or equal to 25 kg 7.5 mg
> greater than 25 kg up to 37.5 kg 11.25 mg
> greater than 37.5 kg 15 mg
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Leuprolide acetate for depot/injectable suspension (e.g., Lupron Depot; Fensolvi), for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, leuprolide acetate for depot/injectable suspension (e.g., Lupron Depot; Fensolvi), for any indication or circumstance not described above, is considered
investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Due to the detail of the policy statement, the document containing the coverage statements for dates prior to February 12, 2025 is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
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| Rationale: |
The non-oncologic indications for leuprolide acetate were removed from policy # 1997128 to create a separate policy addressing non-oncologic indications.
Leuprolide acetate is a gonadotropin-releasing hormone (GnRH) agonist, which may be indicated for treatment of certain conditions, which are hormonally regulated.
A depot formulation of leuprolide (Lupron Depot-Ped) is FDA labeled for the treatment of central precocious puberty (CPP) (FDA, 2020), clinical evidence supports the use of daily SC administered leuprolide acetate for the same indication (Carel, 2009). CPP is defined as early onset of secondary sexual characteristics, generally earlier than 8 years of age in girls and 9 years of age in boys, associated with pubertal pituitary gonadotropin activation. Leuprolide prescribing information states that prior to initiation of treatment, a clinical diagnosis of CPP should be confirmed by blood concentration of luteinizing hormone (LH) (basal or stimulated with a GnRH analog) and assessment of bone age versus chronological age. Once therapy is initiated, CPP patients should be evaluated every 3 to 6 months for pubertal development and growth, and bone age should be measured radiographically every 6 to 12 months (Carel, 2009).
On May 01, 2020, the U.S. Food and Drug Administration (FDA) approved leuprolide acetate (Fensolvi) injectable suspension for subcutaneous use for the treatment of pediatric patients aged 2 years and older with central precocious puberty (CPP) (FDA, 2020). Fensolvi is designed to deliver 45 mg of leuprolide acetate, a GnRH agnosist, at a controlled rate over a six-month therapeutic period. Fensolvi must be administered by a healthcare professional. Response to Fensolvi is monitored with a GnRH agonist stimulation test, basal serum luteinizing hormone (LH) levels or serum concentration of sex steroid levels at 1 to 2 months following initiation of therapy and as needed to confirm adequate suppression of pituitary gonadotropins, sex steroids, and progression of secondary sexual characteristics. Height is measured every 3 to 6 months and bone age is monitored periodically.
The efficacy of Fensolvi was evaluated in an uncontrolled, open-label, single arm clinical trial in which 64 pediatric patients (62 females and 2 males, naïve to previous GnRH agonist treatment) with CPP received at least one dose of Fensolvi at a dosing interval of 24 weeks and were observed for 12 months. The mean age was 7.5 years (range 4 to 9 years) at the start of treatment. In pediatric patients with CPP, Fensolvi reduced stimulated and basal gonadotropins to prepubertal levels. Suppression of peak stimulated LH concentrations to <4 IU/L was achieved in 87% of pediatric patients by month 6 and in 86% of patients by month 12. In addition, the study demonstrated that leuprolide acetate suppressed sex hormones to pre-pubertal levels, and stopped or reversed the progression of clinical signs of puberty. Suppression of estradiol or testosterone concentration to prepubertal levels at the 6-month assessment was achieved in 97% and 100% of patients, respectively. Suppression of estradiol or testosterone was maintained at the 12-month assessment with 98% (55/56 females) and 50% (1/2 males) maintaining suppression. Fensolvi arrested or reversed progression of clinical signs of puberty with reductions in growth velocity and bone age. Mean growth velocity decreased from 8.9 ± 13.1 cm/yr at 1 month to 6.9 ± 3.1 cm/yr at 6 months and to 6.4 ± 1.9 cm/yr at 12 months. Eight female patients out of 62 did not meet the primary efficacy criteria for LH <4 IU/L at 6 months. In four of the eight patients, the LH level at 6 months was between 4.2 and 4.8 IU/L. The remaining four patients had LH levels >5 IU/L. However, post stimulation estradiol was suppressed to prepubertal levels (<20 pg/mL) in seven of the eight patients at month 6 and was maintained through month 12.
Leuprolide has been used in the treatment of true (central) precocious puberty, defined as sexual maturation less than age 8 in girls, and sexual maturation less than age 9 in boys. The available literature suggests tumors should be ruled out by lab tests, CT, MRI, or ultrasound. Leuprolide is not indicated for precocious pubarche alone or pseudoprecocious puberty (gonadotropin-independent precocious puberty). According to established guidelines, recommended starting doses are: Lupron Depot Ped: 0.3 mg/kg every 4 weeks (minimum 7.5 mg), or Lupron injection: 50 mcg/kg daily. Doses may be titrated upwards in order to achieve hormonal down-regulation.
Studies of leuprolide for endometriosis indicate that 6 months is an appropriate length for therapy. Because of lack of safety data with long-term use, and because of concerns expressed in the available literature regarding effects on bone density, treatment after 6 months is typically not recommended. According to established guidelines, recommended dosing of leuprolide for endometriosis is 3.75 mg as a single monthly intra-muscular (IM) injection.
Leuprolide has been studied for the treatment of uterine fibroids (leiomyoma uteri), as a pre-operative adjunct to surgical treatment. Clinical studies have demonstrated the benefit of leuprolide in reducing vascular and surgical complications secondary to obstructive fibroid size. The American College of Obstetricians and Gynecologists (ACOG) published an updated guideline, Alternatives to Hysterectomy in the Management of Leiomyomas (ACOG, 2008). The guideline did not make any recommendations for the use of Lupron or GnRH agonists for the primary treatment of leiomyomas. The following recommendation was made: “Use of gonadotropin-releasing hormone (GnRH) agonists have been shown to improve hematologic parameters, shorten hospital stay, and decrease blood loss, operating time, and postoperative pain when given for 2-3 months preoperatively. Benefits of preoperative use of GnRH agonists should be weighed against their cost and side effects for individual patients”.
Leuprolide has been used as treatment for various other conditions (e.g., polycystic ovarian disease, hypermenorrhea, pre-menstrual syndrome, paraphilias, and endometrial cancer).
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2022. No new literature was identified that would prompt a change in the coverage statement.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2023. No new literature was identified that would prompt a change in the coverage statement.
May 2024 Update
In a retrospective clinical study, after a thorough gynecologic evaluation, young female oncology patients with regular menstrual cycles undergoing myelosuppressive treatments received either depo-medroxyprogesterone acetate (DMPA), or D-tryptophan-6-luteinizing hormone-releasing hormone depot treatment (gonadotropin-releasing hormone agonist [GnRH-a]), or no treatment before the administration of myelosuppressive chemotherapy. Only patients who later developed severe thrombocytopenia (<25,000 platelets per mL) were included in the study. Daily blood counts, menorrhagia, nonvaginal bleeding episodes, and the need for blood products, gynecologic consultations, and other medical interventions were determined.
Of 101 women with cancer who met the inclusion criteria, 42 patients received DMPA, 39 patients received GnRH-a, and 20 patients remained untreated. The mean duration (6 standard deviation) of severe thrombocytopenia was 24.76 6 23.6 days. Four patients were not included because of significant gynecologic pathologies. General bleeding from nongynecological sites was similar for all groups and was not associated with vaginal bleeding. Severe or moderate menorrhagia was documented in none of the 39 women who received GnRH-a, in 9 patients (21.4%) who received DMPA, and in 9 untreated patients (40%; P ¼.02). Fewer calls for urgent gynecologic consultations were documented in the GnRH-a group compared with the untreated group (P <.0001).
Female patients undergoing myelosuppressive therapy are at high risk of developing significant menorrhagia during prolonged, severe thrombocytopenia. Pretreatment gynecologic evaluation can detect significant pelvic pathologies. GnRH-a treatment effectively prevented menorrhagia, whereas DMPA administration was less effective. (Meirow D, Rabinovici J, Katz D, 2007)
September 2024 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2024.
2025 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2025. Removed stuttering priapism indication as
the most recent AUA Guidelines regarding management or priapism, the panel states: “clinicians should inform patients with recurrent ischemic priapism that optimal strategies to prevent subsequent episodes are unknown”. (This includes preventive treatment with hormonal manipulation). Also, it states that “clinicians should inform patients with recurrent ischemic priapism that hormonal regulators may impair fertility and sexual function. (Strong Recommendation, Evidence Level: Grade B)” (Bivalacqua, 2022). Replaced “administration” with “initiation” for clarity in off-label menstrual suppression criteria.
2026 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2026.
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| CPT/HCPCS: | |
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| References: |
ACOG.(2008) Alternative to hysterectomy in the management of leiomyomas. American College of Obstetricians and Gynecologists (ACOG). 2008 Aug. 14 p. (ACOG practice bulletin; no. 96).
Benassi L, Rossi T, et al.(2002) Abdominal or vaginal hysterectomy for enlarged uteri: a randomized clinical trial. Am J Ob Gyn 2002; 187:1561-5. Bivalacqua TJ, Allen BK, Brock GB, et al.(2022) The diagnosis and management of recurrent ischemic priapism, priapism in sickle cell patients, and non-ischemic priapism: an AUA/SMSNA guideline. J Urol. 2022;208(1):43-52. Brito VN, Spinola-Castro AM, Kochi C, et al.(2016) Central precocious puberty: revisiting the diagnosis and therapeutic management. Arch Endocrinol Metab. 2016 Apr;60(2):163-72 Lupron Depot-Ped [package insert]. North Chicago, IL: AbbVie Inc.; January 2019. Carel JC, Eugster EA, Rogol A, et al.(2009) Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics. 2009 Apr;123(4):e752-62. Epub 2009 Mar 30. Darai E, Soriano D, et al.(2001) Vaginal hysterectomy for enlarged uteri, with or without laparoscopic assistance: randomized study. Obstet Gynecol 2001; 97:712-6. Doucette RC, Sharp HT, Alder SC.(2001) Challenging generally accepted contraindications to vaginal hysterectomy. Am J Ob Gyn 2001; 184:1386-91. Am J Ob Gyn 2001; 184:1386-91. U.S. Food and Drug Administration (FDA).(2020) Highlights of Prescribing Information Lupron Depot 03/18/2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020708s038lblrpl.pdf. Last accessed 10/08/2021. U.S. Food and Drug Administration (FDA).(2020) Highlights of Prescribing Information. Fensolvi (leuprolide acetate) 05/01/2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213150s000lbl.pdf. Last accessed 10/08/2021. U.S. Food and Drug Administration (FDA).(2021) Highlights of Prescribing Information.Lupron Depot-Ped. 03/11/2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/020263s044s047lbl.pdf. Last accessed 10/08/2021. |
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| Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants. | |
| CPT Codes Copyright © 2026 American Medical Association. | |