Leuprolide acetate (Lupron®, Lupron Depot ®, Lupron Depot-Ped ®, Eligard®, Fensolvi™, Vabrinty™) and leuprolide mesylate (Camcevi^TM, Camcevi ETM®) are synthetic analogs of gonadotropin releasing hormone (GnRH). Although leuprolide has potent GnRH agonist properties during short-term or intermittent therapy, the principal effect of the drug during long-term administration is inhibition of gonadotropin secretion and suppression of ovarian and testicular steroidogenesis.

Triptorelin extended-release (Triptodur®) and triptorelin pamoate (Trelstar®) are synthetic decapeptide agonist analogs of GnRH that reversibly inhibits gonadotropin secretion when administered in continuous doses.

Histrelin (Supprelin LA®) is a synthetic nonapeptide analog of GnRH. Contained in an implant, histrelin (Supprelin LA) is released via a diffusion-controlled hydrogel polymer reservoir. Histrelin (Supprelin LA) functions as a GnRH agonist, and is a potent inhibitor of gonadotropin secretion when administered in continuous doses.

The use of leuprolide acetate (Lupron) may be considered medically necessary for the following conditions: 

Anemia due to Uterine Fibroids

• For the preoperative treatment of anemia due to uterine fibroids in combination with iron supplementation when iron therapy alone fails to correct the anemia:
  • Duration of therapy not to exceed three (3) months; or

Central Precocious Puberty (CPP)

• For treatment of children with central precocious puberty (CPP) when ALL the following criteria are met:
  • Confirmed clinical diagnosis of CPP defined by the following:
    • Measurement of LH and FSH following stimulation with a GnRH analog; and
    • Bone age versus chronological age assessment supports diagnosis of CPP; and
  • Individual has onset of secondary sexual characteristics;
    • Less than 8 years of age for females; or
    • Less than 9 years of age for males; or
    • If age is greater than the above, the prescriber attests medical necessity; and
  • Initial authorization will be for a period of up to 12 months.

Endometriosis

• For the management of endometriosis, including pain relief and reduction of endometriotic lesions; and
• Duration of initial treatment or retreatment not to exceed six (6) months; or

Prostate Cancer

• As palliative treatment of advanced prostate cancer; or

Compendia Sources

• Leuprolide acetate (Lupron) may be considered medically necessary for treatment of any of the current category 1, 2A, or 2B NCCN recommendations.

The use of leuprolide/leuprolide acetate (Lupron) not meeting the criteria as indicated in this policy is considered not medically necessary.

The use of leuprolide acetate for depot suspension (Lupron Depot) may be considered medically necessary for ANY of the following conditions:

Anemia due to Uterine Fibroids

• The preoperative treatment of anemia due to uterine fibroids in combination with iron supplementation when iron therapy alone fails to correct the anemia:
  • Duration of therapy not to exceed three (3) months and limited to one injection; or

Endometriosis

• The management of endometriosis, including pain relief and reduction of endometriotic lesions:
  • Duration of initial treatment or retreatment not to exceed six (6) months; or
• As initial management of painful symptoms of endometriosis and for management of recurrence of symptoms in combination with norethindrone acetate 5 mg tablet taken once daily as add-back therapy:
  • Duration of initial treatment or retreatment not to exceed six (6) months; or

Prostate Cancer

• The palliative treatment of advanced prostatic cancer; or

Compendia Sources

Leuprolide acetate for depot suspension may be considered medically necessary for treatment of any of the current category 1, 2A, or 2B NCCN recommendations.

The use of leuprolide acetate for depot suspension (Lupron Depot) not meeting the criteria as indicated in this policy is considered not medically necessary.

The use of leuprolide acetate for depot suspension (Lupron Depot Ped), leuprolide acetate (Fensolvi), triptorelin extended-release (Triptodur), or histrelin acetate subcutaneous implant (Supprelin LA) may be considered medically necessary for the treatment of children with central precocious puberty: when ALL the following criteria are met:

• If the request is for leuprolide acetate (Fensolvi) or triptorelin extended-release (Triptodur), the individual is two (2) years of age or older; and
• Confirmed clinical diagnosis of CPP defined by any of the following:
  • Measurement of LH and FSH elevated following stimulation with a GnRH analog; and
  • Assessment confirms bone age advancement beyond chronological age; and
• Individual has onset of secondary sexual characteristics;
  • Less than 8 years of age for females; or
  • Less than 9 years of age for males; or
  • If age is greater than the above, the prescriber attests medical necessity; and
• Initial authorization will be for a period of up to 12 months.

Reauthorization criteria

• Reauthorization of leuprolide acetate (Lupron Depot Ped), leuprolide acetate (Fensolvi), triptorelin extended-release (Triptodur), or histrelin acetate subcutaneous implant (Supprelin LA) may be considered medically necessary when ALL of the following criteria are met:
  • Individual is currently receiving therapy; and
  • Documentation of positive clinical response (e.g. pre-pubertal slowing or decline, normalization of FSH or LH, or normalization of bone age); and
• Reauthorization will be for a period of up to 12 months.

The use of leuprolide acetate for depot suspension (Lupron Depot Ped), leuprolide acetate (Fensolvi), triptorelin extended-release (Triptodur), or histrelin acetate subcutaneous implant (Supprelin LA) not meeting the criteria as indicated in this policy is considered not medically necessary.

The use of leuprolide acetate (Eligard, Vabrinty), leuprolide mesylate (Camcevi, Camcevi ETM), or triptorelin pamoate (Trelstar) may be considered medically necessary for the following condition: 

Prostate Cancer

• For the treatment of adult individuals with advanced prostate cancer; or

Compendia Sources

• Leuprolide acetate (Eligard, Vabrinty), leuprolide mesylate (Camcevi, Camcevi ETM), or triptorelin pamoate (Trelstar) may may be considered medically necessary for treatment of any of the current category 1, 2A, or 2B NCCN recommendations.

The use of leuprolide acetate (Eligard, Vabrinty) leuprolide mesylate (Camcevi, Camcevi ETM), or triptorelin pamoate (Trelstar) may not meeting the criteria as indicated in this policy is considered not medically necessary.

Other Medically Accepted Non-FDA Approved Indications, Class IIb or Higher Grade Recommendations

The use of histrelin acetate (Supprelin LA), leuprolide acetate (Lupron Depot, Lupron Depot-Ped Fensolvi), or triptorelin (Triptodur, Trelstar) may be considered medically necessary for puberty suppression in individuals with gender dysphoria when ALL of the following criteria are met:

• The adolescent has demonstrated a long-lasting and intense pattern of gender non-conformity or gender dysphoria (whether suppressed or expressed); and
• Gender dysphoria emerged or worsened with the onset of puberty; and
• Any co-existing psychological, medical, or social problems that could interfere with treatment (e.g., that may compromise treatment adherence) have been addressed, such that the adolescent’s situation and functioning are stable enough to start treatment; and
• The adolescent has given informed consent and, particularly when the adolescent has not reached the age of medical consent, the parents or other caretakers or guardians have consented to the treatment and are involved in supporting the adolescent throughout the treatment process.

The use of histrelin acetate (Supprelin LA), leuprolide acetate (Lupron Depot, Lupron Depot-Ped, Fensolvi), or triptorelin (Triptodur, Trelstar) not meeting the criteria as indicated in this policy is considered not medically necessary.

NOTE*: First generation antiandrogen must be given for seven (7) or more days to prevent testosterone flare if metastases are present in weight-bearing bone.

**

NOTE: Men with breast cancer should be treated similarly to postmenopausal women, except that use of an aromatase inhibitor is ineffective without concomitant suppression of testicular steroidogenesis.

**

NOTE: In addition to the above criteria, product specific dosage and/or frequency limits may apply in accordance with the U.S. Food and Drug Administration (FDA)-approved product prescribing information, national compendia, Centers for Medicare and Medicaid Services (CMS) and other peer reviewed resources or evidence-based guidelines. Highmark may deny, in full or in part, reimbursement for utilization that does not fall within the applicable dosage and/or frequency limits.

References

1. National Comprehensive Cancer Network (NCCN). Leuprolide Acetate. NCCN Drugs and Biologics Compendium®. 2025.

2. National Comprehensive Cancer Network (NCCN). Leuprolide Acetate for Depot Suspension. NCCN Drugs and Biologics Compendium®. 2025.

3. National Comprehensive Cancer Network (NCCN). Histrelin acetate. NCCN Drugs and Biologics Compendium®.2025.

4. National Comprehensive Cancer Network (NCCN). Triptorelin pamoate. NCCN Drugs and Biologics Compendium®. 2025.

5. Lupron Depot (leuprolide acetate for depot suspension), for intramuscular use. [package insert]. AbbVie. North Chicago, IL. Revised 08/2025.

6. Eligard® (leuprolide acetate for injectable suspension) [package insert]. Tolmar Inc.,Fort Collins, CO. Revised 02/2025.

7. Maru S, Uchino H, Osawa T, Chiba S, Mouri G, & Sazawa A. Long-term treatment outcomes of intermittent androgen deprivation therapy for relapsed prostate cancer after radical prostatectomy. PLoS ONE. 2018;13(5):1-11.

8. Venturelli M, Guatoli G, Omarini C, & Moscetti L. Spotlight on triptorelin in the treatment of premenopausal women in early-stage breast cancer. Breast Cancer. 2018;10:39-49.

9. Kittai AS, Blank J, Graff JN. Gonadotropin-releasing hormone antagonists in prostate cancer. Oncology. 2018;32(12):599-606.

10. Micromedex DrugDex Compendium®. 2025.Leuprolide

11. Clinical PharmacologyTM Compendium. 2025.Tampa FL: Gold Standard, Inc. Triptorelin.

12. Micromedex DrugDex Compendium®. 2025.Triptorelin.

13. Clinical PharmacologyTM Compendium 2025.Tampa FL: Gold Standard, Inc. Histrelin.

14. Micromedex DrugDex Compendium®. 2025. Histrelin.

15. Clinical PharmacologyTM Compendium 2025.Tampa FL: Gold Standard, Inc. Leuprolide/norethindrone.

16. Micromedex DrugDex Compendium®. 2025. Leuprolide/norethindrone.

17. Lupron Depot 3.75 mg or 11.25 mg (leuprolide acetate for depot suspension), for intramuscular use. [package insert] AbbVie. North Chicago, IL. Revised 09/2025.

18. Lupron Depot-Ped (leuprolide acetate for depot suspension), injection. [package insert] AbbVie. North Chicago, IL. Revised 11/2025.

19. Lupaneta Pack (leuprolide acetate for depot suspension; norethindrone acetate tablets), co-packaged for intramuscular use and for oral use, respectively. [package insert]. AbbVie. North Chicago, IL. Revised 08/2023.

20. Vantas (histrelin acetate) subcutaneous implant. [package insert]. Endo Pharmaceuticals Solutions Inc. Malvern, PA. Revised 09/2025.

21. Supprelin LA (histrelin acetate implant) subcutaneous implant [package insert]. Endo Pharmaceuticals Solutions Inc. Malvern, PA. Revised 09/2025.

22. Triptodur (triptorelin) for extended-release injectable suspension, for intramuscular use. Arbor Pharmaceuticals, LLC. Atlanta, GA. Revised 09/2025.

23. Trelstar (triptorelin pamoate for injectable suspension), intramuscular use. [package insert] Allergan. Irvine, CA. Revised 12/2021.

24. Radix A, Davis AM. Endocrine treatment of gender-dysphoric/gender-incongruent Persons. JAMA. 2017;318(15):1491-1492.

25. Fensolvi (leuprolide acetate) for injection suspension, for subcutaneous use [package insert]. Tolmar, Inc. Fort Collins, CO. Revised 09/2025.

26. Chew D, Anderson J, Williams K, May T, Pang K. Hormonal treatment in young people with gender dysphoria: a systematic review. Pediatrics. 2018;141(4):1-18.

27. McKay RR, Ye H, Xie W, et al. Evaluation of intense androgen deprivation before prostatectomy: a randomized phase II trial of enzalutamide and leuprolide with or without abiraterone. J Clin Oncol. 2019;37(11):923-931.

28. Shore N, Mincik I, DeGuenther M, et al. A phase 3, open-label, multicenter study of a 6-month pre-mixed depot formulation of leuprolide mesylate in advanced prostate cancer patients. World J Urol. 2020; 38(1):111-119.

29. Camcevi, Camcevi ETM (leuprolide) injectable emulsion, for subcutaneous use. [package insert]. Foresee Pharmaceuticals Co.,Ltd. Taipei City, Taiwan. Revised 09/2025.

30. National Comprehensive Cancer Network® (NCCN) Drugs and Biologics Compendium. Leuprolide mesylate. 2025.