GnRH Analogs for the Treatment of Non-Oncologic Indications Form

Overview Clinical criteria Overview Coding Document history References This document addresses the use of Gonadotropin Releasing Hormone (GnRH) Analogs for the Treatment of Non-Oncologic Indications. Included in this review are
Fensolvi (leuprolide acetate) Lupron Depot, Lupron Depot-Ped (leuprolide acetate) Lupaneta Pack (leuprolide acetate for depot suspension and norethindrone acetate tablets) • • • • Supprelin LA 12 month implant (histrelin acetate)
• Synarel Nasal Spray (nafarelin acetate) • • Vantas (histrelin acetate) • Triptodur (triptorelin pamoate extended-release)
Zoladex (goserelin acetate) Summary of FDA-approved Non-Oncology related indications and commercially available GnRH Agents Agent Lupaneta Pack (leuprolide acetate-norethindrone acetate) 1 month, 3 month Lupron Depot (leuprolide acetate) 1 month, 3 month, 6-month Zoladex (goserelin acetate) 1 month Synarel (nafarelin acetate) 1 month Lupron Depot-Ped (leuprolide acetate) 1 month, 3 month, 6- month Supprelin LA (histrelin acetate) 12 month Triptodur (triptorelin) 6 month Vantas (histrelin acetate) Fensolvi (leuprolide acetate) injectable suspension 45 mg kit Endo x x x x IET CPP UL x x x x x x x x Endo = Endometriosis, IET = Induce Endometrial Thinning, CPP = Central Precocious Puberty, UL = Uterine Leiomyomata (fibroids)
GnRH analogs are a group of hormonal drugs consisting of GnRH agonists and antagonists, both of which suppress pituitary hormones. GnRH agonists typically act over several days and GnRH antagonists act quickly within several hours. Affecting the pituitary gland in the brain, GnRH analogs suppress function of the ovaries and testes, blocking the production of testosterone in males and estrogen in females. Repeated administration of these drugs will cause gonadal hormone dependent tissues/organs to reduce or cease activity, such as the normal prostate gland that is dependent on testosterone for growth and function. This effect is reversible on discontinuation of the drug therapy.
Central Precocious Puberty (CPP) is defined as the full activation of the hypothalamic-pituitary-gonadal (HPG) axis before 8 years of age in girls and before 9 years of age in boys. The diagnosis may be considered in girls who have progressive breast development and who cross percentiles upward on the linear growth chart. CPP is far less common in boys but may be considered if there is evidence of both testicular and penile enlargement before 9 years of age (Kaplowitz 2016). The diagnostic evaluation of suspected CPP will typically include a bone age determination, which is often useful in predicting adult height. Baseline laboratory testing may include FSH, LH, and either estradiol or testosterone. The decision as to when to stop therapy is complex but typically occurs when it is apparent that continued pubertal suppression is no longer beneficial to the child. Thus, if the child is able to cope with puberty, and the predicted adult height is within the normal range, treatment may be stopped early; it often takes a year or more after cessation for menses to start. Some endocrinologists will end therapy in girls by 10 years of age, and others will continue it until 11 or 12 years of age, depending on clinical circumstances. 1

Gender dysphoria or gender incongruence is a condition wherein an individual's experienced gender is the opposite of his or her natal gender (usually assigned at birth based on anatomic sex). This can result in distress associated with persistent feelings, such as being "Trapped in the wrong body." Gender dysphoria is distinct from cross dressing (transvestitism), inability to accept homosexual orientation, psychotic delusions or personality disorders. Most individuals who express gender dysphoria in adolescence and later are thought to sustain the experienced gender. Guidance from the 2009 and 2017 Endocrine Society Clinical Practice Guidelines for the endocrine treatment of Gender-Dysphoric/Gender Incongruence Persons and “Standards of Care for the Health of Transgender and Gender Diverse People, Version 8 (WPATH)” were utilized in this guideline.
Lupanata was discontinued by the manufacturer. Criteria will remain active until July 2023 as claims can adjudicate several years after agent discontinuation. Vantas was discontinued by the manufacturer. Criteria will remain active until September 2023 as claims can adjudicate several years after agent discontinuation. Clinical Criteria When a drug is being reviewed for coverage under a member’s medical benefit plan or is otherwise subject to clinical review (including prior authorization), the following criteria will be used to determine whether the drug meets any applicable medical necessity requirements for the intended/prescribed purpose.
Fensolvi, Lupron Depot-Ped (leuprolide acetate), Synarel Nasal Spray (nafarelin acetate), Vantas or Supprelin LA (histrelin acetate subcutaneous implant), and Triptodur (triptorelin pamoate intramuscular extended release) in Central Precocious Puberty (CPP) Requests for Fensolvi, Lupron Depot-Ped (leuprolide acetate), Synarel Nasal Spray (nafarelin acetate), Vantas or Supprelin LA (histrelin acetate subcutaneous implant), or Triptodur (triptorelin pamoate intramuscular extended release) may be approved if the following criteria are met: Individual is 14 years of age or younger (clinical judgement; Kaplowitz, et al. 2016); AND I. II. Documentation is provided that individual has a diagnosis of central precocious puberty (defined as the beginning of secondary sexual characteristics before age 8 in girls and 9 in boys) (Kaplowitz, et al. 2016); AND III. Documentation is provided that the diagnosis of CPP has been confirmed by one of the following:
A. A pubertal response to a gonadotropin hormone (GnRH) agonist test; OR B. A pubertal level of a third generation luteinizing hormone (LH) assay; OR C. A pubertal level of an ultra-sensitive luteinizing hormone (LH) assay; OR
D. A pubertal level on a luteinizing hormone (LH) assay that can detect levels less than 0.2; AND IV. The diagnosis has been confirmed by assessment of bone age versus chronological age. Requests for Fensolvi, Lupron Depot-Ped (leuprolide acetate), Synarel Nasal Spray (nafarelin acetate), Vantas, Supprelin LA (histrelin acetate subcutaneous implant), or Triptodur (triptorelin pamoate intramuscular extended release) may not be approved if the following criteria are met: I. II. Individual is diagnosed with peripheral precocious puberty; OR Individual is diagnosed with benign or non-progressive precocious puberty
Zoladex (goserelin acetate), Lupron Depot or Lupron Depot-Ped (leuprolide acetate), Lupaneta Pack (leuprolide acetate for depot suspension and norethindrone), or Synarel Nasal Spray (nafarelin acetate) in Gynecological uses Requests for Zoladex (goserelin acetate), Lupron Depot or Lupron Depot-Ped (leuprolide acetate), or Synarel Nasal Spray (nafarelin acetate) may be approved if the following criteria are met: I. II. Individual has a diagnosis of chronic pelvic pain (defined as ”pain symptoms perceived to originate from pelvic organs or structures typically lasting more than six months…with symptoms suggestive of lower urinary tract, sexual, bowel, pelvic floor, myofascial, or gynecological dysfunction”) (ACOG 2020); OR Individual is using to induce amenorrhea (such as but not limited to menstruating women diagnosed with severe thrombocytopenia or aplastic anemia);
Continuation requests for chronic pelvic pain may approved if the following criterion is met: I. Individual has confirmation of symptomatic relief. Requests for continuation for chronic pelvic pain may not be approved if the following criterion is met:
I. Individual has no symptomatic relief of chronic pelvic pain. Approval Duration 2

For Chronic Pelvic Pain Initial Authorization for Chronic Pelvic Pain: 3 months Reauthorization for Chronic Pelvic Pain: 3 months Requests for Zoladex (goserelin acetate) may be approved if the following criteria are met: I. II. III. Individual is using for treatment of endometriosis and duration of treatment is limited to 6 months; OR Individual is using for dysfunctional uterine bleeding; OR Individual is using for endometrial thinning prior to endometrial ablation for dysfunctional uterine bleeding (3.6 mg implant
only). Requests for Lupron Depot or Lupron Depot-Ped (leuprolide acetate) may be approved if the following criteria are met: I. II. III. IV. Individual is using for initial treatment or retreatment of endometriosis; OR Individual is using for preoperative treatment as adjunct to surgical treatment of uterine fibroids (leiomyoma uteri), such as but not
limited to reducing the size of fibroids to allow for a vaginal procedure (AHFS); OR Individual is using prior to surgical treatment (myomectomy or hysterectomy) in those with a diagnosis of confirmed anemia
(Letheby et al. 2001, 2017); OR Individual is using for endometrial thinning prior to endometrial ablation for dysfunctional uterine bleeding. Approval Duration For Endometriosis:
Initial treatment: 6 months.
Retreatment: A single course may be approved for 6 months. Total duration of therapy should not exceed 12 months. Requests for Lupaneta Pack (leuprolide acetate for depot suspension and norethindrone acetate) may be approved if the following criteria are met: I. Individual is using for initial treatment or retreatment of endometriosis. Approval Duration Initial treatment: 6 months.
Retreatment: A single course may be approved for 6 months. Total duration of therapy should not exceed 12 months. Requests for Synarel (nafarelin acetate) may be approved if the following criteria are met: Individual is using for endometriosis; AND I. II. Duration of treatment with agent is limited to 6 months. Zoladex (goserelin acetate), Vantas or Supprelin LA (histrelin acetate), Fensolvi, Lupron Depot or Lupron Depot-Ped, (leuprolide acetate), Lupaneta Pack (leuprolide acetate for depot suspension and norethindrone acetate tablets), Synarel Nasal Spray (nafarelin acetate), and Triptodur (triptorelin pamoate intramuscular extended release) in Gender Dysphoria/Incongruence Requests for all GnRH Analogs—Zoladex (goserelin acetate), Vantas or Supprelin LA (histrelin acetate), Fensolvi, Lupron Depot or Lupron Depot-Ped, (leuprolide acetate), Lupaneta Pack (leuprolide acetate for depot suspension and norethindrone acetate tablets), Synarel Nasal Spray (nafarelin acetate), or Triptodur (triptorelin pamoate intramuscular extended release) may be approved if the following criteria are met: I. Individual has a diagnosis of gender dysphoria/incongruence (Coleman 2022). Quantity Limits Gonadotropin Releasing Hormone Analogs for the Treatment of Non-Oncologic Indications Quantity Limits
Drug Fensolvi (leuprolide acetate) 45 mg kit Lupaneta Pack (leuprolide/norethindrone) 3.75 mg/5 mg
Lupaneta Pack (leuprolide/norethindrone) 11.25 mg/5 mg
Lupron Depot (leuprolide acetate) 3.75 mg, 7.5 mg Lupron Depot (leuprolide acetate) 11.25 mg, 22.5 mg Lupron Depot (leuprolide acetate) 30 mg Lupron Depot (leuprolide acetate) 45 mg Lupron Depot Ped (leuprolide acetate) (1-month kit) 7.5, 11.25 or 15 mg Limit 1 kit per 24 weeks (6 months) 1 pack per 4 weeks 1 pack per 12 weeks 1 kit per 4 weeks 1 kit per 12 weeks 1 kit per 16 weeks 1 kit per 24 weeks (6 months) 1 kit per 4 weeks 3

Lupron Depot Ped (leuprolide acetate) (3-month kit) 11.25 or 30 mg Lupron Depot Ped (leuprolide acetate) 45 mg
Supprelin LA (histrelin acetate) 50 mg Synarel (nafarelin acetate) 2 mg/mL (60 sprays/bottle) Triptodur (triptorelin) 22.5mg kit Vantas (histrelin acetate) 50 mg Zoladex (goserelin acetate) 3.6 mg Implant Zoladex (goserelin acetate) 10.8 mg Implant Coding 1 kit per 12 weeks 1 kit per 24 weeks 1 implant per year
5 bottles per 30 days 1 kit per 24 weeks (6 months) 1 implant per year 1 per 4 weeks 1 per 12 weeks The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member. HCPCS
J1675 J1950 J1951 J1954 J3315 J3316 J9202 J9217 J9225 J9226 S9560 Injection, histrelin acetate, 10 micrograms Injection, leuprolide acetate (for depot suspension), per 3.75 mg [Lupron Depot, Lupron Depot-Ped,
Lupaneta Pack] Injection, leuprolide acetate for depot suspension (4ensolvi), 0.25 mg Injection, leuprolide acetate for depot suspension (Lutrate), 7.5 mg Injection, triptorelin pamoate, 3.75 mg [Trelstar, Trelstar Depot, Trelstar LA] Injection, triptorelin, extended-release, 3.75 mg [Triptodur] Goserelin acetate implant, per 3.6 mg [Zoladex] Leuprolide acetate (for depot suspension), 7.5 mg [Eligard, Lupron Depot, Lupron Depot-Ped, Lupaneta
Pack] Histrelin implant (Vantas), 50 mg Histrelin implant (Supprelin LA), 50 mg Home injectable therapy; hormonal therapy (e.g., leuprolide, goserelin), including administrative services,
professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and
nursing visits coded separately), per diem ICD-10 Diagnosis All diagnoses excluding oncologic diagnoses Document History Revised: 12/11/2023