SYNAREL, Nafarelin Acetate Form

Nafarelin acetate (Synarel®) is a gonadotropin-releasing hormone (GnRH) receptor agonist. FDA Approved Indication(s) Synarel is indicated for: • Treatment of central precocious puberty (CPP) (gonadotropin-dependent precocious puberty) in children of both sexes; • Management of endometriosis, including pain relief and reduction of endometriotic lesions. Experience with Synarel has been limited to women 18 years of age and older treated for 6 months. Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
It is the policy of health plans affiliated with Centene Corporation® that Synarel is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Central Precocious Puberty (must meet all):

1. Diagnosis of CPP confirmed by all of the following (a, b, and c): a. Elevated basal luteinizing hormone (LH) level > 0.2 - 0.3 mIU/L (dependent on type of assay used) and/or elevated leuprolide-stimulated LH level > 3.3 - 5 IU/L (dependent on type of assay used); b. Bone age advanced > 1 year beyond chronological age; c. Age at onset of secondary sex characteristics (i or ii): i. Female: < 8 years; ii. Male: < 9 years;
2. Prescribed by or in consultation with a pediatric endocrinologist;
   
   3. Member meets one of the following age requirements (a or b):
      a. Female: 2 to ≤ 11 years; b. Male: 2 to ≤ 12 years;

3. Dose does not exceed 1,800 micrograms per day.
   Approval duration: 12 months B. Endometriosis (must meet all):

   1. Diagnosis of endometriosis;
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   CLINICAL POLICY Nafarelin Acetate

4. Prescribed by or in consultation with a gynecologist;
   3. Age ≥ 18 years;
   4. Endometriosis as a cause of pain is one of the following (a or b): a. Surgically confirmed; b. Both of the following (i and ii): i. Clinically suspected; ii. Failure of a 3-month trial of one of the following within the last year, unless clinically adverse effects are experienced or all are contraindicated (1, 2, or 3): 1) A non-steroidal anti-inflammatory drug (see Appendix B for examples); 2) An oral or injectable depot contraceptive (see Appendix B for examples); 3) A progestin (see Appendix B for examples);
5. For members currently receiving treatment with Synarel, total duration of therapy has not exceeded 12 months;
6. Dose does not exceed 800 micrograms per day. Approval duration: 6 months C. Gender Dysphoria, Gender Transition (off-label) (must meet all):
   1. Diagnosis of gender dysphoria or request is for gender transition;
   2. Prescribed by or in consultation with an endocrinologist and a provider with expertise in gender dysphoria and transgender medicine based on a certified training program or affiliation with local transgender health services (e.g., mental health professional such as psychologist, psychiatrist, see Appendix D);
7. Age and pubertal development - meets (a or b): a. Member is < 18 years of age and has reached or passed through Tanner Stage 2;
   Age ranges approximating Tanner Stage 2 pubertal development extend from 8 to 13 years of age in girls and 9 to 14 years of age in boys. b. Member is ≥ 18 years of age and has failed to achieve physiologic hormone levels with gender-affirming hormonal therapy (e.g., estrogen, testosterone) unless contraindicated or clinically significant adverse effects are experienced;
   4. Member demonstrates understanding of expected GnRH analogue treatment outcomes and has given consent for such treatment;
8. If member has a psychiatric comorbidity, member is followed by mental health provider;
9. Psychosocial support will be provided during treatment;
   7. Dose is within FDA maximum limit for any FDA-approved indication (see Section V) or is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).
      Approval duration:
      Medicaid/HIM – 12 months D. Other diagnoses/indications (must meet 1 or 2):

10. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: HIM.PA.33 for health insurance marketplace and CP.PMN.255 for Medicaid; or Page 2 of 9

    CLINICAL POLICY Nafarelin Acetate b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: HIM.PA.103 for health insurance marketplace and CP.PMN.16 for Medicaid; or

    2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: HIM.PA.154 for health insurance marketplace and CP.PMN.53 for Medicaid.
       II. Continued Therapy A. Central Precocious Puberty (must meet all):
11. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);
12. Member is responding positively to therapy as evidenced by, including but not limited to, improvement in any of the following parameters: decreased growth velocity, cessation of menses, softening of breast tissue or testes, arrested pubertal progression;
13. Member meets one of the following age requirement (a or b):
    a. Female: ≤ 11 years; b. Male: ≤ 12 years;
14. If request is for a dose increase, new dose does not exceed 1,800 micrograms per day.
    Approval duration: 12 months B. Endometriosis (must meet all):
15. Currently receiving medication via Centene benefit or member has previously met initial approval criteria;
16. Member is responding positively to therapy as evidenced by, including but not limited to, improvement in any of the following parameters: improvement in dysmenorrhea, dyspareunia, pelvic pain/induration/tenderness, size of endometrial lesions;
17. Total duration of Synarel therapy has not exceeded 12 months;
    
    4. If request is for a dose increase, new dose does not exceed 800 micrograms per day. Approval duration: up to a total treatment duration of 12 months C. Gender Dysphoria, Gender Transition (off-label) (must meet all):

18. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);

    2. Member is responding positively to therapy; Page 3 of 9

    CLINICAL POLICY Nafarelin Acetate

19. If request is for a dose increase, new dose is within FDA maximum limit for any FDA-approved indication (see Section V) or is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).
    Approval duration:
    Medicaid/HIM – 12 months D. Other diagnoses/indications (must meet 1 or 2):

20. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: HIM.PA.33 for health insurance marketplace and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: HIM.PA.103 for health insurance marketplace and CP.PMN.16 for Medicaid; or

    2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: HIM.PA.154 for health insurance marketplace and CP.PMN.53 for Medicaid.
       III. Diagnoses/Indications for which coverage is NOT authorized:
       A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – HIM.PA.154 for health insurance marketplace and CP.PMN.53 for Medicaid, or evidence of coverage documents.
       IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key CPP: central precocious puberty FDA: Food and Drug Administration GnRH: gonadotropin-releasing hormone LH: luteinizing hormone Appendix B: Therapeutic Alternatives
       This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.
       Drug Name Dosing Regimen Dose Limit/ Maximum Dose Varies – refer to specific prescribing information NSAIDs*: ibuprofen, naproxen, fenoprofen, ketoprofen, mefenamic acid, meclofenamate, indomethacin, tolmetin, diclofenac, etodolac, diflunisal, meloxicam, piroxicam Varies – refer to specific prescribing information Page 4 of 9

    CLINICAL POLICY Nafarelin Acetate Drug Name Dosing Regimen Dose Limit/ Maximum Dose 1 tablet/day
    1 tablet PO QD
    The progestin norethindrone also is labeled for endometriosis - see prescribing information for dosing regimen. Progestin-containing oral contraceptives: norethindrone, ethinyl estradiol + (desogestrel, ethynodiol diacetate, drospirenone, etonogestrel, levonorgestrel, norelgestromin, norethindrone, norgestimate, or norgestrel); estradiol valerate + dienogest; mestranol + norethindrone Depot injection progestin contraceptives: medroxyprogesterone acetate (Depo-Provera®, Depo-SubQ Provera 104®) IM: Depo-Provera: 150 mg every 13 weeks IM: 150 mg/3 months SC: Depo-SubQ Provera 104: 104 mg every 12 to 14 weeks
    Depo-SubQ Provera 104 also is labeled for endometriosis - same dosing regimen. SC: 104 mg/3 months Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. *Examples provided may not be all-inclusive Appendix C: Contraindications/Boxed Warnings • Contraindication(s): o Hypersensitivity o Undiagnosed abnormal vaginal bleeding o Pregnancy o Breast-feeding • Boxed warning(s): none reported Appendix D: General Information • World Professional Association for Transgender Health (WPATH) offers their Global Education Institute (GEI) Certified Training Courses: Best Practices in Transgender Medical and Mental Health Care. Additionally, the following link provides a search tool to locate WPATH member providers: https://www.wpath.org/provider/search • Transgender Care Therapy Certification Training is also offered by the International Transgender Certification Association (ITCA). Professionals with expertise in transgender care can be located using the following search tool: https://transgendercertification.com/locate-a-professional/ • The draft of WPATH Standards of Care Version 8 are available and open for public comment. These standards of care recommend that adolescents are managed by a multidisciplinary care team that involves both medical and mental health professionals. The list of key disciplines includes but is not limited to: adolescent medicine/primary care, endocrinology, psychology, psychiatry, speech/language pathology, fertility, social work, support staff, and the surgical team. The need to include a healthcare professional Page 5 of 9

    CLINICAL POLICY Nafarelin Acetate with some expertise in mental health does not dictate the inclusion of a psychologist, psychiatrist or social work in every assessment. Instead, a general practitioner, nurse or other qualified clinician could fulfill this requirement as long as they have sufficient expertise to diagnose gender incongruence, recognize mental health concerns, distinguish between these concerns and gender dysphoria, incongruence or diversity, assist a transgender person in care planning and preparing for gender affirmative medical and surgical treatments, and refer to a mental health professional if needed. V. Dosage and Administration
    Indication Central precocious puberty Dosing Regimen 1,600 micrograms (8 sprays) per day administered as 2 sprays to each nostril BID; OR 1,800 micrograms (9 sprays) per day administered as 3 sprays in one nostril TID (alternate nostrils throughout day). Endometriosis 400 micrograms (2 sprays) per day administered as 1 spray to one nostril BID (alternate nostrils) starting between days 2 and 4 of the menstrual cycle. If persistent regular menstruation after 2 months of treatment with 400 micrograms daily, dose may be increased to 800 micrograms (4 sprays) per day administered as 1 spray to each nostril BID. VI. Product Availability
    Nasal spray: 8 mL containing 2 mg/mL solution Maximum Dose 1,800 micrograms per day 800 micrograms per day
    VII.