Elagolix (Orilissa), Elagolix/Estradiol/Norethinedrone (Oriahnn) Form

Elagolix (Orilissa®) is a gonadotropin-releasing hormone (GnRH) receptor antagonist. Elagolix/estradiol/norethinedrone; elagolix (Oriahnn®) is a combination of a GnRH receptor antagonist with an estrogen and progestin. FDA Approved Indication(s) Orilissa is indicated for the management of moderate to severe pain associated with endometriosis. Oriahnn is indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women. Limitation(s) of use:
• For Orilissa, the duration of use should be limited based on the dose and coexisting condition. • Use of Oriahnn should be limited to 24 months due to the risk of continued bone loss, which may not be reversible. 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 Orilissa and Oriahnn are medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Endometriosis Pain (must meet all):

1. Diagnosis of pain due to endometriosis;

   2. Request is for Orilissa;
   3. Prescribed by or in consultation with a gynecologist or reproductive endocrinologist;
   4. Age ≥ 18 years;
   5. Failure of a 3-month trial within the last year of an agent from one of the following drug classes, unless clinically significant adverse effects are experienced or all are contraindicated (a or b): a. Non-steroidal anti-inflammatory drug (see Appendix B for examples); Page 1 of 8

   CLINICAL POLICY Elagolix, Elagolix/Estradiol/Norethinedrone b. Oral or depot injectable progestin or progestin-containing contraceptive (see Appendix B for examples);

2. Member has not already received ≥ 24 cumulative months of treatment with elagolix- containing products (e.g., Orilissa, Oriahnn);
3. Dose does not exceed 400 mg per day. Approval duration: 6 months for 200 mg twice daily; 12 months for 150 mg once daily Total duration of therapy should not exceed 6 months for 200 mg twice daily or 24 months for 150 mg once daily. B. Heavy Menstrual Bleeding Associated with Uterine Fibroids (must meet all):
4. Diagnosis of uterine leiomyomas (fibroids) confirmed by ultrasound;
   2. Request is for Oriahnn;
   3. Prescribed by or in consultation with a gynecologist or reproductive endocrinologist;
   4. Age ≥ 18 years;
   5. Member has experienced heavy menstrual bleeding for at least 2 consecutive cycles;
   6. Failure of a 3-month trial of a combination estrogen-progestin contraceptive agent (see Appendix B for examples);
5. Member has not already received ≥ 24 cumulative months of treatment with elagolix- containing products (e.g., Orilissa, Oriahnn);
   8. Dose does not exceed 600 mg of elagolix per day. Approval duration: 12 months Total duration of therapy should not exceed 24 months. C. Other diagnoses/indications (must meet 1 or 2):
6. 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: CP.CPA.190 for commercial, 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: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
7. 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: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
   II. Continued Therapy A. Endometriosis Pain (must meet all):

8. Member meets one of the following (a or b): Page 2 of 8

   CLINICAL POLICY Elagolix, Elagolix/Estradiol/Norethinedrone 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);

9. Request is for Orilissa;
   3. Member is responding positively to therapy as evidenced by improvement in dysmenorrhea, dyspareunia, pelvic pain/induration/tenderness, or size of endometrial lesions;
10. Member has not already received ≥ 24 cumulative months of treatment with elagolix- containing products (e.g., Orilissa, Oriahnn);
11. If request is for a dose increase, new dose does not exceed 400 mg per day. Approval duration: up to 6 months for 200 mg twice daily; up to 12 months for 150 mg once daily Total lifetime duration of therapy should not exceed 6 months for 200 mg twice daily or 24 months for 150 mg once daily. Requests for dose de-escalated continuation of therapy after 6 months of 200 mg twice daily will be denied based upon lack of clinical evidence of safety of continued dosing beyond 6 months. B. Heavy Menstrual Bleeding Associated with Uterine Fibroids (must meet all):
12. 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);
13. Request is for Oriahnn;
    3. Member is responding positively to therapy as evidenced by reduced menstrual blood loss;
14. Member has not already received ≥ 24 cumulative months of treatment with elagolix- containing products (e.g., Orilissa, Oriahnn);
15. If request is for a dose increase, new dose does not exceed 600 mg of elagolix per day. Approval duration: up to 12 months
    Total duration of therapy should not exceed 24 months. C. Other diagnoses/indications (must meet 1 or 2):

16. 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: CP.CPA.190 for commercial, 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: Page 3 of 8

    CLINICAL POLICY Elagolix, Elagolix/Estradiol/Norethinedrone CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

17. 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: CP.CPA.09 for commercial, 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 – CP.CPA.09 for commercial, 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 BMD: bone mineral density FDA: Food and Drug Administration GnRH: gonadotropin-releasing hormone OATP: organic anion transporting polypeptide 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 Varies – refer to specific prescribing information Dose Limit/ Maximum Dose Varies – refer to specific prescribing information 1 tablet PO QD 1 tablet/day
    IM: 150 mg every 13 weeks SC: 104 mg every 12 to 14 weeks 1 tablet PO QD
    IM: 150 mg/3 months SC: 104 mg/3 months 1 tablet/day
    NSAIDs: ibuprofen, naproxen, fenoprofen, ketoprofen, mefenamic acid, meclofenamate, indomethacin, tolmetin, diclofenac, etodolac, diflunisal, meloxicam, piroxicam 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®) Combination estrogen-progestin contraceptive agent: ethinyl estradiol + (desogestrel, ethynodiol diacetate, drospirenone, etonogestrel, levonorgestrel, norelgestromin, norethindrone, norgestimate, or norgestrel) Page 4 of 8

    CLINICAL POLICY Elagolix, Elagolix/Estradiol/Norethinedrone 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. Appendix C: Contraindications/Boxed Warnings • Contraindication(s): o Pregnancy o Known osteoporosis o Severe hepatic impairment o Concomitant use of strong organic anion transporting polypeptide (OATP) 1B1 inhibitors (e.g., cyclosporine and gemfibrozil) o Orilissa only:  Hypersensitivity reaction to ORILISSA or any of its inactive components. Reactions have included anaphylaxis and angioedema.
    o Oriahnn only:
     With a high risk of arterial, venous thrombotic, or thromboembolic disorders. Examples include women over 35 years of age who smoke, and women who are known to have:
    • Current or history of deep vein thrombosis or pulmonary embolism
    • Vascular disease (e.g., cerebrovascular disease, coronary artery disease, peripheral vascular disease)
    • Thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation)
    Inherited or acquired hypercoagulopathies
    • • Uncontrolled hypertension
    • Headaches with focal neurological symptoms or have migraine headaches with aura if over age 35
     With current or history of breast cancer or other hormonally-sensitive malignancies, and with increased risk for hormonally-sensitive malignancies
     With undiagnosed abnormal uterine bleeding  With known anaphylactic reaction, angioedema, or hypersensitivity to Oriahnn or any of its components • Boxed warning(s):
    o Orilissa: None reported o Oriahnn: Thromboembolic disorders and vascular events
    Appendix D: General Information • Orilissa and Oriahnn cause dose-dependent decrease in bone mineral density (BMD). BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment. The impact of these BMD decreases on long-term bone health and future fracture risk are unknown. V. Dosage and Administration
    Drug Name Elagolix (Orilissa) Endometriosis Indication pain Dosing Regimen 150 mg PO QD or 200 mg PO BID Maximum Dose 150 mg/day x 24 months if no Page 5 of 8

    CLINICAL POLICY Elagolix, Elagolix/Estradiol/Norethinedrone Drug Name Indication Dosing Regimen Elagolix/estradiol/ norethinedrone; elagolix (Oriahnn) Heavy menstrual bleeding due to uterine fibroids PO for up to 24 months: one capsule (elagolix 300 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) in the morning and one capsule (elagolix 300 mg) in the evening
    Maximum Dose coexisting conditions or x 6 months if member has moderate hepatic impairment OR 400 mg/day x 6 months See regimen VI. Product Availability
    Drug Name Elagolix (Orilissa) Elagolix/estradiol/ norethinedrone; elagolix (Oriahnn) Product Availability Tablets: 150 mg, 200 mg Morning (AM) capsule: elagolix 300 mg, estradiol 1 mg, norethindrone acetate 0.5 mg Evening (PM) capsule: elagolix 300 mg VII.