Sirolimus Protein-Bound Particles (Fyarro), Topical Gel (Hyftor) Form

Sirolimus protein-bound particles (Fyarro™) and topical gel (Hyftor™) are mammalian target of rapamycin (mTOR) inhibitors. FDA Approved Indication(s) Fyarro is indicated for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa). Hyftor is indicated for the treatment of facial angiofibroma associated with tuberous sclerosis in adults and pediatric patients 6 years of age and older. 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 Fyarro and Hyftor are medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Perivascular Epithelioid Cell Tumor (PEComa) (must meet all):

1. Diagnosis of locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa);

2. Request is for Fyarro;

   3. Prescribed by or in consultation with an oncologist;
   4. Age ≥ 18 years;
   5. Use as a single agent;
   6. Member does not have PEComa type lymphangioleiomyomatosis;
   7. Request meets one of the following (a or b): a. Dose does not exceed 100 mg/m² IV on Days 1 and 8 of each 21 day cycle; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN
      Approval duration: 6 months B. Facial Angiofibroma Associated with Tuberous Sclerosis (must meet all):
   8. Diagnosis of facial angiofibroma associated with tuberous sclerosis; Page 1 of 6

   CLINICAL POLICY Sirolimus

3. Request is for Hyftor;
   3. Prescribed by or in consultation with an oncologist, neurologist, or dermatologist;
   4. Age ≥ 6 years;
   5. Dose does not exceed any of the following (a or b): a. Age 6 to 11 years: 600 mg (2 cm); b. Age ≥ 12 years: 800 mg (2.5 cm).
      Approval duration: 3 months C. Other diagnoses/indications (must meet 1 or 2):
4. 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
5. 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. Perivascular Epithelioid Cell Tumor (PEComa) (must meet all):
6. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Fyarro for a covered indication and has received this medication for at least 30 days;
7. Request is for Fyarro;
   3. Member is responding positively to therapy;
   4. If request is for a dose increase, request meets one of the following (a or b): a. Both of the following (i and ii): i. New dose does not exceed 100 mg/m² IV on Days 1 and 8 of each 21 day cycle; ii. Dose is at least 45 mg/m² IV on Days 1 and 8 of each 21 day cycle; b. New dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN Approval duration: 12 months B. Facial Angiofibroma Associated with Tuberous Sclerosis (must meet all):

8. Member meets one of the following (a or b): Page 2 of 6

   CLINICAL POLICY Sirolimus 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 Hyftor;
   3. Member is responding positively to therapy as evidenced by, including but not limited to, a reduction in the size and/or redness of facial angiofibroma;
10. If request is for a dose increase, new dose does not exceed any of the following (a or b): a. Age 6 to 11 years: 600 mg (2 cm); b. Age ≥ 12 years: 800 mg (2.5 cm).
    Approval duration: 12 months C. Other diagnoses/indications (must meet 1 or 2):
11. 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

12. 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 FDA: Food and Drug Administration NCCN: National Comprehensive Cancer Network Appendix B: Therapeutic Alternatives
    Not Applicable
    PEComa: perivascular epithelioid cell tumor
    Page 3 of 6

    CLINICAL POLICY Sirolimus Appendix C: Contraindications/Boxed Warnings • Contraindication(s): History of severe hypersensitivity to sirolimus, other rapamycin derivatives, or albumin.
    • Boxed warning(s): None reported V. Dosage and Administration
    Indication Locally advanced unresectable or metastatic malignant PEComa Drug Name Sirolimus protein-bound particles (Fyarro) Sirolimus topical gel (Hyftor) Facial angiofibroma associated with tuberous sclerosis Dosing Regimen 100 mg/m² administered as an IV infusion over 30 minutes on Days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity Apply to the skin of the face affected with angiofibroma twice daily Maximum Dose 100 mg/m² administered as an IV infusion over 30 minutes on Days 1 and 8 of each 21-day cycle Age 6 to 11 years: 600 mg (2 cm)
    Age ≥ 12 years: 800 mg (2.5 cm)
    VI. Product Availability
    Drug Name Sirolimus protein-bound particles (Fyarro) Sirolimus topical gel (Hyftor) Availability Lyophilized powder for infusion: 100 mg of sirolimus formulated as albumin-bound particles in single-dose vial for reconstitution Topical gel, 0.2%: 2 mg of sirolimus per gram VII.