Givosiran (Givlaari) Form

Givosiran (Givlaari®) is an aminolevulinate synthase 1-directed small interfering RNA. FDA Approved Indication(s) Givlaari is indicated for the treatment of adults with acute hepatic porphyria (AHP). 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 Givlaari is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Acute Hepatic Porphyria (must meet all):

1. Diagnosis of AHP (i.e., acute intermittent porphyria [AIP], hereditary coproporphyria [HCP], variegate porphyria [VP], or ALA dehydratase-deficiency [ALAD] porphyria) confirmed by one of the following (a or b):
   a. Genetic testing (i, ii, iii, or iv): i. AIP: positive HMBS (aka PBGD) mutation; ii. HCP: positive CPOX mutation; iii. VP: positive PPOX mutation; iv. ALAD porphyria: positive ALAD mutation; b. History of at least a four-fold increase of 5-aminolevulinic acid (ALA) or porphobilinogen (PBG) using a random urine sample within the past year (see Appendix E);

2. Prescribed by or in consultation with a gastroenterologist, hematologist, hepatologist, or neurologist;

   3. Age ≥ 18 years;
   4. History of ≥ 2 porphyria attacks in a 6-month period requiring hospitalization, urgent healthcare visit, or intravenous Panhematin® (hemin for injection) administration at home, and one of the following (a or b): a. The porphyria attacks occurred within the last 6 months; b. The porphyria attacks occurred in any 6-month period, and member is currently receiving prophylactic Panhematin therapy (e.g., once or twice a week on a regular basis);
      Prior authorization may be required. Page 1 of 8

   CLINICAL POLICY Givosiran

3. Panhematin, as a prophylactic treatment, is not prescribed concurrently with Givlaari (note: use of Panhematin for treatment of acute porphyria attacks while taking Givlaari is appropriate);
4. Documentation of member’s current body weight (in kg);
   
   7. Dose does not exceed 2.5 mg/kg once monthly. Approval duration:
      Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer B. Other diagnoses/indications (must meet 1 or 2):
5. 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
6. 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. Acute Hepatic Porphyria (must meet all):
7. 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);
8. Member is responding positively to therapy as evidenced by one of the following (a or b): a. Decreased number of porphyria attacks requiring hospitalization, urgent healthcare visit, or intravenous Panhematin administration at home; b. No increase in porphyria attacks requiring hospitalization, urgent healthcare visit, or intravenous Panhematin administration at home if member was receiving prophylactic Panhematin therapy prior to Givlaari initiation;

9. Documentation of member’s current body weight (in kg);

   4. If request is for a dose increase, new dose does not exceed 2.5 mg/kg once monthly. Approval duration:
      Medicaid/HIM – 12 months Page 2 of 8

   CLINICAL POLICY Givosiran Commercial – 6 months or to the member’s renewal date, whichever is longer B. 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: 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

11. 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 AHP: acute hepatic porphyria AIP: acute intermittent porphyria ALA: 5-aminolevulinic acid ALAD: ALA dehydratase-deficiency FDA: Food and Drug Administration HCP: hereditary coproporphyria PBG: porphobilinogen VP: variegate porphyria 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 6 mg/kg of hematin in any 24 hour period Panhematin (hemin for injection) AIP 1 to 4 mg/kg/day of hematin for 3 to 14 days based on the clinical signs. Standard dose in clinical practice per the package insert is 3 to 4 mg/kg/day - in Page 3 of 8

    CLINICAL POLICY Givosiran Drug Name Dosing Regimen Dose Limit/ Maximum Dose more severe cases this dose may be repeated every 12 hours. 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): severe hypersensitivity to Givlaari; reactions have included anaphylaxis • Boxed warning(s): none reported Appendix D: Porphyria Laboratory and Genetic Testing Resources (not all inclusive) • Mayo Medical Laboratories (Rochester, MN) • University of Texas Medical Branch at Galveston - Porphyria Research Center (Galveston, TX) • Department of Genetics, Icahn School of Medicine - Mount Sinai Porphyria Comprehensive Diagnostic and Treatment Center (New York, NY) • Invitae (San Francisco, CA) • LabCorp (Burlington, NC) Appendix E: ALA and PBG Laboratory Testing Concentrations of ALA or PBG in a random urine sample greater than four times the upper limit of normal establish the diagnosis of AHP (Wang 2019). Variations in reference ranges and reporting (e.g., with or without creatinine correction) may differ across U.S. laboratories; however, four times the upper limit of normal based on a random urine sample remains an appropriate evaluative tool. Examples of laboratory reporting variations:ALA/PBG values below are chosen for demonstration purposes only and do not reflect actual required values. • Corrected for creatinine:Additional units applicable here include mg/mmol creatinine. o ALA = 38 mg/g creatinine (reference range 0-7 mg/g creatinine);
    o PBG = 85 mg/g creatinine (reference range 0-4 mg/g creatinine).
    See Wang et al (2019) for additional information. • Uncorrected for creatinine:Additional units applicable here include mcmol/L. o ALA = 40 mg/L (reference range 0.0-5.4 mg/L);
    o PBG = 90 mg/L (reference range 0.0-2.0 mg/L).
    See LabCorp (www.labcorp.com) and Mayo Medical Laboratories (www.mayoclinicalabs.com) testing information for additional information. __ Wang B, Rudnick S, Cengia B, Bonkovsky HL. Acute hepatic porphyrias: Review and recent progress. Hepatology Communications, 2019; 3(2): 193:206. Page 4 of 8

    CLINICAL POLICY Givosiran V. Dosage and Administration
    Indication Dosing Regimen AHP 2.5 mg/kg once monthly by subcutaneous injection Maximum Dose 2.5 mg/kg/month Missed dose: Administer Givlaari as soon as possible after a missed dose. Resume dosing at monthly intervals following administration of the missed dose.
    Dose modification for adverse reactions:
    • In patients with severe or clinically significant transaminase elevations, who have dose interruption and subsequent improvement, reduce the dose to 1.25 mg/kg once monthly.
    In patients who resume dosing at 1.25 mg/kg once monthly without recurrence of severe or clinically significant transaminase elevations, the dose may be increased to the recommended dose of 2.5 mg/kg once monthly. • VI. Product Availability
    Single-dose vial: 189 mg/mL VII.