Glycerol Phenylbutyrate (Ravicti) Form

Glycerol phenylbutyrate (Ravicti®) is a nitrogen-binding agent. FDA Approved Indication(s) Ravicti is indicated for chronic management of patients with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. Ravicti must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements). Limitation(s) of use: • Ravicti is not indicated for the treatment of acute hyperammonemia in patients with UCDs because more rapidly acting interventions are essential to reduce plasma ammonia levels. • The safety and efficacy of Ravicti for the treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established. 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 Ravicti is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Urea Cycle Disorder (must meet all):

1. Diagnosis of a UCD caused by one or more of the following, confirmed by enzymatic, biochemical, or genetic analysis: a. Carbamyl phosphate synthetase 1 (CPS1) deficiency; b. Ornithine transcarbamylase (OTC) deficiency; c. Argininosuccinate synthetase (AS) deficiency (also known as classic citrullinemia or type I citrullinemia, CTLN1); d. Argininosuccinate lyase (ASL) deficiency (also known as argininosuccinic aciduria); e. Arginase deficiency;

2. Prescribed by or in consultation with a physician experienced in treating metabolic disorders;
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   CLINICAL POLICY Glycerol Phenylbutyrate

3. For members with UCD caused by CPS1, OTC, or AS deficiency: Both of the following (a and b):
   a. Member must use generic sodium phenylbutyrate, unless contraindicated or clinically significant adverse events are experienced; b. If member has intolerance or contraindication to generic sodium phenylbutyrate, member must use Pheburane®, unless contraindicated or clinically significant adverse effects are experienced;
4. Dose does not exceed 17.5 mL (19 g) per day. Approval duration:
   Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less 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. Urea Cycle Disorder (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);

   2. Member is responding positively to therapy;
   3. If request is for a dose increase, new dose does not exceed 17.5 mL (19 g) per day.
      Approval duration:
      Medicaid/HIM – 12 months Commercial – 12 months or duration of request, whichever is less Page 2 of 6

   CLINICAL POLICY Glycerol Phenylbutyrate B. Other diagnoses/indications (must meet 1 or 2):

8. 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

9. 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 ASL: argininosuccinate lyase AS: argininosuccinate synthetase CPS1: carbamyl phosphate synthetase 1
   CTLN1: type I citrullinemia FDA: Food and Drug Administration NAGS: N-acetyl glutamate synthetase OTC: ornithine transcarbamylase UCD: urea cycle disorder Dose Limit/ Maximum Dose 20 g/day 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 and may require prior authorization.
   Drug Name Dosing Regimen sodium phenylbutyrate (Buphenyl®, Pheburane®) UCD caused by CPS1, OTC, or ASS deficiency: Weight ≥ 20 kg: 9.9 to 13 g/m2/day PO in equally divided doses with each meal or feeding Weight < 20 kg: 450 to 600 mg/kg/day PO in equally divided doses with each meal or feeding 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. Page 3 of 6

   CLINICAL POLICY Glycerol Phenylbutyrate Appendix C: Contraindications/Boxed Warnings • Contraindication(s): hypersensitivity • Boxed warning(s): none reported Appendix D: Urea Cycle Disorders UCDs are caused by a deficiency in any of the below enzymes in the pathway that transforms nitrogen to urea: • Carbamyl phosphate synthetase 1 (CPS1) deficiency • Ornithine transcarbamylase (OTC) deficiency • Argininosuccinate synthetase (AS) deficiency (also known as classic citrullinemia or type I citrullinemia, CTLN1) • Argininosuccinate lyase (ASL) deficiency (also known as argininosuccinic aciduria) • N-acetyl glutamate synthetase (NAGS) deficiency • Arginase deficiency V. Dosage and Administration
   Indication UCD Maximum Dose 17.5 mL/day Dosing Regimen Total daily dosage given in 3 equally divided doses up to nearest 0.5 mL (age ≥ 2 years) or 0.1 mL (age < 2 years): • In phenylbutyrate-naïve patients, the Ravicti dosage is 4.5-11.2 mL/m2/day In patients switching from sodium phenylbutyrate, the total daily dosage of Ravicti (mL) equals the daily dosage of sodium phenylbutyrate (g) x 0.81 (powder) or x 0.86 (tablets) • VI. Product Availability
   Oral liquid: 1.1 g/mL VII.