WHA

Urea Cycle Disorder Agents (Buphenyl, sodium phenylbutyrate, Pheburane, Ravicti, Olpruva)

Self-Administration – oral 

Preferred agent: generic sodium phenylbutyrate powder

Diagnosis considered for coverage:

Buphenyl (sodium phenylbutyrate)

  • Urea cycle disorders (UCDs): Indicated as adjunctive therapy in the chronic management of patients with urea cycle disorders involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), or argininosuccinic acid synthetase (AS). It is indicated in all patients with neonatal-onset deficiency (complete enzymatic deficiency, presenting within the first 28 days of life). It is also indicated in patients with late-onset disease (partial enzymatic deficiency, presenting after the first month of life) who have a history of hyperammonemic encephalopathy. It is important that the diagnosis be made early and treatment initiated immediately to improve survival. Any episode of acute hyperammonemia should be treated as a life-threatening emergency.

Pheburane (sodium phenylbutyrate)

  • Urea cycle disorders (UCDs): Indicated as adjunctive therapy to standard of care, which includes dietary management, for the chronic management of adult and pediatric patients with urea cycle disorders (UCDs), involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC) or argininosuccinic acid synthetase (AS). Limitations of use: Episodes of acute hyperammonemia may occur in patients while on Pheburane. Pheburane is not indicated for the treatment of acute hyperammonemia, which can be a life-threatening medical emergency that requires rapid acting interventions to reduce plasma ammonia levels.

Ravicti (glycerol phenylbutyrate)

  • Urea cycle disorders (UCDs): Indicated for use as a nitrogen-binding agent 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). Limitations 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.

Olpruva (sodium phenylbutyrate)

  • Urea cycle disorders (UCDs): Indicated for use as a nitrogen-binding agent, as an adjunctive therapy to standard of care, which includes dietary management, for the chronic management of adult and pediatric patients weighing 20 kg or greater and with a body surface area (BSA) of 1.2 m or greater, with urea cycle disorders (UCDs) involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), or argininosuccinic acid synthetase (AS). Limitations of Use: Olpruva is not indicated for the treatment of acute hyperammonemia.
Coverage Criteria:

For diagnosis of urea cycle disorder (UCD):

  • Diagnosis of urea cycle disorder (UCD); AND 
  • One of the following deficiencies: 
    • carbamylphosphate synthetase (CPS) 
    • ornithine transcarbamylase (OTC) 
    • argininosuccinic acid synthetase (AS); AND
  • Prescribed by or in consultation with a specialist focused on the treatment of metabolic disorders; AND
  • Molecular genetic testing confirms mutations in the CPS1, OTC, or ASS1 gene; AND
  • Used as an adjunct with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements); AND
  • (For Brand Buphenyl, generic sodium phenylbutyrate tablet, and Pheburane only): Trial and failure, or intolerance to generic sodium phenylbutyrate powder; AND
  • (For Olpruva and Ravicti only): All of the following: 
    • Inadequate response to one of the following: 
      • Dietary protein restriction 
      • Amino acid supplementation; AND
    • One of the following: 
      • Both of the following: 
        • Patient is 18 years of age or older, and
        • Trial and failure, contraindication, or intolerance to BOTH generic sodium phenylbutyrate powder and Pheburane 
      • Patient is less than 18 years of age 
Reauthorization Criteria:

For diagnosis of urea cycle disorder (UCD):

  • Documentation of positive clinical response to therapy (e.g., plasma ammonia and amino acid levels within normal limits); AND
  • Used as an adjunct with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements)
Coverage Duration: 
  • Initial: 1 year
  • Reauthorization: 1 year
Dosing:
  • The usual total daily dose of BUPHENYL Tablets and Powder and PHEBURANE for patients with urea cycle disorders is 450–600 mg/kg/day in patients weighing less than 20 kg, or 9.9–13.0 g/m2/day in larger patients. 
  • The recommended dosage of OLPRUVA for patients with urea cycle disorders is 9.9 −13g/m2/day. Divide the calculated total daily dose into three to six doses. Administer as three to six divided doses and take with food.
  • The maximum dosage for OLPRUVA, BUPHENYL, and PHEBURANE is 20 grams per day.
  • The recommended dosage range for RAVICTI in patients naïve to phenylbutyrate (PBA) is 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day).
  • The maximum total daily dosage for RAVICTI is 17.5 mL (19 g).
  • Monitor plasma ammonia levels to determine the need for dosage adjustment. Adjust the OLPRUVA dosage to maintain the plasma ammonia level within the normal range for the patient’s age, taking into consideration their clinical condition.
Authorization is not covered for the following:

The use of this drug for indications not listed in this policy does not meet the coverage criteria established by the Western Health Advantage (WHA) Pharmacy and Therapeutics (P&T) Committee.

Additional Information: 
  • OLPRUVA is an innovative formulation of sodium phenylbutyrate packaged in single-dose envelopes.
  • UCDs are a group of rare, genetic disorders that can cause harmful ammonia to build up in the blood, potentially resulting in brain damage and neurocognitive impairments, if ammonia levels are not controlled. 
  • In its New Drug Application (NDA), Acer cited preclinical and clinical safety and efficacy data from the reference listed drug, BUPHENYL powder. In its NDA, Acer also provided additional data including studies that evaluated the bioavailability and bioequivalence of OLPRUVA compared to BUPHENYL powder.
  • OLPRUVA is not approved in pediatric patients weighing less than 20 kg or in pediatric patients weighing 20 kg or greater with a BSA of less than 1.2 m2.
Policy Updates:
  • 12/02/2013 –Policy for Ravicti approved
  • 03/01/2024 –New policy for Olpruva approved by WHA P&T Committee. Policy for Ravicti updated. Combination of all UCD agents (Buphenyl, Pheburane, Ravicti, Olpruva) into one policy. (P&T, 02/20/2024)
References:
  1. Buphenyl Prescribing Information. Ucyclyd Pharma, Inc. Scottsdale, AZ. April 2023. 
  2. Ah Mew N, Simpson KL, Gropman AL, et al. Urea Cycle Disorders Overview. 2003 [updated 2017]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Mirzaa GM, Amemiya A, eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022. Urea Cycle Disorders Overview - GeneReviews® - NCBI Bookshelf (nih.gov). Accessed April 11, 2022. 
  3. Häberle J, Burlina A, Chakrapani A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis. 2019;42(6):1192-1230. doi: 10.1002/jimd.12100. 
  4. Ravicti [Prescribing Information]. Horizon Pharma USA, Inc. Lake Forest, IL. September 2021. 
  5. Pheburane Prescribing Information. Medunik USA, Inc. Bryn Mawr, PA. June 2022. 
  6. Olpruva Prescribing Information. Acer Therapeutics Inc.. Newton, MA. December 2022. 
  7. UpToDate. Urea Cycle Disorders Management. Available at:https://www.uptodate.com/contents/urea-cycle-disorders-management?search=urea%20cycle%20disorders&source=search_result&selectedTitle=2~42&usage_type=default&display_rank=2. Accessed July 11, 2023. 
  8. Olpruva manufacturer Website. Available at: https://olpruva.com/?utm_source=google&utm_medium=cpc&utm_campaign=OLPRUVA+Patient+Launch&utm_content=Now+Available&utm_keyword=olpruva&utm_id=engage&gclid=EAIaIQobChMI5K700NKCgAMVUQx9Ch3R2AXrEAAYAiAAEgITp_D_BwE. Accessed July 11, 2023. 
     

Last review date: March 1, 2024