CurrentCignaPolicy N/A

Phenylbutyrate Products for Urea Cycle Disorders

Policy governs prior authorization and medical necessity criteria for Cigna prescription coverage of phenylbutyrate products (sodium and glycerol formulations) for treatment of urea cycle disorders, and applies to providers prescribing these agents under Cigna benefit plans.

Policy Summary

PayerCigna

PolicyPhenylbutyrate Products for Urea Cycle Disorders

Policy CodePolicy N/A

Change TypeClarified / Revised

Effective DateN/A

Next Review DateN/A

Key ActionObtain prior authorization and document diagnosis confirmation (genetic or enzymatic testing OR elevated ammonia) and that medication is prescribed with a protein-restricted diet.

SourceLink

POLICY UPDATE CHANGES

Genetic or enzymatic testing confirmation language was modified to allow either genetic or enzymatic testing confirming a urea cycle disorder.

Reference to Ravicti was updated to use its generic name, glycerol phenylbutyrate.

4Phenylbutyrate products listed

1 yrApproval when diagnosis confirmed

3 moApproval with ammonia only

03/18/2026Review date

Coverage Criteria for Phenylbutyrate Products

Policy Summary

PayerCigna

PolicyPhenylbutyrate Products for Urea Cycle Disorders

Policy CodePolicy N/A

Change TypeClarified / Revised

Effective DateN/A

Next Review DateN/A

Key ActionObtain prior authorization and document diagnosis confirmation (genetic or enzymatic testing OR elevated ammonia) and that medication is prescribed with a protein-restricted diet.

SourceLink

On This Page

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Initial therapy — Urea Cycle Disorders

Covered when ALL of the following are met:

UCD approval criteria

Diagnosis confirmation
- Genetic or enzymatic test confirmation: Genetic or enzymatic testing confirmed a urea cycle disorder
  If met, approve for 1 year
- Elevated ammonia: Hyperammonemia diagnosed with an ammonia level above the upper limit of the normal reference range for the reporting laboratoryAbove the laboratory upper limit of normal (age-dependent)
  If met, approve for 3 months; reference ranges are dependent upon patient's age
Dietary management: Medication is prescribed in conjunction with a protein-restricted diet
No concurrent phenylbutyrate therapy: Patient will not be receiving concurrent therapy with another phenylbutyrate product
Examples include sodium phenylbutyrate (Buphenyl, generic), Pheburane, Olpruva, and glycerol phenylbutyrate (Ravicti, generic)
Specialist prescriber: Medication is prescribed by or in consultation with a metabolic disease specialist (or specialist who focuses in the treatment of metabolic diseases)

Phenylbutyrate products listed in this policy (including Buphenyl, Olpruva, Pheburane, and Ravicti/glycerol phenylbutyrate) are not medically necessary for uses that do not meet the coverage criteria specified in this document. The policy will be updated as new published data become available.

Use of the listed phenylbutyrate products for indications other than the FDA‑approved chronic management of urea cycle disorders is considered not medically necessary.

Drug Products and Relevant Clinical Codes

Covered drug productsNDC | drug namesCovered

Buphenyl	sodium phenylbutyrate tablets and powder for oral solution
Olpruva	sodium phenylbutyrate for oral suspension
Pheburane	sodium phenylbutyrate oral pellets
Ravicti / glycerol phenylbutyrate	glycerol phenylbutyrate oral liquid

Ammonia level

Threshold descriptionAmmonia level above the upper limit of normal reference range for the reporting laboratory (age-dependent)

Age dependenceReference ranges for ammonia are dependent on the patient's age

Clinical implicationElevated ammonia meeting this threshold can be used as confirmation for hyperammonemia to support a 3-month approval when genetic/enzymatic testing is not available

Provider Requirements and Prior Authorization

Prior Authorization

Prior Authorization Required

All approvals are provided for the duration indicated in the policy: approve for 1 year when diagnosis is confirmed by genetic or enzymatic testing; approve for 3 months when approval is based solely on an elevated ammonia level. Prior authorization is recommended and therapy must be prescribed by or in consultation with a metabolic disease specialist (or specialist who focuses in the treatment of metabolic diseases).

Approval durations: 1 year (genetic/enzymatic confirmation); 3 months (ammonia elevation only)
Prescriber requirement: metabolic disease specialist or consultation

Documentation Required

Dietary Management Required

Therapy must be used as an adjunct to dietary management. The medication should be prescribed in conjunction with a protein-restricted diet and is intended to complement (not replace) dietary protein restriction and/or amino acid supplementation.

Required: prescribed in conjunction with a protein-restricted diet
Ravicti and sodium phenylbutyrate products indicated as adjuncts to dietary management

Documentation Required

Required Clinical Documentation

Prescribers must document confirmation of diagnosis either by genetic or enzymatic testing OR by elevated ammonia level above the reporting laboratory's upper limit of normal. Documentation should also show the medication is indicated and that the patient will not be receiving concurrent therapy with another phenylbutyrate product.

Diagnosis confirmation: genetic or enzymatic testing OR ammonia > lab ULN
Exclude concurrent use of other phenylbutyrate products (Buphenyl, Pheburane, Olpruva, Ravicti/generic)
Evidence of specialist involvement (prescribed by or in consultation with metabolic disease specialist)

Denial Risk

Billing and Coding Denial Risk

Claims submitted without covered diagnosis or procedure codes consistent with the coverage criteria — including lack of documentation of a covered UCD diagnosis or absence of required specialist consultation and dietary-management documentation — may be denied. Providers must use the most appropriate codes as of the date of submission.

Claims lacking covered diagnosis/procedure codes or required supporting documentation will be denied
Use most appropriate codes as of the submission effective date

Background on Urea Cycle Disorders

Urea cycle disorders (UCDs) are rare inborn errors of metabolism caused by inherited deficiencies of enzymes in the urea cycle (for example, carbamoyl phosphate synthase, ornithine transcarbamylase, or argininosuccinate synthase). These defects impair ammonia detoxification, leading to accumulation of ammonia (hyperammonemia) that can cause encephalopathy and neurologic injury. Management includes dietary protein restriction and ammonia‑lowering therapies such as phenylbutyrate products for chronic control; acute hyperammonemia may require dialysis and other emergent measures.

Definitions

Urea cycle disorders

DefinitionUrea cycle disorders (UCDs) are inherited enzyme defects impairing ammonia detoxification leading to hyperammonemia and neurologic injury.

Common enzyme deficienciesIncludes deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), and argininosuccinic acid synthetase (AS)

Clinical consequencesAccumulation of ammonia may cause disturbed brain function, decreased mental awareness, vomiting, slurred speech, unstable gait, and potentially fatal encephalopathy

Management overviewTreatment includes dietary protein restriction, ammonia scavengers (phenylbutyrate products), hemodialysis for acute crises, and possible amino acid supplementation