Medical Policies - Prescription Drugs

Sodium Phenylbutyrate


Effective Date:10-15-2017



Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

Sodium phenylbutyrate may be considered medically necessary as an adjunctive therapy in the chronic management of urea cycle disorders (UCD) involving either complete (presenting within the first 28 days of life), or partial (presenting after the first month of life and with history of hyperammonemic encephalopathy) deficiency of the following enzymes:

Carbamoylphosphate synthetase (CPS);

Ornithine transcarbamoylase (OTC); or

Argininosuccinic acid synthetase (AS).

Sodium phenylbutyrate may be considered medically necessary for the following off-label indications that have been designated under the Orphan Drug Program by the U.S. Food and Drug Administration (FDA):

As an adjunct to surgery, radiation therapy and/or FDA-approved chemotherapy for primary or recurrent malignant glioma;

Sickle-cell disorders, including SS hemoglobinopathy, SC hemoglobinopathy, and S-thalassemia hemoglobinopathy; or

Treatment of acute promyelocytic leukemia.

Sodium phenylbutyrate is considered not medically necessary and contraindicated in the management of acute hyperammonemia.

Sodium phenylbutyrate is considered experimental, investigational and/or unproven for all other indications, including but not limited to:

All malignancies (other than glioma and acute promyelocytic leukemia when used as specified in the FDA Orphan Drug designation);

Benign brain tumors;

Human Immunodeficiency Virus (HIV); or

Cystic fibrosis (CF).


A urea cycle disorder (UCD) is a genetic disorder caused by a deficiency of one of the enzymes usually found in the urea cycle; this enzyme is responsible for removing ammonia from the blood stream. The urea cycle involves a series of biochemical steps in which nitrogen, a waste product of protein metabolism, is removed from the blood and converted to urea. Normally, the urea is transferred into the urine and removed from the body. In UCD, the nitrogen accumulates in the form of ammonia and is not removed from the body resulting in hyperammonemia. Ammonium is highly toxic to nerve cells and hyperammonemia may result in metabolic derangement, leading to anorexia, lethargy, confusion, coma, brain damage, and death. (1)

UCD occur in both children and adults. Newborns with severe mutations become catastrophically ill within 36-48 hours of birth. Children with less severe mutations can remain undiagnosed because symptoms are not appropriately recognized. Adults may have subtle symptoms in their lifetime that go unrecognized or unheeded. (1)

The estimated incidence of UCD is 1 in 8500 births. Because many cases are undiagnosed, the exact incidence of these cases is unknown and underestimated. (1)

Regulatory Status

In 1996, the U.S. Food and Drug Administration (FDA) granted marketing approval for sodium phenylbutyrate (Buphenyl®), with labeled indications for the management of UCD. Sodium phenylbutyrate is rapidly metabolized by beta-oxidation to phenylacetate. Phenylacetate conjugates with glutamine to promote the synthesis of phenylacetylglutamine, which serves as a substitute vehicle for waste nitrogen excretion that is eliminated with the urine. Per the FDA, sodium phenylbutyrate is contraindicated in the management of acute hyperammonemia. (2, 3)

The FDA also designated sodium phenylbutyrate orphan drug status for use in the treatment of the following (4):

Acute promyelocytic leukemia,

An adjunctive treatment of recurrent malignant glioma; and

Sickling disorders (S-S, S-C, and S-thalassemia hemoglobinopathies).

The Orphan Drug Act designation is granted by the FDA to encourage the development of drugs involved in the diagnosis, prevention or treatment of a medical condition affecting fewer than 200,000 people in the country. (5)


This policy was created September 2004 and updated periodically with literature review of the MedLine database. The most recent update with literature search was completed through August 2017.

Sodium phenylbutyrate has been approved by the U.S. Food and Drug Administration (FDA) for use in patients with urea cycle disorders (UCD). The FDA also gave sodium phenylbutyrate orphan drug designation for treatment of acute promyelocytic leukemia, an adjunct to surgery, radiation therapy, and chemotherapy for treatment of patients with primary or recurrent malignant glioma. Due to the nature of orphan drugs, the literature on these indications is sparse.

Maestri et al. conducted a study of 24 infants born before 1990 and rescued from hyperammonemic coma caused by neonatal-onset argininosuccinate synthetase deficiency (ASD), who was referred for enrollment in ongoing clinical studies of sodium benzoate, sodium phenylacetate, and sodium phenylbutyrate. The cumulative survival rate was 87.5% at 5 years and 72% at 10 years of age. Survivors include 15 patients currently treated with high doses of sodium phenylbutyrate; two patients withdrew. Among the treated group, 11 were classified as severely to profoundly mentally retarded. The remaining 4 patients had intelligence quotient (IQ) measurements in the borderline to mentally retarded range. All patients had intercurrent hyperammonemic episodes; study data indicates that the frequency of the episodes decreased with implementation of the current protocol. These patients were growth retarded, but most had height-for-weight scores within 2 standard deviations (SD) of the mean. Laboratory studies of plasma amino acids and of hematopoietic, renal, and hepatic function were within normal limits with the exception of slightly elevated serum aminotransferase values. Study results indicate that these drugs are safe and that the current protocol improves survival rates. However, survival is accompanied by mental retardation, growth retardation, risk of hyperammonemic episodes, and the necessity of lifetime adherence to strict medication and dietary management. (6)

Collins et al. treated 11 patients with homozygous beta thalassemia (three transfusion dependent) and 1 sickle-beta-thalassemia patient with 20 g/d (forty 500-mg tablets) of sodium phenylbutyrate for 41 to 460 days. All patients showed an increase in the percent of F reticulocytes associated with treatment, but only 4 patients responded by increasing their hemoglobin (Hb) levels by greater than 1 g/dL (mean increase, 2.1 g/dL; range, 1.2 to 2.8 g/dL). None of the transfusion-dependent thalassemia subjects responded. Increase in Hb was associated with an increase in red blood cell number (mean increase, 0.62 x 10(12)/L), and mean corpuscular volume (mean increase, 6 fL). Changes in percent HbF (fetal hemoglobin), absolute HbF levels, or alpha to non-alpha-globin ratios as measured by levels of mRNA and globin protein in peripheral blood did not correlate with response to treatment. Response to treatment was not associated with the type of beta-globin mutation, but baseline erythropoietin levels of greater than 120 mU/mL was seen in all responders and only 2 of 8 nonresponders to sodium phenylbutyrate. Compliance with treatment was greater than 90% as measured by pill counts. The authors concluded that sodium phenylbutyrate increases Hb in some patients with thalassemia, but the precise mechanism of action is unknown. (7)

Baker et al. reported a 44-year-old female with a recurrent, multicentric, malignant glioma who experienced a durable remission lasting more than four years. The patient initially presented with seizures caused by a biopsy-proven anaplastic astrocytoma of the frontal lobe. The patient was treated with radiation therapy and Procarbazine-CCNU-Vincristine (PCV). However, the tumor progressed and extended to the corpus callosum with midline shift, refractory to four cycles of continuous 72-h infusion of BCNU/Cisplatinum. Additional enhancing lesions appeared in the left frontal and left temporal lobes. The patient was started on sodium phenylbutyrate, 18 g daily in three divided oral doses, and reduced to 9 g/day and eventually to 4.5 g/day to eliminate mild, reversible side effects. Four years later, the patient has a KPS functional score (Karnofsky Performance Status scale) of 100%. Phenylbutyrate is a well-tolerated, oral agent that shows potential for the treatment of malignant gliomas. Further studies should be considered to identify a subset of patients that have tumors sensitive to phenylbutyrate, either as a single agent or in combination with radiation therapy or other chemotherapeutic agents. (8)

A Phase I study demonstrated promising preliminary evidence of clinical activity in acute myeloid leukemia and myelodysplastic syndrome (MDS); however, plasma concentrations achieved at the maximum tolerated dose were less than those targeted based on in vitro studies. Because prolonged exposure to suboptimal concentrations of phenylbutyrate in vitro led to pharmacodynamic changes similar to a more brief exposure to higher concentrations, Gore et al. conducted a study of the feasibility of prolonged administration of sodium phenylbutyrate. Selected patients with acute myeloid leukemia and MDS were treated with sodium phenylbutyrate as a continuous intravenous infusion via ambulatory infusion pump. Sequential cohorts were treated for 7 consecutive days out of 14, or with 21 consecutive days out of 28. Prolonged infusions were well tolerated; dose-limiting central nervous system toxicity developed in 1 of 23 patients treated. End-of-infusion plasma concentrations were maintained within a range sufficient to inhibit HDAC (histone deacetylases). Two patients on the 21/28 schedule developed hematological improvement. Prolonged infusions of phenylbutyrate are well tolerated making this an attractive platform for the clinical investigation of HDAC inhibition. (9)

Intravenous arginine butyrate has been shown to increase HbF in sickle cell and thalassemia patients. Dover et al. observed that sodium 4-phenylbutyrate, a drug administered orally to treat UCD, increases HbF production in non-anemic children and adults. They treated six subjects with sickle cell disease over a period of 14 to 179 days. All subjects received their initial therapy of 9 to 13 g/m2/day as 0.5-g tablets of sodium 4-phenylbutyrate as inpatients. All subjects showed a rapid increase in the percentage of F-reticulocytes (pretreatment, 1% to 20%; posttreatment, 10% to 44%). Four subjects were treated only 11 to 25 days as inpatients. Two of these four subjects failed to respond to the outpatient component because of their inability to maintain an intake of 30 to 40 tablets per day. One subject (C) developed a rash at day 10 and discontinued treatment at day 14. Another subject (B) was transfused for a painful crisis on day 25. Subject A, treated for 179 days, had an increased percentage of F cells, from 54% to 77%, and increased HbF levels, from 10.6% to 18%. Subject F, treated for 154 days, had an increased percentage of F cells, from 59% to 73%, and an increased percentage of HbF, from 10.4% to 16%. All subjects showed some increase in weight. Subject A developed mild transient ankle edema. Myelotoxicity was not seen in any treated patient. Oral administration of sodium 4-phenylbutyrate rapidly increased F-cell production in sickle cell disease. (10)

In patients with homozygous beta-thalassemia, therapy with sodium phenylbutyrate (20 grams daily for up to 460 days) has been associated with inconsistent hematologic responses. Although F reticulocyte percentages have increased consistently, an increase in hemoglobin of more than 1 gram/deciliter has been less common (about 35% of patients). Transfusion-dependent patients have not responded. Changes in fetal hemoglobin or absolute fetal hemoglobin levels (or alpha- to non-alpha- globin ratios) did not correlate with hemoglobin responses. However, patients with a baseline erythropoietin level of greater than 120 mU/mL were more likely to respond to phenylbutyrate (with an increase in hemoglobin) than those with lower baseline erythropoietin values (9). Overall data suggests limited benefits of sodium phenylbutyrate in beta-thalassemia. However, combination studies with phenylbutyrate and erythropoietin are needed.

A biopsy-proven malignant myeloma that progressed under treatment with radiation and standard chemotherapy (procarbazine-CCNU-vincristine (PCV)) regressed completely during 9 months of treatment with sodium phenylbutyrate. Phenylbutyrate 18 grams (g) per day orally, in 3 divided doses, were started for the 44-year-old woman after a year and a half of unsuccessful conventional treatment. After the first month, the dose was reduced to 9 g per day to minimize side effects (nausea, headache, dizziness). Later, the dose was again reduced to 4.5 g per day because of mild elevation of serum transaminases. Seizures caused by the tumor were being controlled with anticonvulsants. After 9 months, the tumor had regressed completely. Anticonvulsant treatment was discontinued, with no recurrence of seizures. Phenylbutyrate was discontinued after 28 months. Four years after the start of phenylbutyrate treatment, she remained tumor-free and with a KPS of 100% (10). Treatment with phenylbutyrate resulted in durable remission in one patient with a malignant glioma that was resistant to radiation and standard chemotherapy

Constant infusion of sodium phenylbutyrate at the maximum tolerated dose resulted in sustained hematological improvement (HI) in 2 of 10 patients receiving the drug on a 21-days-on/7- days-off cycle over 3 months (3 cycles), whereas none of 13 patients showed sustained HI on a 7-days-on/7-days-off cycle (6 cycles) over 3 months. There were no complete or partial remissions. All patients had MDS or acute myeloid leukemia (AML). Sodium phenylbutyrate was delivered by a continuous ambulatory infusion pump through an indwelling central venous catheter. All patients received 375 milligrams/kilogram/day (mg/kg/day), the maximum tolerated dose. HI was defined as a 50% or greater restoration of the deficit from normal in one or more peripheral blood cell lines but insufficient to meet criteria for partial or complete remission, or a 50% or greater decrease in the need for transfusions of packed red blood cells or platelets. There was one case of neurocortical toxicity (on the 7/7 schedule), which reversed completely within 48 hours of cessation of infusion. Ten of the 13 patients on the 7/7 schedule and 4 of 10 on the 21/7 schedule were hospitalized for granulocytopenic fever (10). Constant infusion of sodium phenylbutyrate resulted in sustained hematological improvement in 2 of 23 patients

Oral therapy with sodium phenylbutyrate (9 to 13 grams/square meter/day for up to 179 days) has produced an increase in F reticulocytes in patients with sickle cell anemia. However, a significant increase in fetal hemoglobin was not a universal finding (30% of patients). Some patients discontinued therapy due to the requirement of having to ingest up to 40 tablets daily. The number of patients studied has been small, and further investigations are needed, especially combined therapy with phenylbutyrate and hydroxyurea as these agents may differ in mechanism of action.

Iannitti and Palmieri published a literature review of clinical and experimental applications for sodium phenylbutyrate. The authors state that the therapy for the urea cycle disorders is directed at decreasing the requirement for urea biosynthesis by decreasing dietary nitrogen intake and increasing waste nitrogen excretion. It is achieved by prescribing phenylbutyrate, a precursor of phenylacetate (PAA) that conjugates with glutamine to yield phenylacetylglutamine, a waste nitrogen compound that is rapidly excreted in the urine. The use of phenylbutyrate to treat UCD is due to its ability to be oxidized in the liver to PAA, which is then conjugated with glutamine, resulting in phenylacetylglutamine, which is excreted in the urine and hence 2 mol of nitrogen is lost for each mole of the given phenylbutyrate. An early diagnosis is fundamental because the prognosis often depends on urgent treatment. (11)

Summary of Evidence

A search of peer reviewed literature identified no new clinical trial publications or any additional information that would change the coverage position of this medical policy. There is inadequate evidence in the published medical literature demonstrating that the use of sodium phenylbutyrate improves the clinical outcomes of patients with HIV, cystic fibrosis, or any malignancies other than acute promyelocytic leukemia and malignant glioma.


Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.


Because it is an oral medication (powder, tablet or liquid form) sodium phenylbutyrate does not have a HCPCS code. However, the non-classified code J9999 might be reported.


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Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.


The following codes may be applicable to this Medical policy and may not be all inclusive.

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ICD-9 Diagnosis Codes

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ICD-9 Procedure Codes

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ICD-10 Diagnosis Codes

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Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <>.


1. What is a Urea Cycle Disorders? National Urea Cycle Disorders Foundation. 2005-2017. Available at <> (accessed - 2017 August 28).

2. FDA - Buphenyl® (sodium phenylbutyrate). FDA Approved products. U.S. Food and Drug Administration. Available at <> (accessed - 2017 August 28).

3. FDA - Buphenyl® (sodium phenylbutyrate tablets, powder). FDA Label. U.S. Food and Drug Administration. Available at <> (accessed - 2017 August 28).

4. FDA - Orphan Drug Designations and Approvals. U.S. Food and Drug Administration. Available at <> (accessed - 2017 August 28).

5. FDA - How to Apply for Orphan Drug Designation. U.S. Food and Drug Administration. Available at <> (accessed - 2017 August 28).

6. Maestri NE, Clissold DB, Brusilow SW. Long-term survival of patients with argininosuccinate synthetase deficiency. J Pediatr. 1995; 127:929-35. PMID 8523191

7. Collins AF, Pearson HA, Giardina P, et al. Oral sodium phenylbutyrate therapy in homozygous beta thalassemia: a clinical trial. Blood. 1995; 85:43-49. PMID 7528572

8. Baker MJ, Brem S, Daniels S, et al. Complete response of a recurrent, multicentric malignant glioma in a patient treated with phenylbutyrate. J Neurooncol. Sep 2002; 59:239-242. PMID 12241121

9. Gore SD, Weng LJ, Figg WD, et al. Impact of prolonged infusions of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin Cancer Res. Apr 2002; 8:963-970. PMID 11948101

10. Dover GJ, Brusilow S, Charache S. Induction of fetal hemoglobin production in subjects with sickle cell anemia by oral sodium phenylbutyrate. Blood. Jul 1994; 84:339-343. PMID 7517215

11. Iannitti T, Palmieri B. Clinical and experimental applications of sodium phenylbutyrate. Drugs R D. Sep 1 2011;11(3):227-49. PMID 21902286

12. Sodium Phenylbutyrate. Micromedex® Solutions (2017 Truven Health Analytics). Available at <> (accessed - 2017 August 28).

Policy History:

Date Reason
10/15/2017 Document updated with literature review. Coverage unchanged.
7/1/2016 Reviewed. No changes.
6/1/2015 Document updated with literature review. Coverage unchanged.
7/1/2014 Reviewed. No changes.
10/15/2013 Document updated with literature review. Coverage unchanged.
8/15/2009 Medical policy number changed. Routine updated with literature search. Coverage unchanged.
7/1/2007 Revised/updated entire document
9/1/2004 New medical document

Archived Document(s):

Title:Effective Date:End Date:
Sodium Phenylbutyrate02-15-202106-30-2022
Sodium Phenylbutyrate03-15-202002-14-2021
Sodium Phenylbutyrate06-15-201803-14-2020
Sodium Phenylbutyrate10-15-201706-14-2018
Sodium Phenylbutyrate07-01-201610-14-2017
Sodium Phenylbutyrate06-01-201506-30-2016
Sodium Phenylbutyrate07-01-201405-31-2015
Sodium Phenylbutyrate10-15-201306-30-2014
Sodium Phenylbutyrate08-15-200910-14-2013
Sodium Phenylbutyrate07-01-200708-14-2009
Sodium Phenylbutyrate09-01-200406-30-2007
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