EFFECTIVE 8/1/2020

Pharmacy Benefit Coverage Criteria

Effective Date ...... 8/1/2020 Next Review Date… ...... 8/1/2021 Coverage Policy Number ...... P0115

Uridine triacetate

Table of Contents Related Coverage Resources

Medical Necessity Criteria ...... 1 FDA Approved Indications ...... 2 Recommended Dosing ...... 2 Background ...... 3 References ...... 4

INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients. Coverage Policies are intended to provide guidance in interpreting certain standard benefit plans administered by Cigna Companies. Please note, the terms of a customer’s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer’s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer’s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations.

Medical Necessity Criteria

Uridine triacetate (Xuriden®) is considered medically necessary when ALL of the following criteria are met: • Diagnosis of hereditary as confirmed by at least ONE of the following: o Molecular genetic testing confirming mutation in the UMPS gene o Clinical diagnosis supported by BOTH of the following: . First-degree family relative (i.e., parent or sibling) with hereditary orotic aciduria . Urinary orotic acid level above the normal reference range for the reporting laboratory • Prescribed by, or in consultation with, a metabolic specialist, geneticist, or physician specializing in the condition being treated

Initial and reauthorization is up to 12 months.

Uridine triacetate (Xuriden®) is considered medically necessary for continued use when the initial criteria are met.

When coverage is available and medically necessary, the dosage, frequency, duration of therapy, and site of care should be reasonable, clinically appropriate, and supported by evidence-based literature and adjusted based upon severity, alternative available treatments, and previous response to therapy.

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Uridine triacetate (Xuriden®) is considered experimental, investigational or unproven for ANY other use.

Note: Receipt of sample product does not satisfy any criteria requirements for coverage.

FDA Approved Indications

FDA Approved Indication Xuriden is indicated in adult and pediatric patients for the treatment of hereditary orotic aciduria.

Recommended Dosing

FDA Recommended Dosing Recommended Dosage The recommended starting dosage of oral XURIDEN is 60 mg/kg once daily. Increase the dosage of XURIDEN to 120 mg/kg (not to exceed 8 grams) once daily for insufficient efficacy, such as occurrence of one of the following: • Levels of orotic acid in urine remain above normal or increase above the usual or expected range for the patient • Laboratory values (e.g., red blood cell or white blood cell indices) affected by hereditary orotic aciduria show evidence of worsening • Worsening of other signs or symptoms of the disease The XURIDEN dose to be administered at the 60 mg/kg and 120 mg/kg dose levels by body-weight is presented in Tables 1 and 2. A 2 gram packet of XURIDEN contains approximately ¾ teaspoon of XURIDEN. Therefore, in the tables below for patients requiring doses in multiples of 2 grams (¾ teaspoon) an entire packet(s) may be administered without weighing or measuring.

XURIDEN Daily Dose Based on Body Weight (kg) Patient Weight Table 1: XURIDEN 60 mg/kg§ Dose Level Dose to be Administered Kilograms Dose in Teaspoons Using a Scale (grams) up to 5 0.4 1/8 6-10 0.4 to 0.6 ¼ 11-15 0.7 to 0.9 16-20 1 to 1.2 ½ 21-25 1.3 to 1.5 26-30 1.6 to 1.8 ¾ * 31-35 1.9 to 2.1* 36-40 2.2 to 2.4 41-45 2.5 to 2.7 1 46-50 2.8 to 3 51-55 3.1 to 3.3 1 ¼ 56-60 3.4 to 3.6 61-65 3.7 to 3.9** 66-70 4 to 4.2** 1 ½ ** 71-75 4.3 to 4.5 Above 75 6*** 2 *** § total daily dose by weight category in the tables was rounded to achieve the approximate dose level * may use 1 entire 2 gram packet without weighing or measuring ** may use 2 entire 2 gram packets without weighing or measuring *** may use 3 entire 2 gram packets without weighing or measuring

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Patient Weight Table 2: XURIDEN 120 mg/kg§ Dose Level Dose to be Administered Using Kilograms Dose in Teaspoons a Scale (grams) up to 5 0.8 ¼ 6-10 0.8 to 1.2 ½ 11-15 1.4 to 1.8 ¾ 16-20 2 to 2.4 1 21-25 2.6 to 3 26-30 3.2 to 3.6 1 ¼ 31-35 3.8 to 4.2** 1 ½ ** 36-40 4.4 to 4.8 1 ¾ 41-45 5 to 5.4 2*** 46-50 5.6 to 6 51-55 6.2 to 6.6 2 ¼ 56-60 6.8 to 7.2 2 ½ 61-65 7.4 to 7.8 66-70 8**** 71-75 8**** 2 ¾ **** Above 75 8**** § total daily dose by weight category in the tables was rounded to achieve the approximate dose level ** may use 2 entire 2 gram packets without weighing or measuring *** may use 3 entire 2 gram packets without weighing or measuring **** may use 4 entire 2 gram packets without weighing or measuring

Drug Availability Oral granules: 2 grams of orange-flavored oral granules (95% w/w) in single-use packets

Background

Disease Overview Hereditary orotic aciduria, also known as orotic aciduria type 1, is an extremely rare, autosomal recessive genetic disorder estimated to affect less than 1:1,000,000 live births. Only about 20 cases have been reported in the medical literature. In hereditary orotic aciduria, mutation in the UMPS gene leads to defective uridine 5’monophosphate synthase. Deficiency in this enzyme prevents the last two steps in , leading to inadequate levels of and excess levels of orotic acid (a uridine precursor). Because the condition is so rare, hereditary orotic aciduria is not fully understood. Affected infants may develop megaloblastic anemia, developmental delays, or failure to thrive. Orotic acid crystals in the urine can lead to urinary obstruction. Xuriden replaces uridine in the circulation, and as a result of feedback inhibition, overproduction of orotic acid is reduced. (Xuriden Package Insert, 2017, National Organization for Rare Disorders, 2018, Genetic and Rare Diseases Information Center, 2019)

Professional Societies/Organizations Published guidelines do not address hereditary orotic acidura at this time.

Off Label Uses AHFS Drug Information 2019 Edition does not support any off-label uses of Xuriden.

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References

1. Xuriden® oral granules [prescribing information]. Rockville, MD: Wellstat Therapeutics; February 2017. 2. Hereditary orotic aciduria. National Organization for Rare Disorders. Updated 2018. Available at: https://rarediseases.org/rare-diseases/hereditary-orotic-aciduria/. Accessed on July 9, 2019. 3. Orotic aciduria type 1. Genetic and Rare Diseases Information Center. Updated September 13, 2017. Available at: https://rarediseases.info.nih.gov/diseases/5429/orotic-aciduria-type-1. Accessed on July 9, 2019.

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