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Harliku Prior Authorization with Quantity Limit Program Summary

Policy Number: PH-1248

This program applies to Blue Partner, Commercial, GenPlus, NetResults A series, SourceRx, SourceRx-Performance, and Health Insurance Marketplace formularies.

POLICY REVIEW CYCLE

Effective Date

Date of Origin   

01-01-2026           

01-01-2026

FDA LABELED INDICATIONS AND DOSAGE

Agent(s)

FDA Indication(s)

Notes

Ref#

Harliku™

(nitisinone)

Tablet

Reduction of urine homogentisic acid (HGA) in adult patients with alkaptonuria (AKU)

1

See package insert for FDA prescribing information:  https://dailymed.nlm.nih.gov/dailymed/index.cfm

CLINICAL RATIONALE

Alkaptonuria

Alkaptonuria (AKU) is a rare genetic disease caused by a deficiency of homogentisate 1,2-dioxygenase (HGD) due to a mutation of the HGD gene. This enzyme converts homogentisic acid (HGA) into maleylacetoacetic acid in the tyrosine degradation pathway. Diagnosis of AKU is based on the detection of a significant amount of HGA in the urine.(2,3,4) A normal 24-hour urine sample contains 20-30 mg of HGA in comparison to 1-8 g excreted per day in AKU patients.(2,4)

Whereas several conditions can result in dark urine (e.g., dehydration, medications, kidney or liver disorders), the presence of HGA in the urine is a hallmark of alkaptonuria.(2,3,4) Other disorders resulting from enzyme deficiencies in the tyrosine degradation pathway (i.e., hereditary tyrosinemia [HT] types 1, 2, and 3) do not present with elevated HGA in the urine. Molecular genetic testing is not required to confirm the diagnosis of AKU, but can be used to provide genetic counseling to family members.(3,4)

Treatment for AKU has historically been aimed at the specific symptoms.(3,4)

Efficacy

Harliku (nitisinone) is an FDA-approved treatment for AKU. Nitisinone is a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase enzyme, the second enzyme in tyrosine catabolism, and dramatically reduces HGA production.(1)

The effectiveness of Harliku was evaluated in an open-label, single center, randomized, no-treatment controlled trial in 40 adult patients diagnosed with AKU (NCT00107783). Patients received either Harliku at 2 mg orally once daily or no treatment for three years. After 1 year of treatment with nitisinone, the average percent reduction in urinary HGA from baseline was 88% (95% CI, 79-97%). At 3 years, the average percent reduction from baseline was 91% (95% CI, 85-97%). Conversely, the untreated control group had an average increase in urinary HGA of 107% (95% CI, 0-216%) from baseline in year 1 and 108% (95% CI, 19-198%) from baseline to year 3. Results also showed nitisinone-treated patients experienced improvements in pain, energy levels, and physical functioning (assessed using the 36-item short-form survey) after 3 years of treatment.(1,5)

In several investigations, nitisinone is proved to be beneficial in preventing the development of ochronosis in childhood and treating the complications of AKU if started in early adulthood.(6,7,8) Nitisinone at 2 mg dose was studied in 58 patients with AKU for a three-year period. At two days after starting nitisinone, repeat urine measurements showed that urinary HGA per day decreased by 78.2% (p<0.0001). Three-month measurements revealed an 88.8% reduction from baseline, and at six months there was an additional decrease to 95.4% (n=25, p=0.0003).(6) Nitisinone was further studied in an open-label, single-center study of 9 alkaptonuria patients (5 women, 4 men; 35-69 years of age) over the course of 3 to 4 months. Each patient received nitisinone in incremental doses (0.35 mg twice daily followed by 1.05 mg twice daily, and remained on this dosage and a regular diet for 3 months. Nitisinone reduced urinary HGA levels 95%. Six of the 7 patients who received nitisinone for more than 1 week reported decreased pain in their affected joints.(8)

Safety

Harliku has no FDA labeled contraindications for use.(1)

REFERENCES

Number

Reference

1

Harliku prescribing information. PCI Pharma Services. June 2025.

2

Kilavuz S, Bulut FD, Kor D, et al. Demographic, phenotypic, and genotypic features of alkatonuria patients: A single center experience. J Pediatr Res. 2018;5:7-11. doi: 10.4274/jpr.20982

3

National Organization for Rare Disorders (NORD): Alkaptonuria. Last updated June 2017. Available at https://rarediseases.org/rare-diseases/alkaptonuria/

4

Introne WJ, Perry M, Chen M. Alkaptonuria. 2003 May [Last updated 2021 Jun ]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available at https://www.ncbi.nlm.nih.gov/books/NBK1454/

5

Introne WJ, Perry MB, Troendle J, et al. A 3-year randomized therapeutic trial of nitisinone in alkaptonuria. Mol Genet Metab. 2011 May;103(4):307-314. doi: 10.1016/j.ymgme.2011.04.016

6

Milan AM, Hughes AT, Ranganath LR, et al. The effect of nitisonone on homogentisic acid and tyrosine: A two-year survey of patients attending the National Alkaptonuria Center, Liverpool. Ann Clin Biochem. 2017 May;54(3):323-330. doi: 10.1177/0004563217691065

7

Abbas K, Basit J, Ebad ur Rehman M. Adequacy of nitisinone for the management of alkaptonuria. Ann Med Surg. 2022 Aug;80:104340. doi: 10.1016/j.amsu.2022.104340

8

Suwannarat P, O'Brien K, Perry MB, et al. Use of nitisinone in patients with alkaptonuria. Metabolism. 2005 Jun;54(6):719-728. doi: 10.1016/j.metabol.2004.12.017

POLICY AGENT SUMMARY PRIOR AUTHORIZATION

Target Brand Agent(s)

Target Generic Agent(s)

Strength

Targeted MSC

Available MSC

Final Age Limit

Preferred Status

Harliku

nitisinone (aku) tab

2 MG

M ; N ; O ; Y

N

POLICY AGENT SUMMARY QUANTITY LIMIT

Target Brand Agent Name(s)

Target Generic Agent Name(s)

Strength

QL Amount

Dose Form

Day Supply

Duration

Addtl QL Info

Allowed Exceptions

Targeted NDCs When Exclusions Exist

Harliku

nitisinone (aku) tab

2 MG

30

Tablets

30

DAYS

CLIENT SUMMARY – PRIOR AUTHORIZATION

Target Brand Agent Name(s)

Target Generic Agent Name(s)

Strength

Client Formulary

Harliku

nitisinone (aku) tab

2 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx ; SourceRx-Performance

CLIENT SUMMARY – QUANTITY LIMITS

Target Brand Agent Name(s)

Target Generic Agent Name(s)

Strength

Client Formulary

Harliku

nitisinone (aku) tab

2 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx ; SourceRx-Performance

PRIOR AUTHORIZATION CLINICAL CRITERIA FOR APPROVAL

Module

Clinical Criteria for Approval

PA

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met:

  1. The patient has a diagnosis of alkaptonuria AND
  2. The patient has greater than or equal to 1 gram of homogentisic acid (HGA) in a 24-hour urine sample (medical records required) AND
  3. If the patient has an FDA labeled indication, then ONE of the following:
    1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
    2. There is support for using the requested agent for the patient’s age for the requested indication AND
  4. The patient has ONE of the following:
    1. Tried and had an inadequate response to TWO prerequisite agents (i.e., nitisinone capsule, Nityr tablet) that is NOT expected to occur with the requested agent OR
    2. Tried and had an inadequate response to ONE prerequisite agent AND an intolerance or hypersensitivity to ONE prerequisite agent that is NOT expected to occur with the requested agent OR
    3. An intolerance or hypersensitivity to TWO prerequisite agents that is NOT expected to occur with the requested agent OR
    4. An FDA labeled contraindication to ALL prerequisite agents that is NOT expected to occur with the requested agent AND
  5. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., geneticist, rheumatologist), or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
  6. The patient does NOT have any FDA labeled contraindications to the requested agent 

Length of Approval: 6 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

*Step therapy requirement may not apply if a prior health plan paid for the medication - documentation of a paid claim may be required.

 

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

  1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process (Note: patients not previously approved for the requested agent will require initial evaluation review) AND
  2. The patient has had clinical benefit with the requested agent as indicated by a reduction in urinary homogentisic acid (medical records required) AND
  3. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., geneticist, rheumatologist), or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
  4. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval: 12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

QUANTITY LIMIT CLINICAL CRITERIA FOR APPROVAL

Module

Clinical Criteria for Approval

Universal QL

Quantity Limit for the Target Agent(s) will be approved when ONE of the following is met: 

  1. The requested quantity (dose) does NOT exceed the program quantity limit OR
  2. The requested quantity (dose) exceeds the program quantity limit AND ONE of the following:
    1. BOTH of the following:
      1. The requested agent does NOT have a maximum FDA labeled dose for the requested indication AND
      2. There is support for therapy with a higher dose for the requested indication OR
    2. BOTH of the following:
      1. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
      2. There is support for why the requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit

Length of Approval: up to 12 months

This pharmacy policy is not an authorization, certification, explanation of benefits or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All pharmacy policies are based on (i) information in FDA approved package inserts (and black box warning, alerts, or other information disseminated by the FDA as applicable); (ii) research of current medical and pharmacy literature; and/or (iii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment. 

The purpose of Blue Cross and Blue Shield of Alabama’s pharmacy policies are to provide a guide to coverage. Pharmacy policies are not intended to dictate to physicians how to practice medicine. Physicians should exercise their medical judgment in providing the care they feel is most appropriate for their patients. 

Neither this policy, nor the successful adjudication of a pharmacy claim, is guarantee of payment.