12.01.089

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: A. The patient’s age is within FDA labeling for the requested indication for the requested agent OR B. 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: A. 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 B. 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 C. An intolerance or hypersensitivity to TWO prerequisite agents that is NOT expected to occur with the requested agent OR D. 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: 12 months NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria. 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.

Module

Clinical Criteria for Approval

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:

A. The patient’s age is within FDA labeling for the requested indication for the requested agent OR

B. 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:

A. 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

B. 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

C. An intolerance or hypersensitivity to TWO prerequisite agents that is NOT expected to occur with the requested agent OR

D. 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: 12 months

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

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.

Module	Ops Set Up	Validation Options	Other Explanation
PA	Documentation: Requirements as noted within the policy;Validation: Apply Baseline and go to Validation Options	Age Verification;Contraindication, intolerance, hypersensitivity

Module

Ops Set Up

Validation Options

Other Explanation

Documentation: Requirements as noted within the policy;Validation: Apply Baseline and go to Validation Options

Age Verification;Contraindication, intolerance, hypersensitivity

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: A. 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 B. 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

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:

A. 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

B. 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

Module	Ops Set Up	Validation Options	Other Explanation
Universal QL	Validation: Apply Baseline and go to Validation Options

Module

Ops Set Up

Validation Options

Other Explanation

Universal QL

Validation: Apply Baseline and go to Validation Options

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

Harliku prescribing information. PCI Pharma Services. June 2025.

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

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

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/

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

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

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

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

Final Module	Target Agent GPI	Target Brand Agent(s)	Target Generic Agent(s)	Strength	Targeted MSC	Targeted NDCs When Exclusions Exist	Final Age Limit	Preferred Status	Effective Date

	309022550003	Harliku	nitisinone (aku) tab	2 MG	M ; N ; O ; Y

Target Agent GPI	Target Brand Name(s)	Target Generic Name(s)	Strength	QL Amount	Dose Form	Days Supply	Duration	Targeted NDCs When Exclusions Exist	Age Limit	Effective Date	Term Date

30902255000310	Harliku	nitisinone (aku) tab	2 MG	30	Tablets	30	DAYS

Target Brand Agent(s)	Target Generic Agent(s)	Strength	Client Formulary

Harliku	nitisinone (aku) tab	2 MG	Commercial ; HIM ; WY NetR-Commercial Custom

Target Brand Agent Name(s)	Target Generic Agent Name(s)	Strength	Client Formulary

Harliku	nitisinone (aku) tab	2 MG	Commercial ; HIM ; WY NetR-Commercial Custom

CLINICAL RATIONALE

REFERENCES

CLIENT SUMMARY – QUANTITY LIMITS