Metabolic Agents - Specialty Pharmacy Clinical Policy Bulletins Aetna Non-Medicare Prescription Drug Plan (2024)

Subject: Metabolic Agents

Policy:

Note: The provision of physician samples does not guarantee coverage under the provisions of the pharmacy benefit. All criteria below must be met in order to obtain coverage of Buphenyl, Carbaglu, Cuprimine, Cystadane, Depen, Kuvan, Nityr, Orfadin, Palynziq, Ravicti, sodium phenylbutyrate, Syprine, Thiola, or Xuriden.

1. Precertification Criteria

Under some plans, including plans that use an open or closed formulary,Buphenyl, Carbaglu, Cuprimine, Cystadane, Depen, Kuvan, Nityr, Orfadin, Palynziq, Ravicti, sodium phenylbutyrate, Syprine, Thiolaand Xuridenis subject to precertification. If precertification requirements apply Aetna considers these drugs to be medically necessary for those members who meet the following precertification criteria:

Buphenyl, sodium phenylbutyrate

Initial Criteria

1. The requested medication (Buphenyl or sodium phenylbutyrate) is being used for adjunctive therapy in the chronic management of patients with urea cycle disorders involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), or argininosuccinic acid synthetase (AS); and
2. There is documentation that the member is adherent to a protein restrictive diet.

Continuation Criteria

1. The requested medication (Buphenyl or sodium phenylbutyrate) is being used for adjunctive therapy in the chronic management of patients with urea cycle disorders involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), or argininosuccinic acid synthetase (AS); and
2. There is clinical documentation indicating that there is disease stability or improvement (e.g., normalized plasma ammonia levels); and
3. There is documentation that the member is adherent to a protein restrictive diet.

Carbaglu

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Initial Criteria

1. Carbaglu is being used as adjunctive therapy in pediatric or adult patients for the treatment of acute hyperammonemia due to N-acetylglutamate synthase (NAGS) deficiency; or
2. Carbaglu is being used as maintenance therapy in pediatric and adult patients for the treatment of chronic hyperammonemia due to NAGS deficiency.

Continuation Criteria

1. Carbaglu is being used as one of the following:
   1. Adjunctive therapy in pediatric or adult patients for the treatment of acute hyperammonemia due to NAGS deficiency; or
   2. Maintenance therapy in pediatric and adult patients for the treatment of chronic hyperammonemia due to NAGS deficiency; and
2. Treatment with Carbaglu resulted in a decrease of plasma ammonia levels from baseline.

Cuprimine

1. The member has a documented diagnosis of one of the following:
   1. Wilson’s disease and treatment with Depen was ineffective, not tolerated, or is contraindicated; or
   2. Cystinuria and the member meets the following criteria (i and ii):
      1. Treatment with conservative measures (e.g. high fluid intake, sodium and protein restriction, urinary alkalinization) was ineffective, not tolerated, or is contraindicated; and
      2. Treatment with Depen was ineffective, not tolerated, or is contraindicated; or
   3. Rheumatoid arthritis and treatment with a one-month trial of methotrexate, leflunomide, and sulfasalazine was ineffective, not tolerated, or all are contraindicated.

Cystadane

Initial Criteria

1. Cystadane is being used for treatment of hom*ocystinuria to decrease elevated hom*ocysteine blood levels. Included within the category of hom*ocystinuria are (a, b, and c):
   1. Cystathionine beta-synthase (CBS) deficiency
   2. 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency
   3. Cobalamin cofactor metabolism (cbl) defect; and
2. CBS deficiency only: Plasma methionine concentrations will be monitored and kept below 1,000 µmol/L through dietary modification and, if necessary, a reduction of Cystadane dose.

Continuation Criteria

1. Cystadane is being used for treatment of hom*ocystinuria (including CBS deficiency, 5,10-MTHFR deficiency, cbl defect) to decrease elevated hom*ocysteine blood levels; and
2. CBS deficiency only: Plasma methionine concentrations will be monitored and kept below 1,000 µmol/L through dietary modification and, if necessary, a reduction of Cystadane dose; and
3. There is clinical documentation indicating that plasma total hom*ocysteine is undetectable or present only in small amounts.

Depen

1. The member has a documented diagnosis of one of the following:
   1. Wilson’s disease; or
   2. Cystinuria and treatment with conservative measures (e.g. high fluid intake, sodium and protein restriction, urinary alkalinization) was ineffective, not tolerated, or is contraindicated; or
   3. Rheumatoid arthritis and treatment with a one-month trial of methotrexate, leflunomide, and sulfasalazine was ineffective, not tolerated, or all are contraindicated.

Kuvan

Initial criteria

1. The patient has a documented diagnosis of phenylketonuria (PKU); and
2. Baseline phenylalanine (Phe) levels are greater than 360 micromol/dl (6 mg/dl) with dietary interventions alone; and
3. Kuvan will be used in conjunction with a Phe-restrictive diet; and
4. The dose is within the range of 5 to 20 mg/kg/day.

Continuationcriteria

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1. The patient has been successfully treated with Kuvan by meeting one of the following criteria:
1. The patient’s blood Phe levels are being maintained within acceptable range (120-360 micromol/dl [2-6 mg/dl]); or
2. The patient has had at least a 30% decrease in blood Phe level from baseline; and
2. The patient continues to use a Phe-restrictive diet in conjunction with Kuvan; and
3. The dose is within the range of 5 to 20 mg/kg/day.

Nityr

1. Nityr is being used as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 (HT-1); and
2. The diagnosis of HT-1 was confirmed by biochemical testing (e.g., elevation of succinylacetone in blood or urine) or DNA testing.

Orfadin

1. Orfadin is being used as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 (HT-1); and
2. The diagnosis of HT-1 was confirmed by biochemical testing (e.g., elevation of succinylacetone in blood or urine) or DNA testing.

Palynziq

Initial criteria

1. The member (18 years of age or older) has a documented diagnosis of phenylketonuria (PKU); and
2. Blood phenylalanine (Phe) levels are greater than 600 micromol/L on existing management (e.g., restriction of dietary phenylalanine and protein intake); and
3. Blood Phe levels will be obtained every 4 weeks until a maintenance dose is established; once a maintenance dose is established, Phe will be obtained at least once every 6 months; and
4. The member will also be prescribed auto-injectable epinephrine due to the risk of anaphylaxis with Palynziq use; and
5. Treatment with sapropterin (Kuvan) was ineffective, not tolerated, or is contraindicated.

Continuation criteria

1. The member (18 years of age or older) has a documented diagnosis of PKU and meets at least one of the following criteria:
1. The member has achieved at least a 20% reduction in blood Phe level from pre-treatment baseline; or
2. The member has achieved a blood Phe levels less than or equal to 600 micromol/L; or
3. The member is currently receiving Palynziq ≤ 20 mg daily, but will be increasing the dose to 40 mg daily; or
4. The member has been receiving Palynziq 40 mg daily for less than 16 weeks of continuous treatment; and
2. Blood Phe levels will be obtained every 4 weeks until a maintenance dose is established; once a maintenance dose is established, Phe will be obtained once every 6 months; and
3. The member will also be prescribed auto-injectable epinephrine due to the risk of anaphylaxis with Palynziq use.

Ravicti

Initial Criteria

1. The member (≥ 2months of age) has a documented diagnosis of a urea cycle disorder with a history of hyperammonemia. Urea cycle disorders include:
   1. Carbamoyl phosphate synthetase I (CPSI) deficiency
   2. Ornithine transcarbamylase (OTC) deficiency
   3. Argininosuccinate synthetase (ASS) deficiency (also known as classic citrullinemia or type I citrullinemia, CTLN1)
   4. Argininosuccinate lyase (ASL) deficiency (also known as argininosuccinic aciduria)
   5. Arginase deficiency (also known as argininemia); and
2. Ravicti is not being used to treat N-acetylglutamate synthase (NAGS) deficiency or acute hyperammonemia; and
3. Ravicti will be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements); and
4. Dietary protein restriction and/or amino acid supplementation alone was ineffective; and
5. Treatment with Buphenyl was ineffective, not tolerated, or is contraindicated.

Continuation Criteria

1. The member (≥ 2 months of age) has a documented diagnosis of a urea cycle disorder with a history of hyperammonemia; and
2. There is clinical documentation indicating that there is disease stability or improvement (e.g., normalized plasma ammonia levels); and
3. Ravicti is not being used to treat N-acetylglutamate synthase (NAGS) deficiency or acute hyperammonemia; and
4. Ravicti will be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements).

Syprine, trientine

1. The member has a documented diagnosis of Wilson’s disease; and
2. Treatment with a one-month trial of Depen was ineffective, not tolerated, or contraindicated.

Thiola

1. The member has a documented diagnosis of severe cystinuria with urinary cystine levels greater than 500 mg/day; and
2. Treatment with conservative measures (e.g. high fluid intake, sodium and protein restriction, urinary alkalinization) was ineffective, not tolerated, or is contraindicated.
3. Treatment with a one-month trial of Depen was ineffective, not tolerated, or contraindicated.

Xuriden

1. The member has a documented diagnosis of hereditary orotic aciduria (HOA).

According to the manufacturer, Palynziq, Ravicti and Xuridencan be dosed up to a maximum daily doseas indicated in the table below. A quantity ofthis drug will beconsidered medically necessary, if above criteria are met,as indicated in the table below:

Drug	Maximum Daily Dose	Dosage Strength	Quantity Limits
Palynziq	1 syringe*	2.5 mg/0.5 ml, 10 mg/0.5 ml, 20 mg/ml	Up to 1 syringe per day*
Buphenyl; sodium phenylbutyrate powder	20 g	3 g/tsp	Up to 1 bottle per 30 days
Buphenyl; sodium phenylbutyrate tablets	20 g	500 mg	Up to 20 g (40 tablets) per day
Ravicti	17.5 ml (19 g)	1.1 gm/ml	Up to 525 mL in 30 days
Xuriden	8 g	2 g	Up to 8 g (4 packets) per day

*Quantities above this amount will require review to determine medical necessity

Place of Service:

Outpatient

The above policy is based on the following references:

1. AHFS Drug Information® with AHFSfirstReleases®. (www.statref.com) American Society Of Health-System Pharmacists®, Bethesda, MD. Updated periodically.
2. DRUGDEX® System [Internet database]. Greenwood Village, CO: Thomson Micromedex. Updated periodically.
3. Drug Facts and Comparisons online. (www.drugfacts.com), Wolters Kluwer Health, St. Louis, MO. Updated periodically.
4. PDR® Electronic Library™ [Internet database]. Greenwood Village, CO: Thomson Micromedex. Updated periodically.
5. Buphenyl [prescribing information]. Scottsdale, AZ: Ucyclyd Pharma, Inc.; March 2009.
6. Carbaglu [prescribing information]. Memphis, TN: Accredo Health Group, Inc.; Aug. 2013.
7. Cuprimine [prescribing information]. Whitehouse Station, NJ: Merck & Co., Inc.; Oct. 2004.
8. Cystadane [prescribing information]. Franklin, TN: Rare Disease Therapeutics, Inc.; April 2010.
9. Depen [prescribing information]. Somerset, NJ: Meda Pharmaceuticals Inc.; April 2009.
10. Kuvan [prescribing information]. Novato, CA: BioMarin Pharmaceutical Inc.; June. 2016.
11. Nityr [prescribing information]. Cambridge, UK: Cycle Pharmaceuticals Ltd.; July 2017.
12. Orfadin [prescribing information]. Waltham, MA: Swedish Orphan Biovitrum.; June 2016.
13. Palynziq [prescribing information]. Novato, CA: BioMarin Pharmaceutical Inc.; May 2018.
14. Ravicti [prescribing information]. Lake Forest, IL: Horizon Pharma USA, Inc.; April. 2017.
15. Thiola [prescribing information]. San Antonio, TX: Mission Pharmacal Company; November 2012.
16. Xuriden [prescribing information]. Gaithersburg, MD: Wellstat Therapeutics; Sept. 2015.
17. Roberts EA, Schilsky ML. AASLD practice guidelines diagnosis and treatment of Wilson Disease: An Update. J Hepatol. 2008;47(6):2089-111.
18. Fernci P, Czlonkowska A, Stremmel W, et al. EASL clinical practice guidelines: Wilson’s disease. J Hepatol. 2012;56(3):671-85.
19. Saag KG, Saag, KG, Bridges, L, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheum. 2016;68(1):1-26.
20. Biyani CS, Cartledge JJ. Cystinuria—diagnosis and management. European Urology. 2006;4:175-183.

Copyright Aetna Inc. All rights reserved. Pharmacy Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.

March 24, 2021

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