CARBAGLU, Carglumic Acid Form

Carglumic acid is a carbamoyl phosphate synthetase 1 (CPS1) activator. FDA Approved Indication(s) Carbaglu is indicated as: • Adjunctive therapy in pediatric and adult patients for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS).
• Maintenance therapy in pediatric and adult patients for the treatment of chronic hyperammonemia due to the deficiency of the hepatic enzyme NAGS.
• Adjunctive therapy to standard of care in pediatric and adult patients for the treatment of acute hyperammonemia due to propionic acidemia (PA) or methylmalonic acidemia (MMA). Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
It is the policy of health plans affiliated with Centene Corporation® that Carbaglu is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Urea Cycle Disorder: NAGS (must meet all):

1. Diagnosis of a urea cycle disorder (UCD) caused by NAGS deficiency;
   2. NAGS deficiency is confirmed by enzymatic, biochemical or genetic analysis;
   3. Prescribed by or in consultation with a physician experienced in treating metabolic disorders;
2. If request is for brand Carbaglu, member must use generic carglumic acid, unless contraindicated or clinically significant adverse effects are experienced;
3. Dose does not exceed 250 mg per kg per day initially, followed by a maintenance dose of 100 mg per kg per day. Approval duration:
   Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less B. Organic Acidemias: Propionic Acidemia, Methylmalonic Acidemia (must meet all):

4. Diagnosis of PA or MMA;

   2. Diagnosis is confirmed by urine organic acid, genetic, or enzymatic analysis; Page 1 of 7

   CLINICAL POLICY Carglumic Acid

5. Prescribed by or in consultation with a physician experienced in treating metabolic disorders;
6. Plasma ammonia level ≥ 70 micromol/L despite standard of care treatment (e.g., intravenous hydration and nutritional support);
7. Prescribed as adjunctive therapy to standard of care (e.g., intravenous glucose, insulin, L-carnitine, protein restriction, dialysis);
8. If request is for brand Carbaglu, member must use generic carglumic acid, unless contraindicated or clinically significant adverse effects are experienced;
9. Dose does not exceed one of the following (a or b): a. Weight ≤ 15 kg: 150 mg/kg/day for 7 days; b. Weight > 15 kg: 3.3 g/m2/day for 7 days. Approval duration: 7 days C. Other diagnoses/indications (must meet 1 or 2):
10. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
11. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
    II. Continued Therapy A. Urea Cycle Disorder: NAGS (must meet all):
    
    1. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);
    2. Member is responding positively to therapy;
    3. If request is for brand Carbaglu, member must use generic carglumic acid, unless contraindicated or clinically significant adverse effects are experienced;

12. If request is for a dose increase, dose does not exceed a maintenance dose of 100 mg per kg per day. Page 2 of 7

    CLINICAL POLICY Carglumic Acid Approval duration:
    Medicaid/HIM – 12 months Commercial – 12 months or duration of request, whichever is less B. Organic Acidemias: Propionic Acidemia, Methylmalonic Acidemia:

13. Re-authorization is not permitted. Members must meet the initial approval criteria. Approval duration: Not applicable C. Other diagnoses/indications (must meet 1 or 2):
14. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

15. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
    III. Diagnoses/Indications for which coverage is NOT authorized:
    A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid, or evidence of coverage documents.
    IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key ASL: argininosuccinate lyase ASS: argininosuccinate synthetase CPS1: carbamyl phosphate synthetase 1
    CTLN1: type I citrullinemia FDA: Food and Drug Administration MMA: methylmalonic acidemia Appendix B: Therapeutic Alternatives
    Not applicable.
    NAGS: N-acetyl glutamate synthetase OTC: ornithine transcarbamylase PA: propionic acidemia UCD: urea cycle disorder Page 3 of 7

    CLINICAL POLICY Carglumic Acid Appendix C: Contraindications/Boxed Warnings • Contraindication(s): none reported
    • Boxed warning(s): none reported Appendix D: Urea Cycle Disorders
    UCDs are caused by a deficiency in any of the below enzymes in the pathway that transforms nitrogen to urea: • N-acetyl glutamate synthetase (NAGS) deficiency • Carbamyl phosphate synthetase 1 (CPS1) deficiency • Ornithine transcarbamylase (OTC) deficiency • Argininosuccinate synthetase (ASS) deficiency (also known as classic citrullinemia or type I citrullinemia, CTLN1) • Argininosuccinate lyase (ASL) deficiency (also known as argininosuccinic aciduria) • Arginase deficiency V. Dosage and Administration
    Indication Dosing Regimen NAGS
    For acute hyperammonemia, initial dose of 100-250 mg/kg/day in 2-4 divided doses. Titrate based on
    plasma ammonia level for patient’s age and clinical symptoms. During acute hyperammonemic episodes, concomitant administration of Carbaglu with other ammonia lowering therapies such as alternate pathway medications, hemodialysis, and dietary protein restriction are recommended. Maximum Dose Based on clinical response PA, MMA For daily maintenance of hyperammonemia, recommended dose is 10-100 mg/kg/day in 2-4 divided doses. Titrate based on plasma ammonia level for patient’s age and clinical symptoms. During maintenance therapy, the concomitant use of other ammonia lowering therapies and protein restriction may be needed based on plasma ammonia levels. 150 mg/kg/day for patients ≤ 15 kg 3.3 g/m2/day for patients > 15 kg Divide the daily dosage into two equal doses and round up to the next multiple of 50 mg; administer each dose 12 hours apart.
    Continue treatment until ammonia level is less than 50 micromol/L and for a maximum duration of 7 days. During acute hyperammonemic episodes, Page 4 of 7 See dosing regimen

    CLINICAL POLICY Carglumic Acid Indication Dosing Regimen Maximum Dose administer Carbaglu with other ammonia lowering therapies, such as intravenous glucose, insulin, L- carnitine, protein restriction, and dialysis. VI. Product Availability
    Tablet for oral suspension: 200 mg VII.