SYPRINE, Trientine HCl Form

Trientine tetrahydrochloride (Cuvrior™) and trientine hydrochloride (Syprine®) are chelating agents. FDA Approved Indication(s) Cuvrior is indicated for the treatment of adult patients with stable Wilson’s disease who are de- coppered and tolerant to penicillamine. Syprine is indicated for the treatment of patients with Wilson’s disease who are intolerant of penicillamine. Limitation(s) of use: Unlike penicillamine, Syprine is not recommended in cystinuria or rheumatoid arthritis. Syprine is not indicated for treatment of biliary cirrhosis. 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 Cuvrior and Syprine are medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Wilson’s Disease (must meet all):

1. Diagnosis of Wilson’s disease;

2. One of the following (a or b): a. Cuvrior: Age ≥ 18 years; b. Syprine: Age ≥ 6 years;

   3. Failure of generic penicillamine (generic of Depen® is preferred) at up to maximally indicated doses, unless contraindicated or clinically significant adverse effects are experienced;
   4. Failure of generic trientine hydrocholoride up to maximally indicated doses, unless contraindicated or clinically significant adverse effects are experienced;
   5. Dose does not exceed one of the following (a or b): a. Cuvrior (both i and ii):
      i. 3,000 mg per day; ii. 10 tablets per day; Page 1 of 7

   CLINICAL POLICY Trientine b. Syprine (i or ii):
   i. Age > 12 years: 2,000 mg per day; ii. Age ≤ 12 years: 1,500 mg per day. Approval duration:
   Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less B. Other diagnoses/indications (must meet 1 or 2):

   1. 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
   2. 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. Wilson’s Disease (must meet all):
   3. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Trientine for a covered indication and has received this medication for at least 30 days;” Currently receiving medication via Centene benefit or member has previously met initial approval criteria;
   4. Member is responding positively to therapy;

3. If request is for a dose increase, new dose does not exceed one of the following (a or b): a. Cuvrior (both i and ii):
   i. 3,000 mg per day; ii. 10 tablets per day; b. Syprine (i or ii): i. Age > 12 years: 2,000 mg per day; ii. Age ≤ 12 years: 1,500 mg per day. Approval duration:
   Medicaid/HIM – 12 months Commercial – 12 months or duration of request, whichever is less Page 2 of 7

   CLINICAL POLICY Trientine B. Other diagnoses/indications (must meet 1 or 2):

   1. 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
   2. 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, CP.PMN.53 for Medicaid, and HIM.PA.154 for health insurance marketplace, or evidence of coverage documents; B. Biliary cirrhosis; C. Cystinuria; D. Rheumatoid arthritis. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key FDA: Food and Drug Administration Appendix B: Therapeutic Alternatives
      This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.
      Drug Name Dosing Regimen Dose Limit/ Maximum Dose Wilson’s disease: 2 g/day (750 mg/day if pregnant) Age ≤ 12 years: 1,500 mg/day Age > 12 years: 2,000 mg/day penicillamine (Depen®, Cuprimine®) Trientine hydrocholoride (Syprine) Wilson’s disease 250 mg PO QID initially; adjust to achieve urinary copper excretion 0.5-1 mg/day
      Wilson’s disease Age ≤ 12 years: 500-750 mg/day PO in divided doses two, three, or four times daily Age > 12 years: 750-1,250 mg/day PO in divided doses two, three, or four times daily Page 3 of 7

   CLINICAL POLICY Trientine Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. Appendix C: Contraindications/Boxed Warnings • Contraindication(s): hypersensitivity
   • Boxed warning(s): none reported Appendix D: General Information • Clinical experience with Syprine is limited, and alternate dosing regimens have not been well-characterized; all endpoints in determining an individual patient’s dose have not been well defined.
   • Syprine and penicillamine cannot be considered interchangeable.
   • The absence of a sulfhydryl moiety renders Syprine incapable of binding cystine and, therefore, it is of no use in cystinuria. In 15 patients with rheumatoid arthritis, Syprine was reported not to be effective in improving any clinical or biochemical parameter after 12 weeks of treatment. • The differences in the FDA-approved indications for Cuvrior and Syprine are due to differing clinical trial design. The clinical trial supporting the Syprine FDA application was conducted in patients with Wilson’s disease intolerant of penicillamine, while the clinical trial for Cuvrior was performed in stable de-coppered Wilson’s disease patients who were tolerant to penicillamine. In the latter trial, Cuvrior was compared to and found to be non-inferior to penicillamine.
   • There are currently no clinical data that investigate any differences in either efficacy or safety of different trientine salts in patients either tolerant or intolerant to penicillamine. Once the trientine salt is broken down in the gut, the active moiety of trientine is the same for both salts. V. Dosage and Administration
   Drug Name Cuvrior Dosing Regimen 300 mg up to 3,000 mg PO BID.
   Maximum Dose 3,000 mg/day Syprine Refer to the prescribing information for detail on switching from penicillamine or other trientine products to Cuvrior Age ≤ 12 years: 500-750 mg/day PO in divided doses two, three, or four times daily Age > 12 years: 750-1,250 mg/day PO in divided doses two, three, or four times daily Age ≤ 12 years: 1,500 mg/day Age > 12 years: 2,000 mg/day
   Cuvrior is not substitutable on a milligram-per-milligram basis with other trientine products VI. Product Availability
   Drug Name Cuvrior Syprine Product Availability Tablet: 300 mg Capsule: 250 mg Page 4 of 7

   CLINICAL POLICY Trientine VII.