CUPRIMINE, Penicillamine Form

Penicillamine (Cuprimine®) is a chelating agent.
FDA Approved Indication(s) Cuprimine is indicated for the treatment of: • Wilson’s disease • Cystinuria • Severe, active rheumatoid arthritis (RA) in patients who have failed to respond to an adequate trial of conventional therapy Limitation(s) of use: Available evidence suggests that Cuprimine is not of value in ankylosing spondylitis.
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 Cuprimine is 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. Member must use generic Depen®, unless contraindicated or clinically significant adverse effects are experienced;
   3. Dose does not exceed both of the following (a and b): a. 2 g per day; b. 8 capsules per day. Approval duration:
      HIM – 6 months Commercial – 12 months or duration of request, whichever is less B. Cystinuria (must meet all):
3. Diagnosis of cystinuria;

4. Failure of a urinary alkalinizing agent (e.g., potassium citrate) unless contraindicated or clinically significant adverse effects are experienced;
   Page 1 of 7

   CLINICAL POLICY
   Penicillamine

   3. Member must use generic Depen®, unless contraindicated or clinically significant adverse effects are experienced;
   4. Dose does not exceed both of the following (a and b): a. 4 g per day; b. 16 capsules per day. Approval duration:
      HIM – 6 months Commercial – 12 months or duration of request, whichever is less C. Rheumatoid Arthritis (must meet all):
   5. Diagnosis of RA;
5. Member meets one of the following (a or b): a. Failure of ≥ 3 consecutive months of methotrexate;
   b. If intolerance or contraindication to methotrexate, failure of ≥ 3 consecutive months of sulfasalazine, leflunomide, or hydroxychloroquine unless contraindicated or clinically significant adverse effects are experienced;

6. Member must use generic Depen®, unless contraindicated or clinically significant adverse effects are experienced;

   4. Dose does not exceed both of the following (a and b): a. Initial therapy: 250 mg (1 capsule) per day for at least the first month; b. Maintenance therapy: 1.5 g (6 capsules) per day. Approval duration:
      HIM – 6 months Commercial – 12 months or duration of request, whichever is less D. Other diagnoses/indications (must meet 1 or 2):
   5. 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 and HIM.PA.33 for health insurance marketplace; 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 and HIM.PA.103 for health insurance marketplace; or
   6. 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 and HIM.PA.154 for health insurance marketplace.
      II. Continued Therapy A. All Indications in Section 1 (must meet all):
   7. Member meets one of the following (a or b): Page 2 of 7

   CLINICAL POLICY
   Penicillamine 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);

7. Member is responding positively to therapy;

8. If request is for a dose increase, new dose does not exceed (a, b, or c): a. Wilson’s disease (both i and ii):
   i. 2 g per day; ii. 8 capsules per day; b. RA (both i and ii):
   i. 1.5 g per day; ii. 6 capsules per day; c. Cystinuria (both i and ii):
   i. 4 g per day; ii. 16 capsules per day. Approval duration:
   HIM – 12 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 and HIM.PA.33 for health insurance marketplace; 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 and HIM.PA.103 for health insurance marketplace; 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 and HIM.PA.154 for health insurance marketplace.
      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 and HIM.PA.154 for health insurance marketplace, or evidence of coverage documents; B. Ankylosing spondylitis. Page 3 of 7

   CLINICAL POLICY
   Penicillamine IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key FDA: Food and Drug Administration RA: rheumatoid arthritis Appendix B: Therapeutic Alternatives Drug Name Dosing Regimen penicillamine (Depen®) Wilson’s disease 250 mg PO QID; adjust to achieve urinary copper excretion 0.5-1 mg/day
   Cystinuria 250 mg PO QD; increase gradually to 1-2 g/day in 4 divided doses and adjust to achieve target urinary cysteine excretion
   RA 125-250 mg PO QD; increase at 1-3 month intervals by 125-250 mg/day according to response and tolerance (typical maintenance range: 500-750 mg/day) – if no improvement at 1-1.5 g/day after 3-4 months, therapy should be discontinued as a response is unlikely to occur Cystinuria 60 mEq/day divided into 3 doses; titrate to achieve a urine pH within target range 6-7 RA 7.5 mg/week PO, SC, or IM or 2.5 mg PO Q12 hr for 3 doses/week RA 2 g/day PO in divided doses RA 100 mg PO QD for 3 days, then 20 mg PO QD RA Initial dose:
   400 – 600 mg/day PO QD Maintenance dose:
   200 – 400 mg/day PO QD potassium citrate methotrexate (Rheumatrex®) sulfasalazine (Azulfidine®) leflunomide (Arava®) hydroxychloroquine (Plaquenil®) Dose Limit/ Maximum Dose Wilson’s disease: 2 g/day (750 mg/day if pregnant) Cystinuria: 4 g/day RA: 1.5 g/day See regimen 30 mg/week 3 g/day 20 mg/day 600 mg/day 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. *Off-label Page 4 of 7

   CLINICAL POLICY
   Penicillamine Appendix C: Contraindications/Boxed Warnings • Contraindication(s): history of penicillamine-related aplastic anemia or agranulocytosis, nursing, patients with RA and cystinuria who are pregnant (exceptions can be made for certain patients with cystinuria), patients with RA and history or other evidence of renal insufficiency • Boxed warning(s): none reported Appendix D: General Information • Although the prescribing information for Cuprimine does not include an absolute maximum dose for Wilson’s disease, it notes it is seldom necessary to exceed a dose of 2 g/day. In addition, both the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver do not recommend doses higher than 1.5 g/day due to potential for rapid and often irreversible neurological deterioration.
   In cystinuria, initial therapy includes high fluid intake, sodium and protein restriction, and urinary alkalinization. The preferred agent for urinary alkalinization is potassium citrate. Other agents that can be used include potassium bicarbonate, acetazolamide, and sodium bicarbonate or citrate. In RA, failure of methotrexate or disease-modifying antirheumatic drugs is defined as < 50% decrease in swollen joint count, < 50% decrease in tender joint count, and < 50% decrease in erythrocyte sedimentation rate (ESR), or < 50% decrease in C-reactive protein (CRP). • • • Examples of positive response include: Wilson’s disease: reduction in 24-hour urinary copper excretion; cystinuria: reduction in urinary cysteine level; RA: improvement in symptoms. V. Dosage and Administration
   Indication Cystinuria Wilson’s disease RA Dosing Regimen 1-4 g/day PO in 4 divided doses 750-1,500 mg/day PO in divided doses 125-250 mg PO QD Maximum Dose 4 g/day 2 g/day 1.5 g/day VI. Product Availability
   Capsule: 250 mg VII.