Effective Date

Date of Origin   

07-01-2024           

Cuprimine®
(penicillamine)*

Capsule

Treatment of Wilson’s disease, cystinuria, and in patients with severe, active rheumatoid arthritis who have failed to respond to an adequate trial of conventional therapy

*generic available

1

Depen®
(penicillamine)*

Tablet

Treatment of Wilson’s disease, cystinuria, and in patients with severe, active rheumatoid arthritis who have failed to respond to an adequate trial of conventional therapy

*generic available

2

Wilson's Disease

Wilson’s disease is an autosomal recessive genetic disorder that leads to impairment of cellular copper transport and affects about one in 30,000 people worldwide. Wilson’s disease can present clinically as liver disease, as a progressive neurological disorder (hepatic dysfunction being less apparent or occasionally absent), as a psychiatric illness or as a combination of these. Wilson’s disease presents with isolated liver disease more often in children and younger adult patients than in older adults. Symptoms at any age are frequently nonspecific.  It is fatal unless it is detected and treated before serious illness from copper poisoning develops.(7)

Copper is present in many foods, and healthy individuals excrete any excess copper. Patients with Wilson’s disease cannot eliminate the extra copper, possibly because the liver lacks the mechanism to excrete free copper into the bile, and it accumulates in the liver, brain and other organs. Copper accumulation begins immediately after birth when hepatocytes begin to store excess copper, but as their capacity is exceeded, copper is released into the blood and is taken up into extrahepatic sites. Symptoms usually appear in late adolescence and patients may experience hepatitis, psychiatric, or neurologic manifestations. Signs may include jaundice, abdominal swelling, vomiting of blood, abdominal pain, tremors, difficulty walking, difficulty talking and difficulty swallowing. Other symptoms may include mental illness, and may consist of homicidal or suicidal behavior, depression and aggression. Women may experience menstrual irregularities, absent periods, infertility, or multiple miscarriages. The disease is always fatal if not diagnosed and treated.(3-5)

Wilson’s disease is diagnosed by relatively simple tests including:(3)

• Ophthalmic slit lamp examination of Kayser-Fleischer rings
• Serum ceruloplasmin test
• 24 hour urine copper test
• Liver biopsy for histology and histochemistry and copper quantification
• Genetic testing, haplotype analysis for sibling and mutation analysis

Wilson’s disease should be considered in any individual between 3 and 55 years of age with liver abnormalities of uncertain cause and should be excluded in any patient with unexplained liver disease along with neurological or neuropsychiatric disorder. Diagnostic testing may include an extremely low ceruloplasmin level (less than 5 mg/dL), basal 24-hour urinary copper excretion greater than 40 mcg, hepatic parenchymal copper concentration greater than 250 mcg/g dry weight, neurological evaluation and radiological imaging of the brain may provide evidence to support diagnosis, generic studies, or a penicillamine challenge study may also be completed for the purpose of diagnosis.(4,7)

Treatment is lifelong and includes a low copper diet and chelation therapy aimed at removing excess copper and preventing its reaccumulation. With proper therapy, disease progress can be halted and often symptoms can be improved. It is recommended that patients avoid the foods that are highest in copper (organ meats, shellfish, chocolate, nuts, and mushrooms), multivitamins or other dietary supplements that may contain copper, and consume only drinking water that testing has shown has less than 0.1 ppm of copper. In addition, chelation therapy drugs approved for treating Wilson’s disease act by binding of copper causing increased urinary excretion and include penicillamine (Cuprimine and Depen) and trientine. Guidelines state that all patients with a newly established diagnosis of Wilson's disease should initiated on lifelong medical therapy. Initial treatment for symptomatic patients should include a chelating agent (penicillamine or trientene). Treatment of asymptomatic patients with Wilson's disease can be a chelating agent or zinc. Galzin (zinc acetate) is a mettalothionein inducer drug approved for treating Wilson’s disease and acts by blocking the absorption of copper in the intestinal tract which depletes accumulated copper and prevents its reaccumulation. Some patients with severe hepatitis or liver failure may require a liver transplant.(4,6,7)

Rheumatoid Arthritis

Rheumatoid arthritis (RA) is the most common inflammatory autoimmune arthritis in adults. The main goal of therapy is to achieve remission, but additional goals include decrease inflammation, relieve symptoms, prevent joint and organ damage, improve physical function/overall well-being, and reduce long term complications.(10,11) The choice of therapy depends on several factors, including the severity of disease activity when therapy is initiated and the response of the patient to prior therapeutic interventions.(10)

American College of Rheumatology (ACR) guidelines list the following guiding principles in the treatment of RA:(10)

• RA requires early evaluation, diagnosis, and management
• Treatment decisions should follow a shared decision-making process
• Treatment decisions should be reevaluated within a minimum of 3 months based on efficacy and tolerability of the disease-modifying antirheumatic drugs (DMARDs) chosen
• Recommendations are limited to DMARDs approved by the US FDA for treatment of RA:
  • Conventional synthetic(cs) DMARDs: hydroxychloroquine, sulfasalazine, methotrexate (MTX), leflunomide
  • Biologic(b) DMARDs: TNF inhibitors (etanercept, adalimumab, infliximab, golimumab, certolizumab pegol), T cell costimulatory inhibitor (abatacept), IL-6 receptor inhibitors (tocilizumab, sarilumab), anti-CD20 antibody (rituximab)
  • Targeted synthetic(ts) DMARDs: JAK inhibitors (tofacitinib, baricitinib, upadacitinib)
• Triple therapy refers to hydroxychloroquine, sulfasalazine, and either methotrexate or leflunomide
• Biosimilars are considered equivalent to FDA-approved originator bDMARDs
• Recommendations referring to bDMARDs exclude rituximab unless patients have had an inadequate response to TNF inhibitors (in order to be consistent with FDA approval) or have a history of lymphoproliferative disorder for which rituximab is an approved therapy
• Treat-to-target refers to a systematic approach involving frequent monitoring of disease activity using validated instruments and modifications of treatment to minimize disease activity with the goal of reaching a predefined target (low disease activity or remission)

D‐penicillamine is a penicillin derived compound originally used to treat patients with rheumatoid arthritis (RA) in the 1950's. Although frequently used in the past, its use has declined because of concerns over its safety and due to the increasing use of other disease modifying anti‐rheumatic drugs (DMARDs) such as methotrexate.(8)

Cystinuria

Cystinuria is the most common genetic cause of recurrent kidney stones. As the result of a genetic defect in proximal tubular reabsorption of filtered cystine, increased urine levels of the poorly soluble amino acid result in recurrent cystine nephrolithiasis. Recurrent cystine stones not only adversely affect the quality of patients suffering from cystinuria but also may result in chronic kidney disease (CKD) from recurrent renal injury. Thus, the mainstay of medical management revolves around prevention of stones.(9)

Medical management of cystinuria begins with a series of core conservative measures aimed at stone prevention—high fluid intake, minimizing intake of dietary sodium and animal protein, and urinary alkalinization. Patients should consume enough fluids to maintain 24-h urine cystine concentrations of less than 250 mg/L (1 mmol/L), usually equating to greater than 3 L urine output each day in adults. Pharmacotherapy for cystinuria should be escalated in a stepwise fashion, with pharmacotherapy with cystine binding thiol drugs (CBTD) added for patients who continue to have recurrent cystine nephrolithiasis despite implementation of and adherence to conservative therapy. These drugs, alpha-mercaptopropionylglycine (tiopronin) and D-penicillamine, work through the reduction of the disulfide bond of cystine, yielding a more soluble drug-cysteine complex and reducing free urinary cystine levels. The use of CBTDs has been demonstrated to be effective in reducing cystine stone growth, new stone formation, and incidence of urologic intervention in retrospective studies. However, their use is limited to cases refractory to conservative therapy given their high cost, adverse effect profile, including drug sensitivity reactions, nephrotic range proteinuria secondary to membranous nephropathy, and very rare liver abnormalities and hematologic disturbances, such as neutropenia and thrombocytopenia.(9)

Safety

Penicillamine is contraindicated in the following:(1,2)   

• Pregnancy, except for the treatment of Wilson’s disease or certain patients with cystinuria
• Breastfeeding
• Patients with a history of penicillamine-related aplastic anemia or agranulocytosis should not be restarted on penicillamine
• Rheumatoid arthritis patients with a history or other evidence of renal insufficiency

1

Cuprimine prescribing information. Bausch Health US LLC. October 2020.

2

Depen prescribing information. Meda Pharmaceuticals. July 2018.

3

Wilson’s Disease Association. http://www.wilsonsdisease.org.

4

Roberts, E.A., Schilsky, M.L. Diagnosis and treatment of Wilson disease: An update. Hepatology. 2008; 47: 2089-2111. https://doi.org/10.1002/hep.22261.

5

EASL Clinical Practice Guidelines: Wilson’s disease. Journal of Hepatology. 2012; 56(3):671-685. doi: 10.1016/j.jhep.2011.11.007. PMID: 22340672.

6

Saroli Palumbo C, Schilsky ML. Clinical practice guidelines in Wilson disease. Ann Transl Med. 2019 Apr;7(Suppl 2):S65. doi: 10.21037/atm.2018.12.53. PMID: 31179302; PMCID: PMC6531645.

7

Schilsky, M, Roberts, E, et al. A multidisciplinary approach to the diagnosis and management of Wilson disease: Executive summary of the 2022 practice guidance on Wilson disease from the American Association for the Study of Liver Diseases. Hepatology ():p n/a, December 07, 2022. | DOI: 10.1002/hep.32805

Cuprimine

Penicillamine Cap 250 MG

250 MG

M ; N ; O ; Y

O ; Y

Depen titratabs

Penicillamine Tab 250 MG

250 MG

M ; N ; O

O ; Y

Cuprimine

Penicillamine Cap 250 MG

250 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Depen titratabs

Penicillamine Tab 250 MG

250 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

*available as a generic

Target Agent(s) will be approved when ONE of the following is met:

1. The patient has a medication history of use in the past 90 days of generic penicillamine tablets OR
2. The patient has an intolerance or hypersensitivity to generic penicillamine tablets that is not expected to occur with the requested agent OR
3. The patient has an FDA labeled contraindication to generic penicillamine tablets that is not expected to occur with the requested agent

Length of Approval: 12 months

*Step therapy requirement may not apply if a prior health plan paid for the medication - documentation of a paid claim may be required.