Drug and Biologic Coverage Policy

Effective Date ...... 6/1/2020 Next Review Date… ...... 6/1/2021 Coverage Policy Number ...... 1703

Penicillamine and trientine hydrochloride

Table of Contents Related Coverage Resources

Coverage Policy ...... 1 Dimercaprol (BAL in Oil®) and Edetate Calcium FDA Approved Indications ...... 3 Disodium (Calcium Disodium Versenate®) - (6019) Recommended Dosing ...... 3 General Background ...... 6 Coding/ Billing Information ...... 8 References ...... 8

INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients. Coverage Policies are intended to provide guidance in interpreting certain standard benefit plans administered by Cigna Companies. Please note, the terms of a customer’s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer’s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer’s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations.

Coverage Policy

Penicillamine (Depen®) and Penicillamine (Cuprimine®) are considered medically necessary when the following criteria are met: • One of the following: o Treatment of Wilson disease with diagnosis as evidenced by meeting EITHER of the following criteria: . Genetic testing results confirming biallelic pathogenic ATP7B mutations (in either symptomatic or asymptomatic individuals) . At least TWO of the following: • Presence of Kayser-Fleischer (KF) rings • Serum ceruloplasmin levels less than 20mg/dL • Liver biopsy findings consistent with Wilson disease • 24-hour urinary copper is greater than 40 μg/24 hours o Diagnostic aide for Wilson disease in symptomatic children (penicillamine challenge studies) o Cystinuria when there is a failure/inadequate response to increased fluid intake, restriction of sodium and protein intake, and urinary alkalinization o Severe, active rheumatoid arthritis AND documented failure/inadequate response (with a minimum 3 month trial), contraindication per FDA label, intolerance, or not a candidate for ONE

Page 1 of 9 Coverage Policy Number: 1703 disease modifying anti-rheumatic drug (DMARD) (for example: methotrexate, leflunomide, sulfasalazine) o Lead poisoning (blood lead level greater than 44 μg/dL) AND documented failure/inadequate response, contraindication per FDA label, or intolerance to succimer and edetate calcium disodium (Calcium disodium versenate)

Coverage for Penicillamine (Depen®) and Penicillamine (Cuprimine®) varies across plans. Refer to the customer’s benefit plan document for coverage details.

Where coverage requires the use of preferred products, the following criteria apply:

For Employer Group Plans: • For brand Cuprimine and brand Depen, ALL of the following: o Documented intolerance or inability to use BOTH generic penicillamine tablets AND generic penicillamine capsules o Documented failure/inadequate response, intolerance, contraindication per FDA label, inability to use, or not a candidate for generic trientine for the treatment of Wilson disease

For Individual and Family Plans (EFFECTIVE 1/1/2021): • For brand Cuprimine and brand Depen, the following criteria are met: o Documented intolerance or inability to use BOTH generic penicillamine tablets AND generic penicillamine capsules

Trientine hydrochloride (Syprine®) is considered medically necessary when BOTH of the following criteria are met: • Treatment of Wilson disease with diagnosis as evidenced by meeting EITHER of the following criteria: o Genetic testing results confirming biallelic pathogenic ATP7B mutations (in either symptomatic or asymptomatic individuals) o At least TWO of the following: . Presence of Kayser-Fleischer (KF) rings . Serum ceruloplasmin levels less than 20mg/dL . Liver biopsy findings consistent with Wilson disease . 24-hour urinary copper is greater than 40 μg/24 hours

Coverage for trientine hydrochloride (Syprine®) varies across plans. Refer to the customer’s benefit plan document for coverage details.

Where coverage requires the use of preferred products, the following criteria apply:

For Employer Group Plans: • For brand Syprine, ALL of the following: o Documented failure/inadequate response, contraindication per FDA label, intolerance, or not a candidate for ALL of the following: Depen (penicillamine tablets), generic penicillamine tablets AND generic penicillamine capsules o Documented intolerance or inability to use generic trientine

Initial authorization is up to 12 months.

Penicillamine and trientine hydrochloride are considered medically necessary for continued use when the initial criteria are met.

Reauthorization for up to 12 months

Page 2 of 9 Coverage Policy Number: 1703 When coverage is available and medically necessary, the dosage, frequency, duration of therapy, and site of care should be reasonable, clinically appropriate, and supported by evidence-based literature and adjusted based upon severity, alternative available treatments, and previous response to therapy.

Penicillamine (Cuprimine, Depen) is considered experimental, investigational or unproven for ANY other use including the following: • Ankylosing spondylitis • Motor neuron disease

Trientine hydrochloride (Syprine) is considered experimental, investigational or unproven for any other indication.

Note: Receipt of sample product does not satisfy any criteria requirements for coverage

FDA Approved Indications

FDA Approved Indication

Product FDA Approved Indication Cuprimine, Cuprimine and Depen are indicated in the treatment of Wilson's disease, cystinuria, and in Depen patients with severe, active rheumatoid arthritis who have failed to respond to an adequate (penicillamine) trial of conventional therapy. Available evidence suggests that Cuprimine/Depen is not of value in ankylosing spondylitis. Syprine Syprine is indicated in the treatment of patients with Wilson's disease who are intolerant of (trientine penicillamine. Clinical experience with Syprine is limited and alternate dosing regimens have hydrochloride) 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. Syprine should be used when continued treatment with penicillamine is no longer possible because of intolerable or life endangering side effects.

Unlike penicillamine, Syprine is not recommended in cystinuria or rheumatoid arthritis. The absence of a sulfhydryl moiety renders it 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. Syprine is not indicated for treatment of biliary cirrhosis.

Recommended Dosing

FDA Recommended Dosing

Product FDA Recommended Dosing Cuprimine, In all patients receiving penicillamine, it is important that Cuprimine/Depen be given on an Depen empty stomach, at least one hour before meals or two hours after meals, and at least one (penicillamine) hour apart from any other drug, food, or milk. Because penicillamine increases the requirement for pyridoxine, patients may require a daily supplement of pyridoxine (see PRECAUTIONS).

Wilson’s Disease - Optimal dosage can be determined by measurement of urinary copper excretion and the determination of free copper in the serum. The urine must be collected in copper-free glassware, and should be quantitatively analyzed for copper before and soon after initiation of therapy with Cuprimine/Depen.

Determination of 24-hour urinary copper excretions is of greatest value in the first week of therapy with penicillamine. In the absence of any drug reaction, a dose between 0.75 and 1.5

Page 3 of 9 Coverage Policy Number: 1703 Product FDA Recommended Dosing g that results in an initial 24-hour cupriuresis of over 2 mg should be continued for about three months, by which time the most reliable method of monitoring maintenance treatment is the determination of free copper in the serum. This equals the difference between quantitatively determined total copper and ceruloplasmin-copper. Adequately treated patients will usually have less than 10 mcg free copper/dL of serum. It is seldom necessary to exceed a dosage of 2 g/day. If the patient is intolerant to therapy with Cuprimine/Depen, alternative treatment is trientine hydrochloride.

In patients who cannot tolerate as much as 1 g/day initially, initiating dosage with 250 mg/day, and increasing gradually to the requisite amount, gives closer control of the effects of the drug and may help to reduce the incidence of adverse reactions.

Cystinuria - It is recommended that Cuprimine/Depen be used along with conventional therapy. By reducing urinary cystine, it decreases crystalluria and stone formation. In some instances, it has been reported to decrease the size of, and even to dissolve, stones already formed.

The usual dosage of Cuprimine/Depen in the treatment of cystinuria is 2 g/day for adults, with a range of 1 to 4 g/day. For pediatric patients, dosage can be based on 30 mg/kg/day. The total daily amount should be divided into four doses. If four equal doses are not feasible, give the larger portion at bedtime. If adverse reactions necessitate a reduction in dosage, it is important to retain the bedtime dose.

Initiating dosage with 250 mg/day, and increasing gradually to the requisite amount, gives closer control of the effects of the drug and may help to reduce the incidence of adverse reactions.

In addition to taking Cuprimine/Depen, patients should drink copiously. It is especially important to drink about a pint of fluid at bedtime and another pint once during the night when urine is more concentrated and more acid than during the day. The greater the fluid intake, the lower the required dosage of Cuprimine/Depen.

Dosage must be individualized to an amount that limits cystine excretion to 100-200 mg/day in those with no history of stones, and below 100 mg/day in those who have had stone formation and/or pain. Thus, in determining dosage, the inherent tubular defect, the patient’s size, age, and rate of growth, and his diet and water intake all must be taken into consideration.

The standard nitroprusside cyanide test has been reported useful as a qualitative measure of the effective dose*: * Lotz, M., Potts, J.T. and Bartter, F.C.: BritMed J 2: 521, August 28, 1965 (in Medical Memoranda).

Add 2 mL of freshly prepared 5 percent sodium cyanide to 5 mL of a 24-hour aliquot of protein-free urine and let stand ten minutes. Add 5 drops of freshly prepared 5 percent sodium nitroprusside and mix. Cystine will turn the mixture magenta. If the result is negative, it can be assumed that cystine excretion is less than 100 mg/g creatinine.

Although penicillamine is rarely excreted unchanged, it also will turn the mixture magenta. If there is any question as to which substance is causing the reaction, a ferric chloride test can be done to eliminate doubt: Add 3 percent ferric chloride dropwise to the urine. Penicillamine will turn the urine an immediate and quickly fading blue. Cystine will not produce any change in appearance.

Rheumatoid Arthritis - The principal rule of treatment with Cuprimine/Depen in rheumatoid arthritis is patience. The onset of therapeutic response is typically delayed. Two or three

Page 4 of 9 Coverage Policy Number: 1703 Product FDA Recommended Dosing months may be required before the first evidence of a clinical response is noted (see CLINICAL PHARMACOLOGY).

When treatment with Cuprimine/Depen has been interrupted because of adverse reactions or other reasons, the drug should be reintroduced cautiously by starting with a lower dosage and increasing slowly.

Initial Therapy - The currently recommended dosage regimen in rheumatoid arthritis begins with a single daily dose of 125 mg or 250 mg which is thereafter increased at one to three month intervals, by 125 mg or 250 mg/day, as patient response and tolerance indicate. If a satisfactory remission of symptoms is achieved, the dose associated with the remission should be continued (see Maintenance Therapy). If there is no improvement and there are no signs of potentially serious toxicity after two to three months of treatment with doses of 500- 750 mg/day, increases of 250 mg/day at two to three month intervals may be continued until a satisfactory remission occurs (see Maintenance Therapy) or signs of toxicity develop (see WARNINGS and PRECAUTIONS). If there is no discernible improvement after three to four months of treatment with 1000 to 1500 mg of penicillamine/day, it may be assumed the patient will not respond and Cuprimine/Depen should be discontinued.

Maintenance Therapy - The maintenance dosage of Cuprimine/Depen must be individualized, and may require adjustment during the course of treatment. Many patients respond satisfactorily to a dosage within the 500-750 mg/day range. Some need less.

Changes in maintenance dosage levels may not be reflected clinically or in the erythrocyte sedimentation rate for two to three months after each dosage adjustment.

Some patients will subsequently require an increase in the maintenance dosage to achieve maximal disease suppression. In those patients who do respond, but who evidence incomplete suppression of their disease after the first six to nine months of treatment, the daily dosage of Cuprimine/Depen may be increased by 125 mg or 250 mg/day at three- month intervals. It is unusual in current practice to employ a dosage in excess of 1 g/day, but up to 1.5 g/day has sometimes been required.

Management of Exacerbations - During the course of treatment some patients may experience an exacerbation of disease activity following an initial good response. These may be self-limited and can subside within twelve weeks. They are usually controlled by the addition of nonsteroidal anti-inflammatory drugs, and only if the patient has demonstrated a true “escape” phenomenon (as evidenced by failure of the flare to subside within this time period) should an increase in the maintenance dose ordinarily be considered.

In the rheumatoid patient, migratory polyarthralgia due to penicillamine is extremely difficult to differentiate from an exacerbation of the rheumatoid arthritis. Discontinuance or a substantial reduction in the dosage of Cuprimine/Depen for up to several weeks will usually determine which of these processes is responsible for the arthralgia.

Duration of Therapy - The optimum duration of Cuprimine/Depen therapy in rheumatoid arthritis has not been determined. If the patient has been in remission for six months or more, a gradual, stepwise dosage reduction in decrements of 125 mg or 250 mg/day at approximately three month intervals may be attempted.

Concomitant Drug Therapy - Cuprimine/Depen should not be used in patients who are receiving gold therapy, anti-malarial or cytotoxic drugs, oxyphenbutazone, or phenylbutazone (see PRECAUTIONS). Other measures, such as salicylates, other nonsteroidal anti- inflammatory drugs or systemic corticosteroids may be continued when Cuprimine/Depen is initiated. After improvement commences, analgesic and anti-inflammatory drugs may be

Page 5 of 9 Coverage Policy Number: 1703 Product FDA Recommended Dosing slowly discontinued as symptoms permit. Steroid withdrawal must be done gradually, and many months of Depen treatment may be required before steroids can be completely eliminated.

Dosage Frequency - Based on clinical experience, dosages up to 500 mg/day can be given as a single daily dose. Dosages in excess of 500 mg/day should be administered in divided doses. Syprine Systemic evaluation of dose and/or interval between dose has not been done. However, on (trientine limited clinical experience, the recommended initial dose of Syprine is 500-750 mg/day for hydrochloride) pediatric patients and 750-1250 mg/day for adults given in divided doses two, three or four times daily. This may be increased to a maximum of 2000 mg/day for adults or 1500 mg/day for pediatric patients age 12 or under.

The daily dose of Syprine should be increased only when the clinical response is not adequate or the concentration of free serum copper is persistently above 20 mcg/dL. Optimal long-term maintenance dosage should be determined at 6-12 month intervals (see PRECAUTIONS, Laboratory Tests).

Drug Availability

Product Drug Availability Cuprimine Available as 250 mg capsules in bottles of 100. (penicillamine) Depen Available as 250 mg scored tablets in bottles of 100. (penicillamine) Syprine Available as 250 mg capsules in bottles of 100. (trientine hydrochloride)

General Background

Disease Overview Wilson Disease Wilson disease (hepatolenticular degeneration) is an autosomal inherited metabolic defect resulting in an inability to maintain a near-zero balance of copper. Excess copper accumulates possibly because the liver lacks the mechanism to excrete free copper into the bile. Hepatocytes store excess copper but when their capacity is exceeded copper is released into the blood and is taken up into extrahepatic sites. This condition is treated with a low copper diet and the use of chelating agents that bind copper to facilitate its excretion from the body. (Valeant Pharmaceuticals North America LLC., 2014)

Wilson disease can be difficult to diagnose clinically and several diagnostic algorithms have been suggested. (Roberts, 2008; EASL, 2012) Affected individuals often have low serum copper and ceruloplasmin levels as well as increased urinary copper excretion, although these levels may be normal in younger or less severely affected individuals. Ceruloplasmin level below 0.2 g/L is suggestive of the disease, but is not diagnostic in the absence of other findings. (Kelly, 2016) Identifying increased levels of copper on liver biopsy can provide diagnostic information; however, individuals with advanced liver disease may have deceptively low copper levels as deposits within the liver are not homogenous. Kayser-Fleischer rings of the cornea, visible by slit-lamp exam, may be present and are associated with a high degree of copper storage. However, approximately half of patients who present with hepatic features of Wilson disease do not have Kayser-Fleischer rings. Genetic testing of the only gene associated with Wilson disease, ATP7B, can also confirm a diagnosis even in the absence of any clinical findings. Identifying biallelic mutations in ATP7B can be used not only to confirm a diagnosis, but can offer early detection to pre-symptomatic siblings or testing to other family members (Weiss, 2016).

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Pharmacology Penicillamine Penicillamine is a chelating agent recommended for the removal of excess copper in patients with Wilson disease. Penicillamine also reduces excess cystine excretion in cystinuria. This is done, at least in part, by disulfide interchange between penicillamine and cystine, resulting in formation of penicillamine-cysteine disulfide, a substance that is much more soluble than cystine and is excreted readily. Penicillamine interferes with the formation of cross-links between tropocollagen molecules and cleaves them when newly formed. The mechanism of action of penicillamine in rheumatoid arthritis is unknown although it appears to suppress disease activity. Unlike cytotoxic immunosuppressants, penicillamine markedly lowers IgM rheumatoid factor but produces no significant depression in absolute levels of serum immunoglobulins. Also unlike cytotoxic immunosuppressants which act on both, penicillamine in vitro depresses T-cell activity but not B-cell activity. In vitro, penicillamine dissociates macroglobulins (rheumatoid factor) although the relationship of the activity to its effect in rheumatoid arthritis is not known. (Aton Pharma. Inc., 2015; Meda Pharmaceuticals Inc., 2009)

Trientine hydrochloride Trientine hydrochloride is a chelating compound for removal of excess copper from the body. (Valeant Pharmaceuticals North America LLC., 2014)

Professional Societies/Organizations

American Academy of Pediatrics (AAP) – Lead Exposure The AAP guidelines recommend that treatment with succimer should begin if the blood lead concentration is greater than 45 g/dL and the exposure has been controlled. There is no data to support succimer use in children whose blood lead concentrations are less than 45 g/dL if the goal of treatment is to improve cognitive test scores. Children with symptoms of lead poisoning, with blood lead concentrations greater than 70 g/dL, or who are allergic or react to succimer will need parenteral therapy with EDTA and hospitalization. There are academic centers that use D-penicillamine, another oral chelator used in Wilson disease, for lead poisoning. (AAP, 2005)

American Association for the Study of Liver Diseases (AASLD) – Wilson disease The American Association for the Study of Liver Diseases (AASLD) provides guidelines for the diagnosis and management of Wilson’s disease (2008). It is noted that while the most experience in the treatment of this condition is with penicillamine; trientine hydrochloride capsules (Syprine, generics), another chelating agent, is also effective for the treatment of Wilson’s disease, especially in patients who are intolerant of penicillamine or have clinical features indicating potential intolerance (history of renal disease of any sort, congestive splenomegaly causing severe thrombocytopenia, autoimmune tendency). The AASLD recommends that initial treatment for symptomatic patients include a chelating agent (penicillamine or trientine). For the treatment of presymptomatic patients or those on maintenance therapy, chelating agents and zinc are both treatment options. In pregnant patients, treatment for Wilson’s disease should be continued due to the risk of liver failure with therapy interruption, but dosage reduction is advisable for penicillamine and trientine. Dose reductions with zinc are not necessary. Satisfactory outcomes have been shown with continuation of therapy with chelating agents (both penicillamine and trientine) during pregnancy. Liver transplantation should be considered in patients with acute liver failure due to Wilson’s disease and in patients with decompensated cirrhosis unresponsive to chelation therapy. (Roberts, 2008)

American College of Rheumatology (ACR) – Rheumatoid Arthritis The ACR’s guidelines for treatment of rheumatoid arthritis does not include penicillamine as a disease-modifying antirheumatic drug (DMARD) and use of penicillamine is not addressed in the guidelines. Conventional or traditional DMARDS include hydroxychloroquine, leflunomide, methotrexate, or sulfasalazine. The ACR defines optimal dosing of RA treatments as dosing to achieve a therapeutic target and the treatment is given for at least 3 months. (Singh, 2016)

American Urological Association (AUA) – Cystinuria The AUA guidelines for the medical management of kidney stones recommends dietary modification (restriction of sodium and protein intake and increased fluid intake) and urinary alkalinization as first-line therapy for patients

Page 7 of 9 Coverage Policy Number: 1703 with cysteine stones. Cystine-binding drugs, such as tiopronin and penicillamine, should be offered when first- line therapy is inadequate. The AUA notes that tiopronin should be considered over penicillamine as tiopronin may be more effective and have less adverse events. (Pearle, 2014)

European Association for the Study of the Liver (EASL) – Wilson’s disease The European Association for the Study of the Liver (EASL) also published a clinical practice guideline for the treatment of Wilson’s disease (2012). Like the AASLD, the EASL acknowledges that numerous studies have demonstrated the effectiveness of penicillamine. The EASL also notes that trientine has been shown to be an effective initial therapy. A chelating agent (penicillamine or trientine) is the recommended initial treatment of symptomatic patients, and again, a chelating agent or zinc may be used for the treatment of presymptomatic patients or patients established on maintenance therapy. In patients with neurological disease established on maintenance therapy either a chelating agent or zinc may be used; zinc may have a role as first-line therapy in these patients. If zinc is used, careful monitoring of transaminases is needed, with changing to chelators if these laboratory parameters are increasing. The EASL guidelines also state that despite teratogenicity concerns with penicillamine, treatment of Wilson’s disease should be continued during pregnancy as the risks of withdrawing therapy outweigh those of continuing therapy. However, penicillamine and trientine dosage reductions are recommended in pregnant patients. (EASL, 2012)

The American Board of Internal Medicine’s (ABIM) Foundation Choosing Wisely® Initiative No recommendations are available for penicillamine or trientine.

Centers for Medicare & Medicaid Services - National Coverage Determinations (NCDs) There are no CMS National Coverage Determinations for penicillamine or trientine.

Clinical Efficacy

AHFS Drug Information 2019 Edition supports the use of penicillamine in accord with the American Academy of Pediatrics (AAP) guideline recommendations. (McEvoy, 2019)

Experimental, Investigational, Unproven Uses

AHFS Drug Information 2019 Edition notes that the use of penicillamine for ankylosing spondylitis or motor neuron disease is ineffective. (McEvoy, 2019)

Coding/ Billing Information

Note: Penicillamine capsule and tablet and trientine hydrochloride are typically covered under pharmacy benefit plans. Certain prescription drugs require an authorization for coverage to ensure that appropriate treatment regimens are followed. Medical drug coding and diagnosis codes, however, are generally not required for pharmacy claims submissions, therefore, this section is not in use.

References

1. American Academy of Pediatrics (AAP). Lead Exposure in Children: Prevention, Detection, and Management. Pediatrics Vol. 116. October 2015. 2. American Academy of Pediatrics (AAP) Council on Environmental Health. Prevention of Childhood Lead Toxicity. Pediatrics 2016; 138 (1): e20161493. 3. Aton Pharma. Inc. Cuprimine (penicillamine) capsules [product information]. Bridgewater, NJ: Aton Pharma Inc., a division of Valeant Pharmaceuticals North America LLC. November 2015. 4. European Association for Study of the Liver (EASL) clinical practice guidelines: Wilson’s disease. J Hepatol. 2012;56(3):671-85. 5. Kelly D, Crotty G, O'Mullane J, Stapleton M, Sweeney B, O'Sullivan SS. The clinical utility of a low serum ceruloplasmin measurement in the diagnosis of Wilson disease. Ir Med J. 2016 Jan; 109 (1): 341-3.

Page 8 of 9 Coverage Policy Number: 1703 6. McEvoy GK, ed. AHFS 2019 Drug Information. Bethesda, MD: American Society of Health-System Pharmacists, Inc; 2019. 7. Meda Pharmaceuticals Inc. Depen (penicillamine tablets, USP) titratable tablets [product information]. Somerset, NJ: Meda Pharmaceuticals Inc. April 2009. 8. Pearle MS, Goldfarb DS, Assimos, DG, et al; American Urological Association. Medical management of kidney stones: AUA guideline. J Urol 2014; 192 (2): 316-24. 9. Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: an update. Hepatology 2008; 47 (6): 2089-2111. 10. Singh JA, Saag KG, Bridges L Jr, et al. 2015 American College of Rheumatology Guidelines for the Treatment of Rheumatoid Arthritis. Arthritis Care Res 2016; 68 (1): 1-26. 11. Valeant Pharmaceuticals North America LLC. Syprine (trientine hydrochloride) capsules [product information]. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC. June 2014. 12. Weiss KH. Wilson Disease. 1999 Oct 22 [Updated 2016 Jul 29]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1512/

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