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Class: Heavy Metal Antagonists
- Disease-modifying Antirheumatic Drugs
- Sulfhydryl Donors
- Antidotes
ATC Class: M01CC01
VA Class: AD300
CAS Number: 52-67-5
Brands: Cuprimine, Depen

Medically reviewed by Last updated on Jan 25, 2021.


  • Only clinicians familiar with the toxicity, special dosage considerations, and therapeutic benefits should prescribe penicillamine.199 200 Do not use casually.199 200

  • Closely monitor patients.199 200

  • Inform patients to promptly report symptoms suggestive of toxicity to their clinician.199 200


Heavy metal antagonist; a disease-modifying antirheumatic drug (DMARD).199 200 c

Uses for Penicillamine

Wilson Disease

Used to promote excretion of copper in the treatment of Wilson disease (hepatolenticular degeneration).199 200 c

Use in conjunction with a low copper diet.103 105 110 200

Improves neurologic, corneal, hepatic, and psychiatric manifestations in symptomatic patients.199 200 c

American Association for the Study of Liver Diseases (AASLD) recommends a chelating agent (penicillamine or trientine) for initial therapy of symptomatic patients.103 Penicillamine traditionally used as the chelating agent of choice, but is associated with many adverse effects.103 Trientine may be better tolerated and should be considered in patients who cannot take penicillamine.103 104 105 110

Neurologic symptoms may worsen in some patients during initial therapy.c

Once symptoms and laboratory abnormalities stabilize with initial chelating therapy (typically after 2–6 months, but potentially up to 5 years), patients may continue on a lower dosage of the chelating agent or switch to zinc for maintenance therapy.103 104 108

Because substantial morbidity and mortality can be prevented in asymptomatic/presymptomatic patients, AASLD and other experts recommend that such patients also be treated with a chelating agent (generally at a lower dosage than that used in symptomatic patients) or zinc.103 104 105 200

Treatment is lifelong unless a liver transplant is performed.103 104 105 108 Discontinuance of therapy may result in clinical decompensation and/or death.103 104 105 108


Used in conjunction with conventional measures (urine dilution and alkalinization) to reduce excretion of cystine and prevent renal calculi in patients with cystinuria when conventional measures alone are not successful.199 200 c

Rheumatoid Arthritis

Management of rheumatoid arthritis in adults.199 200 206 207 208 c Because penicillamine can cause serious adverse reactions, restrict use to patients with severe disease who fail to respond to an adequate trial of conventional therapy; carefully consider benefits versus risks of therapy.199 200

One of several disease-modifying antirheumatic drugs (DMARDs) frequently used in the past for treatment of rheumatoid arthritis; however, use has declined in favor of other DMARDs with lower risk to benefit ratio (e.g., methotrexate).206 207 208 209

Use in conjunction with other measures (e.g., rest, physical therapy, nonsteroidal anti-inflammatory agents [NSAIAs], corticosteroids) when indicated.199 200

Lead Poisoning

Has been used for the treatment of lead poisoning.204 d

AAP considers penicillamine a third-line agent for the treatment of lead poisoning.204 d

Penicillamine Dosage and Administration


  • Individualize dosage according to the condition being treated and patient response.199 200 c

  • When used for cystinuria, high fluid intake (e.g., 500 mL of water at bedtime and again during the night) needed.199 200 c The greater the fluid intake, the lower the penicillamine dosage required.199 200 c


Oral Administration

Administer orally on an empty stomach (i.e., at least 1 hour before or 2 hours after meals, and at least 1 hour apart from any other drug, food, or milk).199 200 c Administer the last dose of the day ≥3 hours after the evening meal.c Administration on an empty stomach ensures maximum absorption and reduces the potential for inactivation of penicillamine by metals in the GI tract.199 200

If used in individuals who cannot swallow capsules, contents may be administered in 15–30 mL of chilled pureed fruit or fruit juice.c

When used for rheumatoid arthritis, administer dosages >500 mg daily in divided doses.199 200 c


Pediatric Patients

Wilson Disease

Optimal dosage determined by measuring urinary copper excretion and/or serum free copper concentrations.199 200 c

A weight-based dosage of 20 mg/kg daily given in 2–3 divided doses has been suggested in children.103


Individualize dosage based on urinary cystine excretion.199 200 c

30 mg/kg daily given in 4 equal doses.199 200 c If 4 equal doses are not feasible, give larger dose at bedtime.199 200 c If dosage reduced because of adverse effects, retain bedtime dose.199 200 c

Lead Poisoning†

20–30 mg/kg daily has been recommended.c


Wilson Disease

Optimal dosage determined by measuring urinary copper excretion and/or serum free copper concentrations.199 200 c

Initially, 250 mg 4 times daily.199 200 c For patients who do not tolerate an initial dosage of 1 g daily, initiate with 250 mg daily and gradually increase dosage.199 200 c

If tolerated, a dosage of 0.75–1.5 g daily should be continued for 3 months; this dosage produces an initial 24-hour cupruresis of >2 mg.199 200 c Subsequent dosage based on serum free copper concentrations.199 200 c

Dosages >2 g daily are seldom necessary.199 200 c


Individualize dosage based on urinary cystine excretion.199 200 c

Initiate with 250 mg daily and gradually increase dosage to provide close control and minimize adverse reactions.199 200 c

Usual dosage is 2 g daily given in 4 equal doses; range is 1–4 g daily.199 200 c If 4 equal doses are not feasible, give larger dose at bedtime.199 200 c If dosage reduced because of adverse effects, retain bedtime dose.199 200 c

Rheumatoid Arthritis
Initial Therapy

Initially, 125–250 mg daily; increase by 125–250 mg daily at 1–3 month intervals as patient response and tolerance allow.199 200 c Many patients achieve remission with dosage of 500–750 mg daily.c

If remission is achieved, continue dosage; if no improvement and no signs of serious toxicity noted with 500–750 mg daily, increase by 250 mg daily at 2–3 month intervals until remission occurs or toxicity develops.199 200 c

Discontinue penicillamine if improvement not observed after 3–4 months of treatment with 1–1.5 g daily.199 200

Maintenance Therapy

Usual dosage 500–750 mg daily; in patients who respond, but have incomplete suppression of disease after the first 6–9 months of therapy, increase daily dosage by 125–250 mg daily at 3 month intervals to a maximum of 1–1.5 g daily.199 200 c

Optimum duration of therapy not established; attempt to reduce dosage by 125–250 mg daily at 3 month intervals in patients with remission of symptoms ≥6 months, 199 200

Exacerbation Therapy

If exacerbation does not subside within 3 months, consider increasing penicillamine dosage.199 200

Prescribing Limits


Wilson Disease

Maximum 2 g daily.199 200 c

Rheumatoid Arthritis

Maximum 1 g daily; occasionally 1.5 g daily required.199 200 c

Special Populations


If penicillamine is used in pregnant women with Wilson disease, the manufacturers recommend a maximum dosage of 750 mg daily.199 200 If cesarean section is planned, the recommended dosage is 250 mg daily during the last 6 weeks of pregnancy; this dosage is continued postoperatively until wound healing is complete.199 200 (See Contraindications and Mucocutaneous Effects under Cautions.)

Surgical Candidates

Reduce dosage to 250 mg daily in patients considering surgery.199 200 Do not reinitiate full dosage until wound healing is complete.199 200 (See Contraindications and Mucocutaneous Effects under Cautions.)

Cautions for Penicillamine


  • Known or suspected pregnancy except when used for the treatment of Wilson disease or in certain individuals with cystinuria.199 200 (See Fetal/Neonatal Morbidity and Mortality and Pregnancy under Cautions.)

  • Breast-feeding.199 200 (See Lactation under Cautions.)

  • History of penicillamine-related aplastic anemia or agranulocytosis.199 200 c

  • Rheumatoid arthritis patients with current or history of renal insufficiency.199 200 c



Hematologic Effects

Aplastic anemia, agranulocytosis, and thrombocytopenia (sometimes fatal) reported.199 200 c Leukopenia and thrombocytopenia reported.199 200 c

For the first month of therapy, monitor WBC counts with differential, hemoglobin, and platelet counts twice weekly, then every 2 weeks for the next 5 months; after 6 months, monitor monthly.199 200 Discontinue penicillamine if WBC count decreases to <3500/mm3.199 200 Temporarily interrupt therapy if platelet count decreases to <100,000/mm3.199 200

Temporarily interrupt therapy if platelet or WBC counts progressively decrease in 3 successive determinations, even if values are still within normal range.199 200 c

Iron deficiency anemia reported, especially in children or premenopausal women.199 200 c Iron therapy may be administered for short periods.199 200 c (See Iron Supplements under Interactions.)

Renal Effects

Slight to moderate proteinuria (<2 g/24 hours) common; may improve spontaneously or following dosage reduction.c

Hematuria or proteinuria may be warning signs of membranous glomerulopathy that can progress to nephrotic syndrome; essential to closely observe patients who develop hematuria or proteinuria.199 200

For the first month of therapy, perform urinalysis twice weekly, then every 2 weeks for the next 5 months; after 6 months, perform monthly.199 200

Determine quantitative 24-hour urinary protein levels every 1–2 weeks in patients with rheumatoid arthritis who develop moderate proteinuria; do not increase penicillamine dosage in these patients.199 200 Reduce dosage or discontinue penicillamine for proteinuria >1 g/24 hours or progressive increases in proteinuria.199 200 Discontinue therapy if gross hematuria or persistent microscopic hematuria develops.199 200

Weigh risks versus benefits of continued therapy in patients with Wilson disease or cystinuria who develop urinary abnormalities.199 200 c

Discontinue immediately if abnormal urinary findings associated with hemoptysis and pulmonary infiltrates develop.199 200 c (See Goodpasture's Syndrome under Cautions.)

Following discontinuance of penicillamine, ≥1 year may be required for urinary abnormalities to resolve.199 200 c

Annual radiograph of the kidneys advised to check for renal stones in patients with cystinuria.199 200


Intrahepatic cholestasis and toxic hepatitis reported rarely.199 200 Monitor liver function every 3–6 months.199 200

Pulmonary Effects

Obliterative bronchiolitis reported rarely.199 200

Goodpasture’s Syndrome

Goodpasture’s syndrome reported rarely.199 200 c Discontinue immediately if abnormal urinary findings associated with hemoptysis and pulmonary infiltrates occur.199 200 c

Myasthenia Gravis

Myasthenic syndrome, sometimes progressing to myasthenia gravis, reported.199 200 c Symptoms typically resolve after discontinuation of penicillamine.199 200 c

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; congenital cutis laxa and associated birth defects reported.199 200 c

Decisions regarding use of penicillamine in pregnant women should be individualized based on the condition being treated.199 200 (See Pregnancy under Cautions.)

Advise women who become pregnant while taking penicillamine that there is a potential hazard to the fetus.199 200

Sensitivity Reactions

Hypersensitivity Reactions

Drug fever, sometimes accompanied by macular cutaneous eruption, reported; usually occurs after 2–3 weeks of therapy.199 200 c Temporarily interrupt therapy if drug fever develops in patients with Wilson disease or cystinuria; restart with low dosage and gradually increase to full dosage once fever subsides.199 200 c Discontinue if drug fever occurs in patients with rheumatoid arthritis; initiate alternative therapy for rheumatoid arthritis.199 200 c

If pruritus or rash accompanied by fever, arthralgia, lymphadenopathy, or other allergic manifestations develop, discontinue penicillamine.199 200 c


Potential for cross-sensitivity between penicillamine and penicillin.199 200 c

Dermatologic Reactions

Most forms of pemphigus reported; pemphigus vulgaris and pemphigus foliaceous reported most frequently.199 200 c Discontinue if pemphigus suspected.199 200 c

Rash may occur early in therapy or, less frequently, after many months of therapy.199 200 c Observe skin and mucous membranes for allergic reactions.199 200 Generalized pruritic, erythematous, maculopapular, or morbilliform rash occurs early; usually resolves following discontinuance of penicillamine and does not recur when drug is restarted at lower dosage.199 200 c Late rash with intense pruritus reported after ≥6 months therapy.199 200 c If late rash occurs, discontinue penicillamine.199 200 Rash may recur if the drug is restarted.199 200 c

Antinuclear Antibodies

Possible positive antinuclear antibody (ANA) titers; patients with increases in ANA titers may develop a syndrome resembling systemic lupus erythematosus.199 200 c Monitor patients who develop an abnormal ANA test; not necessary to discontinue penicillamine.199 200 c

General Precautions

Mucocutaneous Effects

Potential increased skin friability at pressure or trauma sites (i.e., shoulders, elbows, knees, toes, and buttocks);199 200 c may progress to purpuric or vesicular ecchymoses.c Occurs most frequently with dosages >2 g daily;c does not require discontinuance.199 200 c

May affect wound healing; dosage adjustment recommended in patients undergoing surgery.199 200 (See Pregnancy and Surgical Candidates under Dosage and Administration.)

Oral ulcerations with the appearance of aphthous stomatitis reported; rarely, cheilosis, glossitis, gingivostomatitis, and ulceration of the vulva and vagina reported.199 200 c


Penicillamine increases pyridoxine requirement; pyridoxine 25–50 mg daily recommended for patients with Wilson disease or cystinuria; also recommended for rheumatoid arthritis patients with impaired nutrition.199 200 c

Effects on Taste

Hypogeusia reported; may last ≥2–3 months; may progress to full loss of taste; usually self-limiting.199 200 c

Specific Populations


Category D.200 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Contraindicated in women with rheumatoid arthritis who are pregnant.199 200 c (See Contraindications under Cautions.)

If administered to women with Wilson disease during pregnancy, dosage adjustment needed.199 200 (See Pregnancy under Dosage and Administration.)

Use in pregnant women with cystinuria not recommended.199 200 If stone formation continues, consider benefits to the mother versus risk to the fetus.199 200

Use in women of childbearing potential only if potential benefits outweigh risks.199 200


Discontinue nursing because of potential risk to nursing infants.199 200 c (See Contraindications under Cautions.)

Pediatric Use

Efficacy not established for treatment of juvenile rheumatoid arthritis.199 200 c

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.200 Select dosage with caution, starting at the low end of the dosing range, because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.200 May be useful to monitor renal function.200

Skin rash and taste disturbances reported more frequently in geriatric individuals than in younger adults.200

Renal Impairment

Contraindicated for the treatment of rheumatoid arthritis in patients with current or a history of renal insufficiency.199 200 c

Common Adverse Effects

Early and late rashes199 200 c , taste disturbances, 199 200 c proteinuria, 199 200 c anorexia, 199 200 c epigastric pain, 199 200 c nausea, 199 200 c vomiting, 199 200 c diarrhea, 199 200 c leukopenia, 199 200 c thrombocytopenia. 199 200 c

Interactions for Penicillamine

Specific Drugs





Possible decreased plasma penicillamine concentrations200

Separate administration by ≥1 hours200


Potential additive hematologic and/or adverse renal effects199 200 c

Concomitant use not recommended199 200 c

Cytotoxic agents

Potential additive hematologic and/or adverse renal effects199 200 c

Concomitant use not recommended199 200 c

Gold therapy

Potential additive hematologic and/or adverse renal effects199 200 c

Concomitant use not recommended 199 200 c

Iron supplements

Possible decreased plasma penicillamine concentrations199 200

Separate administration by ≥2 hours199 200

Zinc supplements

Possible decreased plasma penicillamine concentrations200

Separate administration by ≥1 hours200

Penicillamine Pharmacokinetics



Absorption from the GI tract is variable; 40–70% of an oral dose (given as capsules) absorbed.200 Peak plasma concentrations usually attained within 1–3 hours.200 c


Presence of food in the GI tract decreases extent of absorption.199 200



Crosses the placenta.c

Plasma Protein Binding

>80% (mainly albumin and ceruloplasmin).200



Metabolized in the liver to inactive metabolites.200 c

Elimination Route

Excreted principally in urine as disulfides.200 c




Capsules and Tablets

20–25°C in tightly closed containers; protect from moisture.199 200


  • Chelates copper, iron, mercury, and lead to form stable soluble complexes that are excreted by the kidney.199 200 c Removes excess copper in patients with Wilson disease.199 200 c

  • Combines with cystine to form penicillamine-cysteine disulfide, a complex that is more soluble than cystine.199 200 c Reduces concentration of cystine in urine of patients with cystinuria.199 200 c

  • Mechanism of anti-inflammatory effects in rheumatoid arthritis not fully determined; inhibits collagen formation; reduces immunoglobulin M rheumatoid factor; depresses T-cell activity; depolymerizes some macroglobulins; does not reduce B-cell activity.199 200 c

  • Inhibits pyridoxal-dependent enzymes.c

Advice to Patients

  • Importance of advising patients to seek immediate medical attention if signs and symptoms of toxicity (e.g., fever, sore throat, chills, bruising, bleeding) develop.199 200

  • Importance of taking penicillamine on an empty stomach (at least 1 hour before or 2 hours after meals, and at least 1 hour apart from any other drug, food, or milk).199 200

  • Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as concomitant illnesses.199 200

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; apprise women of potential risks to fetus.199 200 Importance of women of childbearing potential informing clinician of missed period(s).199 200

  • Importance of informing patients of other important precautionary information.199 200 (See Cautions.)


Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.



Dosage Forms


Brand Names




250 mg




250 mg

Depen Titratable (scored)


AHFS DI Essentials™. © Copyright 2021, Selected Revisions February 4, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.


103. Roberts EA, Schilsky ML, American Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008; 47:2089-111.

104. Hedera P. Update on the clinical management of Wilson's disease. Appl Clin Genet. 2017; 10:9-19.

105. Rodriguez-Castro KI, Hevia-Urrutia FJ, Sturniolo GC. Wilson's disease: A review of what we have learned. World J Hepatol. 2015; 7:2859-70.

108. Bandmann O, Weiss KH, Kaler SG. Wilson's disease and other neurological copper disorders. Lancet Neurol. 2015; 14:103-13.

110. Patil M, Sheth KA, Krishnamurthy AC et al. A review and current perspective on Wilson disease. J Clin Exp Hepatol. 2013; 3:321-36.

199. Meda Pharmaceuticals. Depen (penicillamine) tablets prescribing information. Somerset, NJ; 2012 Aug.

200. Valeant Pharmaceuticals. Cuprimine (penicillamine) capsules prescribing information. Bridgewater, NJ; 2015 Nov.

201. Ramselaar ACP, Dekker AW, Huber-Bruning O et al. Acquired sideroblastic anaemia after aplastic anemia caused by D-penicillamine therapy for rheumatoid arthritis. Ann Rheum Dis. 1987; 46:156-8.

202. Craig HR. Penicillamine induced mammary hyperplasia: report of a case and review of the literature. J Rheumatol. 1988; 15:1294-7.

203. Reid DM, Martynoga AG, Nuki G. Reversible gynecomastia associated with d-penicillamine in a man with rheumatoid arthritis. BMJ. 1982; 285:1083-4.

204. Committee on Drugs, American Academy of Pediatrics. Treatment guidelines for lead exposure in children. Pediatrics. 1995; 96:155-60.

205. Shannon M, Graef J, Lovejoy FH. Efficacy and toxicity of d-penicillamine in low-level lead poisoning. J Pediatr. 1988; 112:799-804.

206. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum. 2002; 46:358-46.

207. Anon. Drugs for rheumatoid arthritis. Med Lett Drugs Ther. 2000; 42:57-64.

208. Suarez-Almazor ME, Spooner C, Belseck E. Penicillamine for treating rheumatoid arthritis. Cochrane Database Syst Rev. 2000; :CD001460.

209. Singh JA, Saag KG, Bridges SL et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res (Hoboken). 2016; 68:1-25.

c. AHFS Drug Information. McEvoy GK, ed. Penicillamine. Bethesda, MD: American Society of Health-System Pharmacists.

d. American Academy of Pediatrics, Committee on Environmental Health. Lead exposure in children: prevention, detection, and management. Pediatrics. 2005; 116:1036-46.