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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 on Jun 1, 2018


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

  • Closely monitor patients.a b

  • Inform patients to promptly report symptoms suggestive of toxicity to their clinician.a b


See also: Orencia

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

Uses for Penicillamine

Wilson’s Disease

Promotes excretion of copper in the treatment of Wilson’s disease.a b c

Used in conjunction with a low copper diet.a b c

Improves neurologic, corneal, hepatic, and psychiatric manifestations in symptomatic patients.a b c

Prevents signs and symptoms of the disease in asymptomatic patients.a b


Use 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.a b c

Rheumatoid Arthritis

Management of rheumatoid arthritis in adults whose symptoms progress despite an adequate regimen of NSAIAs.a b c 206 207

Because penicillamine can cause severe adverse reactions, restrict use to patients with severe disease.a b

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.a b c

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

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.a b c


Pediatric Patients

Wilson’s Disease

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

20 mg/kg daily given in divided doses.c


Individualize dosage based on urinary cystine excretion.a b c

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

Lead Poisoning

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


Wilson’s Disease

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

Initially, 250 mg 4 times daily.a b c For patients who do not tolerate an initial dosage of 1 g daily, initiate with 250 mg daily and gradually increase dosage.a b 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.a b c Subsequent dosage based on serum free copper concentrations.a b c

Dosages >2 g daily are seldom necessary.a b c


Individualize dosage based on urinary cystine excretion.a b c

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

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

Discontinue penicillamine if improvement not observed after 3–4 months of treatment with 1–1.5 g daily.a b c

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.a b 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, a b c

Exacerbation Therapy

If exacerbation does not subside within 3 months, consider increasing penicillamine dosage.a b c

Prescribing Limits


Wilson’s Disease

Maximum 2 g daily.a b c

Rheumatoid Arthritis

Maximum 1 g daily; occasionally 1.5 g daily required.a b c

Special Populations


If penicillamine is used in pregnant women with Wilson's disease, the manufacturers recommend a maximum dosage of 0.75–1 g daily.a b 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.a b (See Contraindications and Mucocutaneous Effects under Cautions.)

Surgical Candidates

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

Cautions for Penicillamine


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

  • Breast-feeding.a b (See Lactation under Cautions.)

  • History of penicillamine-related aplastic anemia or agranulocytosis.a b c

  • Rheumatoid arthritis patients with current or history of renal insufficiency.a b c



Hematologic Effects

Aplastic anemia, agranulocytosis, and thrombocytopenia (sometimes fatal) reported.a b c Leukopenia and thrombocytopenia reported.a b c

For the first 6 months, monitor WBC counts, hemoglobin, and platelet counts every 2 weeks; after 6 months, monitor monthly.a b Discontinue penicillamine if WBC count decreases to <3500/mm3.a b Temporarily interrupt therapy if platelet count decreases to <100,000/mm3.a b

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

Iron deficiency anemia reported, especially in children or premenopausal women.a b c Iron therapy may be administered for short periods.a b 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.a b

For the first 6 months, perform urinalysis every 2 weeks; after 6 months, perform monthly.a b

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.a b Reduce dosage or discontinue penicillamine for proteinuria >1 g/24 hours or progressive increases in proteinuria.a b Discontinue therapy if gross hematuria or persistent microscopic hematuria develops.a b

Weigh risks versus benefits of continued therapy in patients with Wilson's disease or cystinuria who develop urinary abnormalities.a b c

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

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

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


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

Pulmonary Effects

Obliterative bronchiolitis reported rarely.a b

Goodpasture’s Syndrome

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

Myasthenia Gravis

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

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; congenital cutis laxa and associated birth defects reported.a b c

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

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

Sensitivity Reactions

Hypersensitivity Reactions

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

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


Potential for cross-sensitivity between penicillamine and penicillin.a b c

Dermatologic Reactions

Most forms of pemphigus reported; pemphigus vulgaris and pemphigus foliaceus reported most frequently.a b c Discontinue if pemphigus suspected.a b c

Rash may occur early in therapy or, less frequently, after many months of therapy.a b c Observe skin and mucous membranes for allergic reactions.a b 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.a b c Late rash with intense pruritus reported after ≥6 months therapy.a b c If late rash occurs, discontinue penicillamine.a b Rash may recur if the drug is restarted.a b c

Antinuclear Antibodies

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

General Precautions

Mucocutaneous Effects

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

May affect wound healing; dosage adjustment recommended in patients undergoing surgery.a b (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.a b c


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

Effects on Taste

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

Specific Populations


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

Contraindicated in women with rheumatoid arthritis who are pregnant.a b c (See Contraindication under Cautions.)

If administered to women with Wilson's disease during pregnancy, dosage adjustment needed.a b (See Pregnancy under Dosage and Administration.)

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

Use in women of childbearing potential only if potential benefits outweigh risks.a b


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

Pediatric Use

Efficacy not established for treatment of juvenile rheumatoid arthritis.a b c

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.a 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.a May be useful to monitor renal function.a

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

Renal Impairment

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

Common Adverse Effects

Early and late rashesa b c , taste disturbances, a b c proteinuria, a b c anorexia, a b c epigastric pain, a b c nausea, a b c vomiting, a b c diarrhea, a b c leukopenia, a b c thrombocytopenia. a b c

Interactions for Penicillamine

Specific Drugs





Possible decreased plasma penicillamine concentrationsa

Separate administration by ≥1 hoursa


Potential additive hematologic and/or adverse renal effectsa b c

Concomitant use not recommendeda b c

Cytotoxic agents

Potential additive hematologic and/or adverse renal effectsa b c

Concomitant use not recommendeda b c

Gold therapy

Potential additive hematologic and/or adverse renal effectsa b c

Concomitant use not recommended a b c

Iron supplements

Possible decreased plasma penicillamine concentrationsa b

Separate administration by ≥2 hoursa b

Zinc supplements

Possible decreased plasma penicillamine concentrationsa

Separate administration by ≥1 hoursa

Penicillamine Pharmacokinetics



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


Presence of food in the GI tract decreases extent of absorption.a b



Crosses the placenta.c

Plasma Protein Binding

80% (mainly albumin and ceruloplasmin).a



Metabolized in the liver to inactive metabolites.a c

Elimination Route

Excreted principally in urine as disulfides.a c




Capsules and Tablets



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

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

  • 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).a b c

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

  • 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.a b Importance of women of childbearing potential informing clinician of missed period(s).a b

  • Importance of informing patients of other important precautionary information.a b (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




125 mg



250 mg




250 mg

Depen Titratable (with povidone; scored)


AHFS DI Essentials. © Copyright 2019, Selected Revisions June 1, 2008. 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.


200. Merck. Cuprimine (penicillamine) capsules prescribing information (dated 1997 Feb). In: Physicians’ desk reference. 53rd ed. Montvale, NJ; Medical Economics Company Inc; 1999:1766-9.

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.

a. Merck. Cuprimine (penicillamine) capsules prescribing information. Whitehouse Station, NJ; Oct 2004.

b. MedPointe Healthcare Inc. Depen (penicillamine) tablets prescribing information. Somerset, NJ; 2003 Dec.

c. AHFS Drug Information 2007. McEvoy GK, ed. Penicillamine. Bethesda, MD: American Society of Health-System Pharmacists; 2007. From

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