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(pen i SIL a meen)

Index Terms

  • D-3-Mercaptovaline
  • D-Penicillamine
  • β,β-Dimethylcysteine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Cuprimine: 250 mg [contains fd&c yellow #10 (quinoline yellow)]

Tablet, Oral:

Depen Titratabs: 250 mg [scored]

Brand Names: U.S.

  • Cuprimine
  • Depen Titratabs

Pharmacologic Category

  • Chelating Agent


Chelates with lead, copper, mercury and other heavy metals to form stable, soluble complexes that are excreted in urine; depresses circulating IgM rheumatoid factor, depresses T-cell but not B-cell activity; combines with cystine to form a compound which is more soluble, thus cystine calculi are prevented


Rapid but incomplete; 40% to 70%


Hepatic (small amounts metabolized to s-methyl-d-penicillamine)


Urine (primarily as disulfides)

Onset of Action

Rheumatoid arthritis: 2 to 3 months; Wilson disease: 1 to 3 months

Time to Peak

Serum: 1 to 3 hours

Half-Life Elimination

1.7 to 7 hours (Roberts 2008)

Protein Binding

>80% to albumin and ceruloplasmin

Use: Labeled Indications

Treatment of Wilson's disease, cystinuria; adjunctive treatment of severe, active rheumatoid arthritis

Canadian labeling: Additional use (not in U.S. labeling): Treatment of chronic lead poisoning


Renal insufficiency (in patients with rheumatoid arthritis); patients with previous penicillamine-related aplastic anemia or agranulocytosis; breast-feeding; pregnancy (in patients with rheumatoid arthritis)

Canadian labeling: Additional contraindications (not in U.S. labeling): Hypersensitivity to penicillamine or any component of the formulation; use in patients with chronic lead poisoning who have radiographic evidence of lead-containing substances in the GI tract; pregnancy (in patients with chronic lead poisoning); concomitant use with gold therapy, antimalarial or cytotoxic drugs, oxyphenbutazone or phenylbutazone

Dosing: Adult

Note: Dose reduction to 250 mg/day may be considered prior to surgical procedures. May resume normal recommended dosing post-operatively once wound healing is complete.

Cystinuria: Oral: 1-4 g/day in 4 divided doses; usual dose: 2 g/day; initiation of therapy at 250 mg/day with gradual upward titration may reduce the risk of unwanted effects. Note: Adjust dose to limit cystine excretion to 100-200 mg/day (<100 mg/day with history of stone formation).

Lead poisoning: Oral: Canadian labeling: 900-1500 mg/day in 3 divided doses for 1-2 weeks, then 750 mg/day in divided doses until blood lead concentrations <60 mcg/dL or urinary lead excretion <500 mcg/L for 2 consecutive months.

Rheumatoid arthritis: Oral: Initial: 125-250 mg/day, may increase dose by 125-250 mg/day at 1- to 3-month intervals up to 1-1.5 g/day; discontinue in patients failing to improve after 3-4 months at these doses

Wilson's disease: Oral: Note: Dose that results in an initial 24-hour urinary copper excretion >2 mg/day should be continued for ~3 months; maintenance dose defined by amount resulting in <10 mcg serum free copper/dL.

Manufacturer's labeling: 750-1500 mg/day in divided doses; maximum dose: 2000 mg/day. Note: Limit daily dose to 750 mg/day (U.S. labeling) or 1000 mg/day (Canadian labeling) in pregnant women; if planned caesarian, limit dose to 250 mg/day during the last 6 weeks of pregnancy and postoperatively until wound healing is complete.

Alternate recommendations (off-label dosing): To increase tolerability, therapy may be initiated at 250-500 mg/day then titrated upward in 250 mg increments every 4-7 days; usual maintenance dose: 750-1000 mg/day in 2 divided doses; maximum: 1000-1500 mg/day in 2-4 divided doses. (American Association for the Study of Liver Diseases [AASLD] guidelines) (Roberts, 2008).

Dosing: Geriatric

Therapy should be initiated at low end of dosing range and titrated upward cautiously. Refer to adult dosing.

Dosing: Pediatric

Note: Dose reduction to 250 mg/day may be considered prior to surgical procedures. May resume normal recommended dosing postoperatively once wound healing is complete.

Cystinuria: Oral: 30 mg/kg/day in 4 divided doses; Note: Adjust dose to limit cystine excretion to 100-200 mg/day (<100 mg/day with history of stone formation).

Lead poisoning: Oral:

Canadian labeling: 30-40 mg/kg/day or 600-750 mg/m2/day in 1-2 divided doses (maximum dose: 750 mg/day); treat until blood lead concentrations <40 mcg/dL for 2 consecutive months and at least 1 of the following: Decrease in erythrocyte protoporphyrin level to <3-5 times the average normal level or the excretion of coproporphyrin or delta-aminolevulinic acid decreases to the upper limit of normal. Note: Manufacturer labeling recommends initiating therapy only in children who meet the following criteria: Asymptomatic, blood lead concentrations of 50-80 mcg/dL, erythrocyte protoporphyrin level >400-500 mcg/dL erythrocytes, excessive excretion of delta-aminolevulinic acid and/or coproporphyrin.

Alternate recommendations (off-label dosing): Note: The American Academy of Pediatrics (AAP) considers penicillamine a third-line agent for the management of lead poisoning (AAP, 2005; Chandran, 2010): 10-15 mg/kg/day for 4-12 weeks (Chandran, 2010). Note: The CDC recommends chelation treatment when blood lead concentrations are >45 mcg/dL (CDC, 2002). Children with blood lead concentrations >70 mcg/dL or symptomatic lead poisoning should be treated with parenteral agents (AAP, 2005).

Wilson's disease (off-label dosing): Oral: 20 mg/kg/day in 2-3 divided doses, round off to the nearest 250 mg dose (American Association for the Study of Liver Diseases [AASLD] guidelines) (Roberts, 2008). Note: Dose that results in an initial 24-hour urinary copper excretion >2 mg/day should be continued for ~3 months; maintenance dose defined by amount resulting in <10 mcg serum free copper/dL.

Rheumatoid arthritis (off-label use): Oral: Initial: 3 mg/kg/day (≤250 mg/day) for 3 months, then 6 mg/kg/day (≤500 mg/day) in divided doses twice daily for 3 months to a maximum of 10 mg/kg/day in 3-4 divided doses; maximum dose: 750 mg/day (Rosenberg, 1989)

Dosing: Renal Impairment

Manufacturer's labeling: No dosage adjustment provided in manufacturer’s labeling; however, the manufacturer labeling does suggest a cautious approach to dosing as this drug undergoes mainly renal elimination.

Alternate recommendations:

CrCl <50 mL/minute: Avoid use (Aronoff, 2007)

Hemodialysis: Dialyzable; Administer 33% of usual dose (Aronoff, 2007); a dosing decrease from 250 mg/day to 250 mg 3 times/week after dialysis has been suggested in the treatment of rheumatoid arthritis (Swarup, 2004).

Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer's labeling; however, only a small fraction is metabolized hepatically.

Extemporaneously Prepared

A 50 mg/mL oral suspension may be made with capsules. Mix the contents of sixty 250 mg capsules with 3 g carboxymethylcellulose, 150 g sucrose, 300 mg citric acid, and parabens (methylparaben 120 mg, propylparaben 12 mg). Add quantity of propylene glycol sufficient to make 100 mL, then add quantity of purified water sufficient to make 300 mL. Cherry flavor may be added. Label "shake well" and "refrigerate". Stable for 30 days refrigerated.

DeCastro FJ, Jaeger RQ, and Rolfe UT, "An Extemporaneously Prepared Penicillamine Suspension Used to Treat Lead Intoxication," Hosp Pharm, 1977, 2:446-8.


Doses ≤ 500 mg may be administered as single dose; doses >500 mg should be administered in divided doses. For patients who cannot swallow, contents of capsules may be administered in 15-30 mL of chilled puréed fruit or fruit juice within 5 minutes of administration. Administer on an empty stomach (1 hour before or 2 hours after meals) and at least 1 hour apart from other drugs, milk, antacids, and zinc or iron-containing products. Canadian labeling recommends administering at least 2 hours before meals in patients with lead poisoning.

Cystinuria: If administering 4 equal doses is not feasible, administer the larger dose at bedtime.

Dietary Considerations

Should be taken at least 1 hour before or 2 hours after meals on an empty stomach (Note: Canadian labeling recommends administration at least 2 hours before meals in patients with lead poisoning). Pyridoxine supplementation is recommended. Patients with Wilson's disease should receive 25-50 mg/day of pyridoxine (Roberts, 2008); a multivitamin (without copper) may also be considered. Patients with cystinuria or patients with rheumatoid arthritis and impaired nutritional intake should receive 25 mg/day of pyridoxine. For Wilson's disease, decrease copper in diet to <1-2 mg/day and omit chocolate, nuts, shellfish, mushrooms, liver, raisins, broccoli, copper-enriched cereal, multivitamins with copper, and molasses. May consider short courses of iron supplementation if dietary modifications (eg, low copper diet in Wilson’s disease, low methionine diet in cystinuria) results in iron deficiency; pediatric patients and menstruating women may be particularly susceptible to iron deficiency. Allow 2 hours between administration of iron supplementation and penicillamine as iron may decrease drug absorption. For cystinuria, increase daily fluid intake including 1 pint (~500 mL) of fluid prior to bedtime and 1 additional pint during the night. For lead poisoning, decrease calcium in diet.


Store in tight, well-closed containers.

Drug Interactions

Antacids: May decrease the serum concentration of PenicillAMINE. Consider therapy modification

Digoxin: PenicillAMINE may decrease the serum concentration of Digoxin. Monitor therapy

Iron Salts: May decrease the absorption of PenicillAMINE. Only oral iron salts are a concern. Exceptions: Ferric Carboxymaltose; Ferric Gluconate; Ferric Hydroxide Polymaltose Complex; Ferric Pyrophosphate Citrate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Consider therapy modification

Multivitamins/Minerals (with ADEK, Folate, Iron): May increase the serum concentration of PenicillAMINE. Management: Consider separating doses of the agents by 2 or more hours to minimize the effects of this interaction; however, the success of this action is unproven. Consider therapy modification

Polaprezinc: May decrease the serum concentration of PenicillAMINE. Consider therapy modification

Adverse Reactions

Frequency may vary by indication.


Gastrointestinal: Diarrhea (17%), dysgeusia (12%)

1% to 10%:

Dermatologic: Skin rash (early and late: 5%)

Genitourinary: Proteinuria (6%)

Hematologic & oncologic: Thrombocytopenia (4%), leukopenia (2%)

Frequency not defined.

Cardiovascular: Local thrombophlebitis, vasculitis (including renal vasculitis)

Central nervous system: Anxiety, agitation, dystonia, Guillain-Barre syndrome, hyperpyrexia, myasthenia (including extraocular muscles), myasthenia gravis, neurological deterioration, neuropathy, psychiatric disturbance

Dermatologic: Alopecia, cheilosis, exfoliative dermatitis, fragile skin (friability increased), lichen planus, papule (white papules at venipuncture and surgical sites), pemphigus, pruritus, skin atrophy (anetoderma), toxic epidermal necrolysis, urticaria, wrinkling of skin (excessive), yellow nail syndrome

Endocrine & metabolic: Hypoglycemia, increased lactate dehydrogenase, thyroiditis

Gastrointestinal: Anorexia, epigastric pain, glossitis, nausea, oral mucosa ulcer, pancreatitis, peptic ulcer (reactivation), stomatitis (gingivostomatitis), vomiting

Genitourinary: Breast disease (mammary hyperplasia), Goodpasture's syndrome, hematuria, nephrotic syndrome

Hematologic & oncologic: Agranulocytosis, aplastic anemia, change in platelet count (increase), eosinophilia, hemolytic anemia, increased monocytes, leukocytosis, lymphadenopathy, positive ANA titer, pure red cell aplasia, sideroblastic anemia, thrombotic thrombocytopenic purpura

Hepatic: Increased serum alkaline phosphatase, hepatic failure, intrahepatic cholestasis, toxic hepatitis

Neuromuscular & skeletal: Arthralgia, connective tissue disease (elastosis perforans serpiginosa), dermatomyositis, lupus-like syndrome, polyarthralgia (migratory, often with objective synovitis), polymyositis

Ophthalmic: Blepharoptosis, diplopia, optic neuritis, visual disturbance

Otic: Tinnitus

Renal: Renal failure

Respiratory: Asthma, bronchiolitis obliterans, hypersensitivity pneumonitis, interstitial pneumonitis, pulmonary fibrosis

Miscellaneous: Fever

ALERT: U.S. Boxed Warning

Experienced physician:

Physicians planning to use penicillamine should thoroughly familiarize themselves with its toxicity, special dosage considerations, and therapeutic benefits. Penicillamine should never be used casually. Each patient should remain constantly under the close supervision of the physician.

Toxicity symptoms:

Patients should be warned to report promptly any symptoms suggesting toxicity.


Concerns related to adverse effects:

• Allergic reactions: Approximately 33% of patients will experience an allergic reaction. Rash may occur early (more commonly) or late in therapy; early-onset rash typically resolves within days of discontinuation of therapy and does not recur upon rechallenge with reduced dose; discontinue therapy for late-onset rash (eg, after >6 months) and do not rechallenge; rash typically recurs with rechallenge. Discontinue therapy for skin reactions accompanied by lymphadenopathy, fever, arthralgia, or other allergic reactions.

• Bronchiolitis obliterans: Has been reported rarely with use; instruct patients to report pulmonary symptoms (eg, unexplained wheezing or cough, exertional dyspnea) and consider pulmonary function testing in such patients.

• Dermatologic: Penicillamine increases the amount of soluble collagen; may increase skin friability, particularly at sites subject to pressure or trauma (eg, knees, elbows shoulders). Purpuric areas with localized bleeding (if skin is broken) or vesicles with dark blood may be observed. Effects are considered localized and do not necessitate discontinuation of therapy; may not recur with dose reduction. Macular cutaneous eruptions are sometimes observed in conjunction with drug fever, usually 2 -3 weeks after therapy initiation. Dose reduction may be considered prior to surgical procedures. May resume normal recommended dosing postoperatively once wound healing is complete.

• Drug fever: Drug fever may be observed, usually 2-3 weeks after therapy initiation. Discontinue use in patients with rheumatoid arthritis, Wilson’s disease, or cystinuria who develop a marked febrile response. Consider alternative therapy for patients with rheumatoid arthritis due to high incidence of fever reoccurrence with penicillamine rechallenge. May resume therapy at a reduced dose in Wilson’s disease or cystinuria upon resolution of fever; dose should then be gradually titrated to effective dose.

• Gastrointestinal: Taste alteration may occur (rare in Wilson’s disease); usually self-limited with continued therapy, however may last ≥2 months and result in total loss of taste. Oral ulceration (eg, stomatitis) may occur; typically recurs on rechallenge but often resolves with dose reduction. Other dose-related lesions (eg, glossitis, gingivostomatitis) have been observed with use and may require therapy discontinuation.

• Goodpasture's syndrome: Penicillamine has been associated with fatalities due to Goodpasture's syndrome. Discontinue therapy immediately in patients with abnormal urinary findings in association with hemoptysis and pulmonary infiltrates on chest x-ray.

• Hematologic toxicities: Penicillamine has been associated with fatalities due to agranulocytosis, aplastic anemia, and thrombocytopenia. Discontinue therapy for WBC <3500/mm3. Withhold therapy at least temporarily for platelet counts <100,000/mm3 or a progressive fall in WBC or platelets in 3 successive determinations, even though values may remain within the normal range. Monitor for signs/symptoms of leukopenia and thrombocytopenia.

• Hepatotoxicity: Monitor liver function tests periodically due to rare reports of intrahepatic cholestasis or toxic hepatitis. More frequent monitoring is required during the first year of therapy in patients with Wilson’s disease.

• Lupus erythematosus-like syndrome: May be observed in some patients; positive antinuclear antibody (ANA) test does not necessitate therapy discontinuation but should alert clinicians of possible future development of lupus erythematosus-like syndrome.

• Pemphigus: May occur early or late in therapy; discontinue use with suspicion of pemphigus. May treat with high-dose corticosteroids alone, or in conjunction with an immunosuppressant; treatment duration can range from weeks to >1 year.

• Penicillin cross-sensitivity: Patients with a penicillin allergy may theoretically have cross-sensitivity to penicillamine; however, the possibility has been eliminated now that penicillamine is produced synthetically and no longer contains trace amounts of penicillin.

• Proteinuria/hematuria: Proteinuria or hematuria may develop; monitor for membranous glomerulopathy which can lead to nephrotic syndrome. In rheumatoid arthritis patients, discontinue if gross hematuria or persistent microscopic hematuria develop and discontinue therapy or reduce dose for proteinuria that is either >1 g/day or progressively increasing. Dose reduction may lead to resolution of proteinuria.

• Myasthenia gravis: Penicillamine has been associated with myasthenic syndrome, and in some cases, progression to myasthenia gravis. Resolution of symptoms has been observed in most cases following discontinuation of therapy.

• Toxicity symptoms: [U.S. Boxed Warning]: Patients should be warned to report promptly any symptoms suggesting toxicity (fever, sore throat, chills, bruising, or bleeding); toxicity may be dose related.

Disease-related concerns:

• Cystinuria: Continue treatment on a daily basis; interruptions of even a few days have been followed by hypersensitivity with reinstitution of therapy. Patients should receive pyridoxine supplementation (25 mg/day).

• Lead poisoning: Investigate, identify, and remove sources of lead exposure and confirm lead-containing substances are absent from the GI tract prior to initiating therapy. Do not permit patients to re-enter the contaminated environment until lead abatement has been completed. Penicillamine is considered to be a third-line agent for the treatment of lead poisoning in children due to the overall toxicity associated with its use (AAP, 2005; Chandran, 2010); penicillamine should only be used when unacceptable reactions have occurred with edetate CALCIUM disodium and succimer. Primary care providers should consult experts in the chemotherapy of lead toxicity before using chelation drug therapy.

• Rheumatoid arthritis: Patients with rheumatoid arthritis and impaired nutrition should receive pyridoxine supplementation (25 mg/day).

• Wilson's disease: Continue treatment on a daily basis; interruptions of even a few days have been followed by hypersensitivity with reinstitution of therapy. Worsening of neurologic symptoms may occur during initiation of therapy however discontinuation of therapy is not recommended; may consider concomitant use of short term dimercaprol in patients whose symptoms continue to worsen 1 month following therapy initiation. Patients should receive pyridoxine supplementation (25-50 mg/day; Roberts, 2008).

Concurrent drug therapy issues:

• Hematopoietic-depressant drugs: Use with caution in patients on other hematopoietic-depressant drugs (eg, gold, immunosuppressants, antimalarials, phenylbutazone; Canadian labeling contraindicates concomitant use with these agents); hematologic and renal adverse reactions are similar.

Special populations:

• Elderly: Use with caution in the elderly; may be more susceptible to skin rash and/or taste alterations.

Other warnings/precautions:

• Experienced physician: [U.S. Boxed Warning]: Should be administered under the close supervision of a physician familiar with the toxicity and dosage considerations.

Monitoring Parameters

Urinalysis, CBC with differential, platelet count, skin, lymph nodes, and body temperature twice weekly during the first month of therapy, then every 2 weeks for 5 months, then monthly; LFTs every 6 months; signs/symptoms of hypersensitivity

Cystinuria: Urinary cystine, annual X-ray for renal stones

Lead poisoning: Serum lead concentration (baseline and 7-21 days after completing chelation therapy); hemoglobin or hematocrit, iron status, free erythrocyte protoporphyrin or zinc protoporphyrin; neurodevelopmental changes

Wilson's disease: Serum non-ceruloplasmin bound copper, 24-hour urinary copper excretion, LFTs every 3 months (at least) during the first year of treatment; periodic ophthalmic exam

Urinalysis: Monitor for proteinuria and hematuria. A quantitative 24-hour urine protein at 1- to 2-week intervals initially (first 2-3 months) is recommended if proteinuria develops.

Pregnancy Risk Factor


Pregnancy Considerations

Birth defects, including congenital cutix laxa and associated defects, have been reported in infants following penicillamine exposure during pregnancy. Use for the treatment of rheumatoid arthritis during pregnancy is contraindicated. Use for the treatment of cystinuria only if the possible benefits to the mother outweigh the potential risks to the fetus. Continued treatment of Wilson's disease during pregnancy protects the mother against relapse. Discontinuation has detrimental maternal and fetal effects. Daily dosage should be limited to 750 mg. For planned cesarean section, reduce dose to 250 mg/day for the last 6 weeks of pregnancy, and continue at this dosage until wound healing is complete.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, diarrhea, change in taste, or lack of appetite. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, weight gain), signs of a pancreas problem (pancreatitis; severe abdominal pain, severe back pain, severe nausea, vomiting), signs of lupus (rash on the cheeks or other body parts, sunburn easy, muscle or joint pain, chest pain or shortness of breath, or swelling in the arms or legs), loss of strength and energy, skin changes, enlarged lymph nodes, shortness of breath, muscle pain, muscle weakness, burning or numbness feeling, mood changes, tremors, difficulty moving, rigidity, joint pain, vision changes, back pain, abdominal pain, or blood in urine (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.