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.
Patients should be warned to report promptly any symptoms suggesting toxicity.
Note: Dose reduction to 250 mg/day may be considered prior to surgical procedures (including prior to cesarean delivery in pregnant patients with Wilson disease). May resume normal recommended dosing postoperatively once wound healing is complete. Penicillamine administration increases requirement for pyridoxine. Patients may require a daily supplement of pyridoxine (25 to 50 mg/day) (AASLD [Roberts 2008]; EASL 2012).
Cystinuria: Oral: 1 to 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 to 200 mg/day (<100 mg/day with history of stone formation).
Initial phase: Oral: 125 to 250 mg/day; increase dose in 250 mg increments every 4 to 7 days (EASL 2012). Maximum: 1 to 1.5 g/day in 2 to 4 divided doses (AASLD [Roberts 2008]; EASL 2012).
Maintenance phase: Oral: Usual maintenance dose of 750 to 1,000 mg/day in 2 or 3 divided doses (AASLD [Roberts 2008]; EASL 2012).
Note: Adequacy of the initial dose is monitored by the rate of urinary copper excretion; 24-hour urinary copper excretion may exceed 1,000 mcg/day at treatment initiation and decrease as copper stores are depleted (eg, ~200 to 500 mcg/day during maintenance therapy). Urinary copper excretion rates <200 mcg/day in conjunction with elevated serum nonceruloplasmin-bound copper concentrations (eg, >15 mcg/dL) may suggest nonadherence (AASLD [Roberts 2008]).
Pregnancy: Decrease the dose to the minimum effective dose; consider reducing by 25% to 50% of the prepregnancy dose (AASLD [Roberts 2008]; Dathe 2016; EASL 2012).
Manufacturer's labeling: Dosing in the prescribing information may not reflect current clinical practice. Oral: 750 mg to 1.5 g/day in divided doses; maximum dose: 2 g/day. Note: Limit daily dose to 750 mg/day in pregnant women; if planned cesarean delivery, limit dose to 250 mg/day during the last 6 weeks of pregnancy and postoperatively until wound healing is complete.
Manufacturer's labeling: There are no dosage adjustments provided in the manufacturer's labeling; however, the manufacturer labeling does suggest a cautious approach to dosing as this drug undergoes mainly renal elimination.
CrCl <50 mL/minute: Avoid use (Aronoff 2007).
Hemodialysis: Dialyzable: Administer 33% of usual dose (Aronoff 2007).
There are no dosage adjustments provided in the manufacturer's labeling; however, only a small fraction is metabolized hepatically.
(For additional information see "Penicillamine: Pediatric drug information")
Note: Penicillamine administration increases requirement for pyridoxine. Patients may require a daily supplement of pyridoxine. A dose reduction (to 250 mg/day in adults) may be considered prior to surgical procedures. May resume normal recommended dosing postoperatively once wound healing is complete.
Diagnosis (adjunct): Penicillamine Challenge Test: Limited data available: Children ≥2 years and Adolescents: Oral: 500 mg/dose for 2 doses; administer first immediately prior to a 24-hour urine collection and repeat 12 hours later. Urinary copper excretion >1,600 mcg copper/24 hour (>25 µmol/24 hours) is consistent with Wilson disease (AASLD [Roberts 2008]; EASL 2012; Martins da Costa 1992; Müller 2007).
Treatment: Children and Adolescents: Oral: 20 mg/kg/day in 2 to 3 divided doses, round off to the nearest 250 mg dose; reduce dose by 25% when clinically stable; adult maximum daily dose: 1,500 mg/day (AASLD [Roberts 2008]; EASL 2012)
Cystinuria: Children and Adolescents: Oral: 20 to 40 mg/kg/day in 4 divided doses; maximum daily dose: 40 mg/kg/day (DeBerardinis 2008); adult maximum daily dose: 4,000 mg/day. Manufacturer recommends if 4 equal doses are not possible, give the larger portion at bedtime and suggests dose should be adjusted to limit cysteine excretion to <100 to 200 mg/day (<100 mg/day with history of stone formation and/or pain). A retrospective chart review of 11 patients (age range: 1.2 to 12.5 years) with urolithiasis and high urinary cysteine receiving long-term penicillamine (~3 to 18 years) suggests that gradual initiation of penicillamine effectively lowers urinary cysteine concentrations and may limit toxicity associated with treatment. Therapy was initiated at 5 mg/kg/day and increased weekly by 5 mg/kg/day to a final dose of 20 mg/kg/day; five patients required further increases up to 40 mg/kg/day. Urinary cysteine concentrations decreased 5% to 81% while on treatment. Five patients did not reach the goal urinary cysteine concentration of <1,200 micromolar. Six patients experienced acute stone crisis or had evidence of new stone formation on ultrasound; however, in all cases this was during periods of noncompliance to therapy (DeBerardinis 2008).
Lead poisoning: Note: For the treatment of high blood lead levels in children, the CDC recommends chelation treatment when blood lead levels are >45 mcg/dL (ACCLPP 2012; CDC 2002). AAP considers penicillamine a 3rd line agent for children when blood lead levels are >45 mcg/dL and <70 mcg/dL; children with blood lead levels >70 mcg/dL or symptomatic lead poisoning should be treated with parenteral agents (AAP 2005).
Children and Adolescents: Limited data available, optimal dose not defined: Oral: Initial: 10 mg/kg/day divided twice daily for 2 weeks increase dose to 25 to 40 mg/kg/day (Kliegman 2016); increasing the dose over a few weeks has been suggested to improve tolerability (Shannon 1998). A reduced dosage of 15 mg/kg/day in 2 divided doses has been shown to be effective in the treatment of mild to moderate lead poisoning (blood lead concentration 20 to 40 mcg/dL) with a reduction in adverse effects (Shannon 2000); lower doses (10 to 15 mg/kg/day for 4 to 12 weeks) has also been suggested for treating lead concentrations of 45 to 69 mcg/dL (Chandran 2010).
There are no dosage adjustments provided in the manufacturer’s labeling; however, the manufacturer’s labeling suggests caution as the drug undergoes mainly renal elimination; drug is dialyzable. Based on experience in adult patients, dosing adjustment suggested (particularly with hemodialysis).
There are no dosage adjustments provided in the manufacturer's labeling; however, only a small fraction is metabolized hepatically.
Therapy should be initiated at low end of dosing range and titrated upward cautiously. Refer to adult dosing.
Agranulocytosis: Permanently discontinue penicillamine.
Aplastic anemia: Permanently discontinue penicillamine.
A progressive fall in WBC in 3 successive determinations: Withhold or discontinue penicillamine as appropriate.
WBC <3,500/mm3: Discontinue penicillamine.
Thrombocytopenia (<100,000/mm3 or a progressive fall in 3 successive determinations) with or without bleeding: Withhold or discontinue penicillamine as appropriate.
Anti-glomerular basement membrane (GBM) disease (Goodpasture syndrome): Immediately discontinue penicillamine following the development of abnormal urinary findings associated with hemoptysis and pulmonary infiltrates.
Drug fever: Withhold, reduce dose, or discontinue penicillamine as appropriate in patients who develop a marked febrile response. May resume therapy at a reduced dose upon resolution of fever; dose should then be gradually titrated to effective dose.
Late-onset rash (eg, after >6 months): Discontinue penicillamine; do not restart (rash typically recurs with rechallenge).
Pemphigus: Discontinue penicillamine.
Skin reactions accompanied by lymphadenopathy, fever, arthralgia, or other allergic reactions: Discontinue penicillamine.
Proteinuria and/or hematuria: Reduce dose or discontinue penicillamine as appropriate.
Note: Patients with rheumatoid arthritis who develop moderate degrees of proteinuria may be continued cautiously on penicillamine therapy so long as 24-hour urinary protein is monitored every 1 to 2 weeks; do not increase the dose. If proteinuria exceeds 1 g per 24 hours or is progressively increasing, reduce dose or discontinuance penicillamine as appropriate.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Cuprimine: 250 mg [contains quinoline yellow (d&c yellow #10)]
Generic: 250 mg
D-Penamine: 125 mg [DSC] [gluten free]
Depen Titratabs: 250 mg [scored]
Generic: 250 mg
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Cuprimine: 250 mg [contains quinoline yellow (d&c yellow #10)]
Oral: Doses ≤500 mg may be administered as a single dose; doses >500 mg should be administered in divided doses. For patients who have difficulty swallowing, the contents of the capsules may be administered in 15 to 30 mL of chilled puréed fruit or fruit juice within 5 minutes of preparation. Administer on an empty stomach (1 hour before or 2 hours after meals) and at least 1 hour apart from other drugs, milk, antacids, iron-containing products, and zinc-containing products. Administration closer to meals may be considered if it improves compliance and the patient is stable (AASLD [Roberts 2008]).
Cystinuria: If administering 4 equal doses is not feasible, administer the larger dose at bedtime. Patients should drink about one pint of fluid at bedtime and another pint during the night.
Oral: 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. Patients unable to swallow capsules may mix contents of capsule with fruit juice or chilled pureed fruit (Cuprimine prescribing information [Canada] 2012). Doses ≤500 mg may be administered as single dose; doses >500 mg should be administered in divided doses.
Cystinuria: If administering 4 equal doses is not feasible, administer the larger dose at bedtime. Patients with cystinuria should drink copious amounts of water.
Cystinuria: Treatment of cystinuria.
Wilson disease: Treatment of Wilson disease.
Penicillamine may be confused with penicillin
The Institute for Safe Medication Practices (ISMP) includes this medication (when used for rheumatoid arthritis) among its list of drugs that have a heightened risk of causing significant patient harm when used in error.
Depen [U.S.] may be confused with Depin brand name for nifedipine [India]; Depon brand name for acetaminophen [Greece]; Dipen brand name for diltiazem [Greece]
Pemine [Italy] may be confused with Pamine brand name for methscopolamine [U.S., Canada]
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. 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
Renal: Renal failure
Respiratory: Asthma, bronchiolitis obliterans, hypersensitivity pneumonitis, interstitial pneumonitis, pulmonary fibrosis
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 US 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
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; late-onset rashes (eg, after >6 months) typically recur with rechallenge.
• Anti-glomerular basement membrane (GBM) disease (Goodpasture syndrome): Penicillamine has been associated with fatalities due to anti-GBM disease.
• 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 to 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 to 3 weeks after therapy initiation.
• Gastrointestinal: Taste alteration may occur (rare in Wilson 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.
• Hematologic toxicities: Penicillamine has been associated with fatalities due to agranulocytosis, aplastic anemia, and thrombocytopenia. Monitor for signs/symptoms of leukopenia and thrombocytopenia.
• Hepatotoxicity: Monitor LFTs 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 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. 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. Avoid use in patients with myasthenia gravis (AAN [Narayanaswami 2021]).
• Toxicity symptoms: [US 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.
• 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.
• Lead poisoning: Investigate, identify, and remove sources of lead exposure prior to treatment; do not permit patients to re-enter the contaminated environment until lead abatement has been completed. Consultation with a clinical toxicologist or an expert in the treatment of heavy metal poisoning is highly recommended before initiating chelation therapy. 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; Calello 2018; Chandran 2010); penicillamine should only be used when unacceptable reactions have occurred with edetate CALCIUM disodium and succimer in patients who require chelation (Calello 2018).
• Wilson 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; tolerability may be enhanced by starting with incremental doses (EASL 2012). 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.
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.
• Older adult: Use with caution in the elderly; may be more susceptible to skin rash and/or taste alterations.
• Experienced physician: [US Boxed Warning]: Should be administered under the close supervision of a physician familiar with the toxicity and dosage considerations.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Digoxin: PenicillAMINE may decrease the serum concentration of Digoxin. Risk C: Monitor therapy
Gold Sodium Thiomalate: May enhance the adverse/toxic effect of PenicillAMINE. Specifically, this combination may increase the risk for serious hematologic and/or renal adverse reactions. Risk X: Avoid combination
Mivacurium: PenicillAMINE may enhance the therapeutic effect of Mivacurium. Risk C: Monitor therapy
Polyvalent Cation Containing Products: May decrease the serum concentration of PenicillAMINE. Management: Separate the administration of penicillamine and oral polyvalent cation containing products by at least 1 hour. Risk D: Consider therapy modification
Penicillamine serum levels may be decreased if taken with food. Management: Administer on an empty stomach 1 hour before or 2 hours after meals and at least 1 hour apart from other drugs, milk, antacids, iron-containing products, and zinc-containing products. Certain disease states require further diet adjustment.
Penicillamine-disulphide and cysteine-penicillamine were present in the urine of a newborn following maternal use of penicillamine throughout pregnancy for the treatment of cystinuria (Crawhall 1967).
Birth defects, including congenital cutix laxa and associated defects, have been reported in infants following penicillamine exposure during pregnancy; however, outcome information related to use in pregnancy is limited (AASLD [Roberts 2008]; Dathe 2016).
Continued treatment of Wilson disease during pregnancy protects the mother against relapse. Discontinuation has detrimental maternal and fetal effects. Penicillamine should be decreased to the minimum effective dose during pregnancy to limit fetal exposure during the first trimester, to prevent fetal copper deficiency, and to help promote maternal wound healing if cesarean delivery is planned. Doses may be 25% to 50% of the prepregnancy dose. Close monitoring is recommended (AASLD [Roberts 2008]; EASL 2012).
Use for the treatment of rheumatoid arthritis during pregnancy is contraindicated. Penicillamine should be used for the treatment of cystinuria only if the possible benefits to the mother outweigh the potential risks to the fetus.
It is not known if penicillamine is present in breast milk.
Maternal use of penicillamine may decrease copper and zinc concentrations in breast milk (Kaga 2008). Breastfeeding is not recommended in patients treated for Wilson disease (AASLD [Roberts 2008]; EASL 2012). Breastfeeding is contraindicated by the manufacturer regardless of indication.
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 to 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 to 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 at least 1 hour 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.
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 radiologic examination for renal stones.
Lead poisoning: Serum lead concentration (baseline and 7 to 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 to 3 months) is recommended if proteinuria develops.
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
Onset of action: Rheumatoid arthritis: 2 to 3 months; Wilson disease: 1 to 3 months
Absorption: Rapid but incomplete (40% to 70%); reduced by food, antacids, and iron
Protein binding: >80% to albumin and ceruloplasmin
Metabolism: Hepatic (small amounts metabolized to s-methyl-d-penicillamine)
Half-life elimination: 1.7 to 7 hours (Roberts 2008); large variations exist and a slow elimination phase lasting 4 to 6 days may occur after prolonged treatment has been stopped.
Time to peak, plasma: 1 to 3 hours
Excretion: Urine (primarily as disulfides)
Capsules (Cuprimine Oral)
250 mg (per each): $314.26
Capsules (penicillAMINE Oral)
250 mg (per each): $251.41 - $298.55
Tablets (Depen Titratabs Oral)
250 mg (per each): $86.43
Tablets (penicillAMINE Oral)
250 mg (per each): $65.43
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