Penicillamine is an oral chelating agent. Although it is structurally dissimilar from beta-lactams, penicillamine is identified as a breakdown product of penicillin metabolism. Penicillamine, however, has no antibacterial properties. The D-isomer of penicillamine is used clinically and is prepared synthetically, thereby reducing the incidence of penicillin hypersensitivity reactions. The chelating properties of the drug were discovered in 1953, when it was first found in the urine of patients with liver disease being treated with penicillin. The drug is now used in the removal of excess copper from the circulation of patients with Wilson's disease and in the reduction of cystine excretion in patients with cystinuria. Penicillamine has also been used historically for refractory cases of rheumatoid arthritis, but use is limited due to the potential for myelosuppression, proteinuria, and serious complications of treatment such as autoimmune-mediated diseases.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Penicillamine is administered orally at least 1 hour before or 2 hours after meals and at least 1 hour before or after any other drug, food, or milk. Give last dose 3 hours after the evening meal. Food decreases the oral absorption by about 52%.
-For patients with difficulty swallowing capsules or tablets, the contents of a capsule may be mixed in 15-30 ml of chilled pureed fruit or fruit juice and administered. Alternatively, a 50 mg/ml elixir may be prepared by dissolving forty-eight 250-mg capsules in 100 ml of water, then filter and stir in 100 ml of cherry syrup plus 30 ml of alcohol. Bring the total volume to 240 ml with water. Shake well and store in the refrigerator.
Some patients may experience drug fever, a marked febrile response to penicillamine, usually in the second to third week following initiation of therapy. Drug fever may sometimes be accompanied by a macular cutaneous eruption. In the case of drug fever in patients with Wilson's disease or cystinuria, penicillamine should be temporarily discontinued until the reaction subsides. Then penicillamine should be reinstituted with a small dose that is gradually increased until the desired dosage is attained. Systemic steroid therapy may be necessary, and is usually helpful, in such patients in whom drug fever and rash develop several times. In the case of drug fever in rheumatoid arthritis patients, because other treatments are available, penicillamine should be discontinued and another therapeutic alternative tried since experience indicates that the febrile reaction will recur in a very high percentage of patients upon readministration of penicillamine. Allergic reactions can occur, and patients should be observed for skin and mucous membrane abnormalities. An early rash (unspecified) and pruritus seen in the first few months are typical of drug hypersensitivity; rash is generally a pruritic, erythematous, morbilliform, or maculopapular rash. Early rash usually disappears following discontinuation of the drug. The symptoms can usually be alleviated with an antihistamine. If a late rash, with intense pruritus, develops or if the patient experiences fever, joint pain or myalgia, or lymphadenopathy during treatment, the drug should be discontinued. Late rash generally takes weeks to disappear and reappears upon rechallenge. Rash has been reported in 5% of patients. Migratory joint pain in multiple joints, often with objective synovitis, may occur. Various forms of pemphigus are also common adverse reactions to the drug, and penicillamine should be discontinued if this condition is suspected. There is a possibility that patients could develop exfoliative dermatitis and urticaria. Serious adverse events reported with penicillamine include toxic epidermal necrolysis.
Penicillamine has the potential to produce serious adverse hematologic toxicity. Routine hematological tests should be undertaken every 2 weeks for the first 5 months of penicillamine therapy, followed by monthly tests. Leukopenia and thrombocytopenia have been reported to occur in up to 5% of treated patients; in those treated for rheumatoid arthritis, leukopenia was reported in 2% and thrombocytopenia 4%. Development of thrombocytopenia, agranulocytosis, aplastic anemia, pancytopenia, and sideroblastic anemia can be fatal. Patients should be instructed to promptly report any signs of hematologic toxicity including unusual bleeding, fever, pharyngitis, chills, or bruising (ecchymosis). Hemolysis, including hemolytic anemia, also has been reported. Leukopenia may not be associated with an increase in eosinophils. A confirmed reduced WBC below 35000/mm3 requires discontinuation of therapy. Thrombocytopenia may be idiosyncratic when it is part of aplastic anemia or it may be immune modulated. The development of a platelet count below 100,000/mm3, even without bleeding, requires at least temporary discontinuation of therapy. A progressive fall in either platelet count or WBC in 3 successive determinations, even if values are within normal range, requires at least a temporary discontinuation of therapy. Thrombotic thrombocytopenic purpura (TTP), red cell aplasia, monocytosis, leukocytosis, eosinophilia, thrombocytosis, and thrombophlebitis/phlebitis have also been reported.
Bronchiolitis obliterans has been reported rarely in patients with severe rheumatoid arthritis. Adverse pulmonary effects that occur during administration of penicillamine and may be associated with bronchiolitis obliterans, including exertional dyspnea, cough, or wheezing, should be reported to the patient's physician immediately. Pulmonary function studies may be needed. Additionally, allergic alveolitis, interstitial pneumonitis, and pulmonary fibrosis have been reported in patients with sever rheumatoid arthritis. Bronchial asthma as also been reported.
Due to the risk of serious renal adverse events (nephrotoxicity), routine urinalysis should be performed during the first month, every 2 weeks for the next 5 months, and monthly thereafter in patients receiving penicillamine. Penicillamine-induced hematuria and/or proteinuria (6%) may be indicative of an impending immune-complex membranous glomerulopathy, which can degenerate into nephrotic syndrome. If these effects are indeed determined to be induced by penicillamine, the drug should be discontinued. Rheumatoid arthritis patients who develop moderate proteinuria may be continued on penicillamine if quantitative 24-hour urinary protein determinations are obtained every 1 to 4 weeks. Dosage should not be increased. Proteinuria greater than 1 gram/24 hours, or proteinuria that is progressively increasing, requires a reduction of dose or discontinuation of therapy. Sometimes proteinuria resolves with dosage reduction. Penicillamine should be discontinued with unexplained gross hematuria or persistent microscopic hematuria. Additionally, nephrolithiasis, despite treatment, may occur in patients with Wilson's disease or cystinuria. Renal failure (unspecified) has been reported. Goodpasture's syndrome has occurred rarely with the use of penicillamine. Development of abnormal urinary findings, including fatal glomerulonephritis, hemoptysis, and pulmonary infiltrates requires immediate discontinuation of penicillamine. Intra-alveolar hemorrhage may also be associated with this syndrome. Vasculitis, including fatal renal vasculitis has also been reported.
Adverse GI effects can occur during penicillamine therapy and may occur in up to 17% of patients include nausea, vomiting, anorexia, epigastric pain, and occasional diarrhea. These effects are generally reversible on cessation of therapy. There have been occasional reports of reactivation of peptic ulcer. Additionally, there have been reports of increased serum alkaline phosphate, lactic dehydrogenase, and positive cephalin flocculation and thymol turbidity tests. About 12% of patients report some kind of dysgeusia, generally hypogeusia which appears to be self-limiting, often disappearing after several months of therapy. Hypogeusia is rare and usually self-limited in patients with Wilson's disease, but can last at least 2 to 3 months and may develop into a total loss of taste. Aphthous stomatitis and oral ulceration develop in some patients, but oral lesions that develop are often dose-related. A reduction in dosage usually clears mouth problems, but may preclude any later dosage increase of penicillamine. Rarely cheilosis (cheilitis), glossitis, and gingivostomatitis have been reported.
A myasthenia gravis syndrome has been reported during penicillamine therapy and, although rare, can be fatal. Early warning signs of this syndrome that can progress to myasthenia gravis include ptosis, diplopia, and myasthenia including weakness of extraocular muscles. If penicillamine is withdrawn promptly, symptoms generally disappear. Dystonia, polymyositis, and dermatomyositis have also been reported. Because vitamin B6 deficiency may occur, especially in patients with rheumatoid arthritis, daily vitamin B6 (pyridoxine) supplementation has been recommended to help prevent this issue.
Central nervous system adverse reactions to penicillamine can include tinnitus, peripheral neuropathy, motor neuropathies (including polyradiculoneuropathy, i.e., Guillain-Barre syndrome), and optic neuritis. Muscular weakness may or may not occur with peripheral neuropathies. Onset of new neurological symptoms and worsening of symptoms can occur with penicillamine. Agitation, anxiety, visual and psychic disturbances, and mental disorders have been reported with penicillamine.
Dermatologic adverse events reported with penicillamine include alopecia, lichen planus-like eruption, elastosis perforans serpiginosa, and anetoderma (cutaneous macular atrophy). Increased skin friability, excessive wrinkling of the skin, and the development of small white papules at venipuncture and surgical sites have also occurred. Yellow nail syndrome (nail discoloration) has been reported, but causality is not known..
Rarely reported reactions to penicillamine include thyroiditis, hypoglycemia in association with anti-insulin antibodies.
Due to rare reports of intrahepatic cholestasis and toxic hepatitis with penicillamine, liver function tests are recommended every 6 months during therapy (every 3 months for Wilson's disease). Hepatic dysfunction and hepatic failure have been reported.
Pancreatitis has rarely been reported with the use of penicillamine.
Some patients receiving penicillamine will develop a positive antinuclear antibody (ANA) test and some of these may have lupus-like symptoms similar to other drug-induced lupus. Arthralgia is likely present. A positive ANA test does not mandate discontinuation of therapy; however, this syndrome may develop again in the future.
New primary malignancy may be a possibility with penicillamine therapy. There have been reports associating penicillamine with leukemia; however, a casual relationship has not been established. Mammary hyperplasia (breast gigantism or breast hypertrophy - breast enlargement, a benign condition) has also rarely been reported.
Administration of penicillamine requires an experienced clinician who is familiar with the toxicities, special dosage considerations, and therapeutic benefits. Never use penicillamine casually. Closely and constantly supervise each patient, and instruct patients to promptly report any possible toxicity symptoms. Toxicities include hematologic, renal, neuromuscular, and allergic reactions, some of which have been fatal. Penicillamine is contraindicated in patients with a prior history of penicillamine hypersensitivity. In addition, there is a possibility of cross-sensitivity between penicillin and penicillamine. Penicillamine should be used cautiously in patients known to have a penicillin hypersensitivity. Synthetic penicillamine is less likely to be contaminated with trace amounts of penicillin than drug produced as a degradation product of penicillin. Some patients may experience drug fever, a marked febrile response to penicillamine, usually in the second to third week following initiation of therapy. Drug fever may sometimes be accompanied by a macular cutaneous eruption. In the case of drug fever in patients with Wilson's disease or cystinuria, penicillamine should be temporarily discontinued until the reaction subsides. Then penicillamine should be reinstituted with a small dose that is gradually increased until the desired dosage is attained. Systemic steroid therapy may be necessary, and is usually helpful, in such patients in whom drug fever and rash develop several times. Rheumatoid arthritis patients who have developed fever during prior administration of penicillamine should not be retreated because experience suggests that febrile reactions will recur; alternative treatments are available for rheumatoid arthritis. A serious rash, such as the appearance of toxic epidermal necrolysis (TEN), necessitates penicillamine discontinuation.
Penicillamine should not be used in patients with previous penicillamine-induced agranulocytosis or aplastic anemia. Use is associated with a high incidence of adverse hematological reactions because of bone marrow suppression. The use of penicillamine has been associated with fatalities due to certain diseases such as aplastic anemia, agranulocytosis (severe neutropenia), and thrombocytopenia. Any patient with a history of hematological disease could experience a severe and possibly fatal reaction. A complete blood count, in addition to hemoglobin and direct platelet count should be performed twice a week, together with monitoring of patients skin, lymph nodes, and body temperature during the first month of therapy, every 2 weeks for the next 5 months, and monthly thereafter. Patients should be instructed to report promptly the development of signs and symptoms of granulocytopenia and/or thrombocytopenia such as fever, sore throat, chills, bruising or bleeding; the prescriber should promptly repeat laboratory testing. Leukopenia and thrombocytopenia have been reported to occur in up to 5% of patients during penicillamine therapy. Leukopenia is of the granulocytic series and may or may not be associated with an increase in eosinophils. A confirmed reduction in WBC below 3500/mm3 mandates discontinuance of penicillamine therapy. Thrombocytopenia may be on an idiosyncratic basis, with decreased or absent megakaryocytes in the marrow, when it is part of an aplastic anemia. In other cases the thrombocytopenia is presumably on an immune basis since the number of megakaryocytes in the marrow has been reported to be normal or sometimes increased. The development of a platelet count below 100,000/mm3, even in the absence of clinical bleeding, requires at least temporary cessation of penicillamine therapy. A progressive fall in either platelet count or WBC in three successive determinations, even though values are still within the normal range, likewise requires at least temporary cessation.
Penicillamine should not be used in patients with various forms of pemphigus because this is a common adverse reaction to penicillamine therapy, and the condition can be exacerbated. Pemphigus vulgaris and pemphigus foliaceus are most frequent.
Penicilliamine use is associated with nephrotoxicity, including kidney damage and use is contraindicated in patients with rheumatoid arthritis and a history or other evidence of renal insufficiency, including renal impairment, or renal failure. Proteinuria and/or hematuria may develop during therapy and may be warning signs of membranous glomerulopathy which can progress to a nephrotic syndrome. Close observation of these patients is essential. In some patients the proteinuria disappears with continued therapy; in others, penicillamine must be discontinued. When a patient develops proteinuria or hematuria the physician must ascertain whether it is a sign of drug-induced glomerulopathy or is unrelated to penicillamine. If the drug is used to treat rheumatoid arthritis (RA) patients with mild or moderate proteinuria, continue to monitor the urine-protein concentration and do not increase the dosage. Quantitative 24-hour urinary protein determinations are recommended every 1 to 2 weeks. Proteinuria that exceeds 1 gram/24 hours or proteinuria that is progressively increasing, requires either penicillamine discontinuance or dosage reduction. Proteinuria may resolve with dosage reduction. If unexplained gross hematuria or persistent microscopic hematuria develops in a patient with RA, discontinue penicillamine. For patients with Wilson's disease or cystinuria who have renal defects, the benefit of therapy must be weighed against the risk of exacerbating the underlying renal disease. An annual radiograph (X-ray) for kidney stones (nephrolithiasis) is advised if penicillamine is used for cystinuria. Cystine stones form rapidly, and up to 1 year or more may be required for any urinary abnormalities to disappear after penicillamine discontinuation. Goodpasture's syndrome, a potentially fatal reaction, has been reported in association with penicillamine. Goodpasture's syndrome has occurred rarely. The development of abnormal urinary findings associated with hemoptysis and pulmonary infiltrates on X-ray requires immediate cessation of penicillamine.
Penicillamine can cause fetal harm when administered to a pregnant woman. Use during pregnancy is contraindicated except in the treatment of Wilson's disease and certain patients with cystinuria. In women with Wilson's disease, drug discontinuation during pregnancy may be fatal; continued treatment throughout pregnancy protects the mother against disease relapse. If penicillamine is administered to pregnant patients with Wilson's disease, a maximum daily dosage of 750 mg is recommended. Further dosage adjustments are required in women undergoing caesarean section. If caesarean section is planned the daily dose should be reduced to 250 mg, but not lower, for the last 6 weeks of pregnancy and postoperatively until wound healing is complete. Penicillamine should be used in females of childbearing potential for the treatment of Wilson's disease or certain patients with cystinuria only when the expected benefits outweigh the possible hazards; women should be apprised of the fetal risk and advised to report immediately any missed menstrual periods or other indications of possible pregnancy, and followed closely for early recognition of pregnancy. If penicillamine is used during pregnancy, or if a patient becomes pregnant while taking penicillamine, warn the patient of the potential hazard to the fetus. Prompt discontinuation is recommended for pregnant patients taking penicillamine for rheumatoid arthritis. Avoidance of penicillamine use during pregnancy to women with cystinuria is also recommended. If stones continue to develop in women with cystinuria, weigh the benefits of continued therapy to the mother against the fetal risks. Although adequate human studies have not been carried out, studies in animals have shown adverse fetal effects (i.e., skeletal defects, cleft palates, and fetal toxicity). Characteristic congenital cutis laxa and associated birth defects have been reported in infants whose mothers received penicillamine during pregnancy. Further, a woman with rheumatoid arthritis treated with less than one gram per day during pregnancy gave birth to an infant with growth retardation, flattened face with broad nasal bridge, low set ears, short neck with loose skin folds, and unusually lax body skin. Reports exist of women with cystinuria on penicillamine who gave birth to infants with generalized connective tissue defects who died following abdominal surgery.
Although insufficient data are available on the administration of penicillamine while breast-feeding, the manufacturers recommend that alternative feeding methods be implemented if use of the drug is continued. According to the manufacturer, use during pregnancy is contraindicated, except for the treatment of patients with Wilson's disease or certain patients with cystinuria.
Penicillamine should be used cautiously in patients with diabetes mellitus. Nighttime hypoglycemia has occurred in 2 insulin dependent diabetic patients started on penicillamine. These patients required reductions in their insulin dosages. Also, penicillamine has been implicated in the formation of anti-insulin antibodies in 2 non-diabetic patients.
Because of rare reports of hepatotoxicity, such as intrahepatic cholestasis, jaundice, and toxic hepatitis, liver function tests (LFTs) are recommended every 6 months for the duration of penicillamine therapy. In patients with Wilson's disease, LFTs are recommended every 3 months, at least during the first year of treatment.
Clinical studies of penicillamine did not include sufficient numbers of geriatric patients (>= 65 years) to adequately determine whether they respond differently from younger subjects. Review of reported clinical trials suggest greater risk in the elderly than in younger patients for overall skin rash and abnormality of taste. In general, dose selection for an elderly patient should be cautious, starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drugs. Penicillamine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and careful monitoring of renal function is recommended.
The efficacy of penicillamine in children with juvenile rheumatoid arthritis (JRA) has not been established.
Onset of new neurological symptoms has been reported with penicillamine. Occasionally, neurological symptoms become worse during initiation of therapy. Myasthenic syndrome sometimes progressing to myasthenia gravis has been reported. Ptosis and diplopia, with weakness of the extraocular muscles, are often early signs of myasthenia. In the majority of cases, symptoms of myasthenia have receded after withdrawal of penicillamine.
For the treatment of Wilson's disease (hepatolenticular degeneration):
Oral dosage:
Adults: 250 mg PO 4 times daily, initially. To enhance tolerability, may also start with 250 to 500 mg/day PO, increased by 250 mg increments every 4 to 7 days, to a maximum of 1,000 to 1,500 mg/day, given in 2 to 4 divided doses. Maintenance dose is usually 750 to 1,000 mg/day given in 2 divided doses; doses exceeding 2,000 mg/day are rarely necessary. Adequate maintenance dose is a 24-hour urinary copper excretion of 200 to 500 mcg (3 to 8 micromol/L). In addition, adequate maintenance can be monitored by determination of free copper in serum. Patients should have a serum free copper level of less than 10 mcg/dL.
Pregnant Adult and Adolescent patients: Do not exceed a total dose of 750 mg/day PO. If a cesarean delivery is planned in advance, reduce dose to 250 mg PO daily for the last 6 weeks of pregnancy and postoperatively until wound healing is complete.
Infants*, Children*, and Adolescents*: 10 to 20 mg/kg/day (Max: 1,500 mg/day) PO, rounded to the nearest 250-mg increment, given in 2 to 3 divided doses. Adequate maintenance dose is a 24-hour urinary copper excretion of 200 to 500 mcg (3 to 8 micromol/L). In addition, adequate maintenance can be monitored by determination of free copper in serum. Patients should have a serum free copper level of less than 10 mcg/dL.
For the treatment of cystinuria:
Oral dosage:
Adults: Initially, 250 mg PO daily. Increase gradually to 1 to 4 grams PO per day, given in 4 divided doses (doses greater than 500 mg/day should be given as divided doses), and adjust to achieve urinary cystine excretion of less than 100 mg/day in patients with a history of renal calculi or pain, or 100 to 200 mg/day in patients with no history of renal calculi. Dosage should be accompanied by a high fluid intake; penicillamine requirements are lower the higher the fluid intake.
Infants, Children, and Adolescents: 30 mg/kg/day PO in 4 divided doses (doses greater than 500 mg/day should be given as divided doses). If 4 equal doses are not feasible, the larger dose should be given at bedtime. Dosage should be adjusted to achieve urinary cystine excretion of less than 100 mg daily when renal calculi are present, or 100 to 200 mg daily when renal calculi are not present. Maximum: 4 grams/day.
For the treatment of arsenic toxicity:
Oral dosage:
Adults: 250 mg PO up to 4 times per day, not to exceed 1 g/day PO.
For the treatment of rheumatoid arthritis:
Oral dosage:
Adults: The recommended initial dose is 125 to 250 mg PO once daily. This dose can be increased at 1 to 3 month intervals by 125 to 250 mg/day according to patient response and tolerance (NOTE: Doses greater than 500 mg/day should be given as divided doses). If no response is evident after 2 to 3 months at a daily dose of 500 to 750 mg PO, the dosage may be increased by 250 mg/day at 2 to 3 monthly intervals until remission or intolerance occurs. If there is no improvement at a dose of 1 to 1.5 g/day after 3 to 4 months, assume there will not be a response and penicillamine therapy should be discontinued. The typical maintenance dosage usually ranges 500 to 750 mg PO daily.
-for the treatment of juvenile rheumatoid arthritis (JRA)/juvenile idiopathic arthritis (JIA)*:
Oral dosage:
Children: Initially, 3 mg/kg (250 mg/day or less) PO for 3 months, then 6 mg/kg (500 mg/day or less) PO in 2 divided doses for 3 months. Continue to a maximum of 10 mg/kg/day PO in 3 to 4 divided doses.
For the treatment of lead toxicity*:
Oral dosage:
Adults: 1 to 1.5 g/day PO, divided every 8 to 12 hours for 4 to 12 weeks.
Children: 30 to 40 mg/kg/day PO or 600 to 750 mg/m2/day PO in 2 to 3 divided doses for 4 to 12 weeks. Maximum dose is 1.5 g/day.
For the treatment of rapidly progressive scleroderma (systemic sclerosis)*:
Oral dosage:
Adults: The effects of penicillamine were studied prospectively in 69 patients with rapidly progressing scleroderma of recent onset in an uncontrolled study. Treatment was initiated with a dose of 250 mg PO once daily and increased by 250 mg every 6 weeks (every 4 weeks for cases of fulminant progression) to a dose of 750 to 1500 mg/day (NOTE: Doses greater than 500 mg/day should be given as divided doses). Sixty patients received at least 750 mg/day of penicillamine for at least 6 months. Of these 60 patients, 58 experienced an arrest in the progression of skin sclerosis, followed by a regression characterized by skin softening, increased pliability and the reappearance of sweating and hair. The total body surface of sclerotic skin also improved considerably with therapy. In patients receiving treatment for at least 6 months, scleroderma-related renal disease was uncommon and pulmonary involvement was not progressive. The period of follow-up was variable and ranged from 10 to 171 months. The overall survival in the treatment group was 88%. Of the 9 patients that did not complete 6 months of therapy, 8 died of scleroderma-related causes. The incidence of adverse effects was high; 27 of 69 patients experienced adverse effects that necessitated a reduction in dose, or discontinuation. Two patients died from adverse reactions related to therapy.
Therapeutic Drug Monitoring:
Wilson's disease
-Determination of free copper or non-ceruloplasmin copper (NCC) concentrations in the serum is the most reliable index for monitoring treatment. The difference between quantitatively determined total copper and ceruloplasmin-copper is the serum free copper concentration. Adequately treated patients usually have less than 10 mcg/dL of free copper in serum.
-Adequate maintenance dose is a 24-hour urinary copper excretion of 250 to 500 mcg (3 to 8 micromol/L). Guidelines recommend measuring 24-hour urinary copper excretion at least every 12 months while on therapy. More frequent determination may be needed when compliance is questioned and when medication dosage is adjusted.
-Monitor liver function tests (LFTs), international normalized ratio (INR), complete blood count (CBC) with differential, and urinalysis on a routine basis.
Maximum Dosage Limits:
-Adults
2 g/day PO for Wilson's disease; 1.5 g/day PO for rheumatoid arthritis and lead toxicity; 1 g/day PO for arsenic toxicity; 4 g/day PO for cystinuria.
-Geriatric
2 g/day PO for Wilson's disease; 1.5 g/day PO for rheumatoid arthritis and lead toxicity; 1 g/day PO for arsenic toxicity; 4 g/day PO for cystinuria.
-Adolescents
1.5 g/day PO for Wilson's disease and lead toxicity; 4 g/day PO for cystinuria; 10 mg/kg/day PO for JRA.
-Children
1.5 g/day PO for Wilson's disease and lead toxicity; 4 g/day PO for cystinuria; 10 mg/kg/day PO for JRA.
-Infants
30 mg/kg/day PO.
Patients with Hepatic Impairment Dosing
Penicillamine is metabolized in the liver and may require a dosage adjustment; however, specific guidelines for dosage adjustments in hepatic impairment are not available.
Patients with Renal Impairment Dosing
Penicillamine is primarily excreted in the urine, but specific guidelines for dosage adjustments in renal impairment are not available.
*non-FDA-approved indication
Albuterol; Budesonide: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Aluminum Hydroxide: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Antacids: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Antimalarials: (Major) Do not use penicillamine concurrently with antimalarials due to an increased risk of severe hematologic and renal adverse reactions.
Antithymocyte Globulin: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Artemether; Lumefantrine: (Major) Do not use penicillamine concurrently with antimalarials due to an increased risk of severe hematologic and renal adverse reactions.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Atovaquone: (Major) Do not use penicillamine concurrently with antimalarials due to an increased risk of severe hematologic and renal adverse reactions.
Atovaquone; Proguanil: (Major) Do not use penicillamine concurrently with antimalarials due to an increased risk of severe hematologic and renal adverse reactions.
Auranofin: (Contraindicated) Gold compounds have adverse reactions similar to those of penicillamine. Concomitant use of these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Azelastine; Fluticasone: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Basiliximab: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Beclomethasone: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Betamethasone: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Budesonide: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Budesonide; Formoterol: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Budesonide; Glycopyrrolate; Formoterol: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Calcium Carbonate: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Calcium Carbonate; Magnesium Hydroxide: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Calcium Carbonate; Simethicone: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Calcium; Vitamin D: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Chloroquine: (Major) Do not use penicillamine concurrently with antimalarials due to an increased risk of severe hematologic and renal adverse reactions.
Ciclesonide: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Corticosteroids: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Cortisone: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Deflazacort: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Dexamethasone: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Digoxin: (Moderate) Decreased serum digoxin concentrations have been reported in patients who received digoxin and penicillamine. Measure serum digoxin concentrations before initiating penicillamine. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary.
Ferric Maltol: (Major) In general, oral mineral supplements should not be given since they may block the oral absorption of penicillamine. However, iron deficiency may develop, especially in children and menstruating or pregnant women, or as a result of the low copper diet recommended for Wilson's disease. If necessary, iron may be given in short courses, but since iron and penicillamine each inhibit oral absorption of the other, 2 hours should elapse between administration of penicillamine and iron doses.
Fludrocortisone: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Flunisolide: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Fluticasone: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Fluticasone; Salmeterol: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Fluticasone; Umeclidinium; Vilanterol: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Fluticasone; Vilanterol: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Formoterol; Mometasone: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Foscarnet: (Moderate) The risk of renal toxicity may be increased if foscarnet is used in conjunction with other nephrotoxic agents such as penicillamine.
Gold: (Contraindicated) Gold compounds have adverse reactions similar to those of penicillamine. Concomitant use of these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Hydrocortisone: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Hydroxychloroquine: (Major) Do not use penicillamine concurrently with antimalarials due to an increased risk of severe hematologic and renal adverse reactions.
Iron Salts: (Major) In general, oral mineral supplements should not be given since they may block the oral absorption of penicillamine. However, iron deficiency may develop, especially in children and menstruating or pregnant women, or as a result of the low copper diet recommended for Wilson's disease. If necessary, iron may be given in short courses, but since iron and penicillamine each inhibit oral absorption of the other, 2 hours should elapse between administration of penicillamine and iron doses.
Iron Salts: (Major) In general, oral mineral supplements should not be given since they may block the oral absorption of penicillamine. However, iron deficiency may develop, especially in children and menstruating or pregnant women, or as a result of the low copper diet recommended for Wilson's disease. If necessary, iron may be given in short courses, but since iron and penicillamine each inhibit oral absorption of the other, 2 hours should elapse between administration of penicillamine and iron doses.
Iron: (Major) In general, oral mineral supplements should not be given since they may block the oral absorption of penicillamine. However, iron deficiency may develop, especially in children and menstruating or pregnant women, or as a result of the low copper diet recommended for Wilson's disease. If necessary, iron may be given in short courses, but since iron and penicillamine each inhibit oral absorption of the other, 2 hours should elapse between administration of penicillamine and iron doses.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) In general, oral mineral supplements should not be given since they may block the oral absorption of penicillamine. However, iron deficiency may develop, especially in children and menstruating or pregnant women, or as a result of the low copper diet recommended for Wilson's disease. If necessary, iron may be given in short courses, but since iron and penicillamine each inhibit oral absorption of the other, 2 hours should elapse between administration of penicillamine and iron doses.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) In general, oral mineral supplements should not be given since they may block the oral absorption of penicillamine. However, iron deficiency may develop, especially in children and menstruating or pregnant women, or as a result of the low copper diet recommended for Wilson's disease. If necessary, iron may be given in short courses, but since iron and penicillamine each inhibit oral absorption of the other, 2 hours should elapse between administration of penicillamine and iron doses.
Magnesium Hydroxide: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Magnesium Salts: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Magnesium Sulfate; Potassium Sulfate; Sodium Sulfate: (Major) Administer penicillamine at least 2 hours before or 6 hours after administration of magnesium sulfate; potassium sulfate; sodium sulfate. The absorption of penicillamine may be reduced by chelation with magnesium sulfate.
Mefloquine: (Major) Do not use penicillamine concurrently with antimalarials due to an increased risk of severe hematologic and renal adverse reactions.
Methylprednisolone: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Mometasone: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) In general, oral mineral supplements should not be given since they may block the oral absorption of penicillamine. However, iron deficiency may develop, especially in children and menstruating or pregnant women, or as a result of the low copper diet recommended for Wilson's disease. If necessary, iron may be given in short courses, but since iron and penicillamine each inhibit oral absorption of the other, 2 hours should elapse between administration of penicillamine and iron doses.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) In general, oral mineral supplements should not be given since they may block the oral absorption of penicillamine. However, iron deficiency may develop, especially in children and menstruating or pregnant women, or as a result of the low copper diet recommended for Wilson's disease. If necessary, iron may be given in short courses, but since iron and penicillamine each inhibit oral absorption of the other, 2 hours should elapse between administration of penicillamine and iron doses.
Olopatadine; Mometasone: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Omeprazole; Sodium Bicarbonate: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Polyethylene Glycol; Electrolytes: (Major) Administer penicillamine at least 2 hours before or 6 hours after administration of magnesium sulfate; potassium sulfate; sodium sulfate. The absorption of penicillamine may be reduced by chelation with magnesium sulfate.
Polyethylene Glycol; Electrolytes; Ascorbic Acid: (Major) Administer penicillamine at least 2 hours before or 6 hours after administration of magnesium sulfate; potassium sulfate; sodium sulfate. The absorption of penicillamine may be reduced by chelation with magnesium sulfate.
Prednisolone: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Prednisone: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Primaquine: (Major) Do not use penicillamine concurrently with antimalarials due to an increased risk of severe hematologic and renal adverse reactions.
Pyridoxine, Vitamin B6: (Moderate) Pyridoxine, vitamin B6 excretion can be increased during the administration of penicillamine, possibly causing anemia or peripheral neuritis. Pyridoxine dosages may need to be increased during concomitant administration of penicillamine.
Pyrimethamine: (Major) Do not use penicillamine concurrently with antimalarials due to an increased risk of severe hematologic and renal adverse reactions.
Quinine: (Major) Do not use penicillamine concurrently with antimalarials due to an increased risk of severe hematologic and renal adverse reactions.
Sodium Bicarbonate: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Sodium Ferric Gluconate Complex; ferric pyrophosphate citrate: (Major) In general, oral mineral supplements should not be given since they may block the oral absorption of penicillamine. However, iron deficiency may develop, especially in children and menstruating or pregnant women, or as a result of the low copper diet recommended for Wilson's disease. If necessary, iron may be given in short courses, but since iron and penicillamine each inhibit oral absorption of the other, 2 hours should elapse between administration of penicillamine and iron doses.
Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Major) Penicillamine may chelate with the magnesium in sodium picosulfate; magnesium oxide; anhydrous citric acid solution. Therefore, penicillamine should be taken at least 2 hours before and not less than 6 hours after the administration of sodium picosulfate; magnesium oxide; anhydrous citric acid solution.
Sulfadiazine: (Major) Do not use penicillamine concurrently with antimalarials due to an increased risk of severe hematologic and renal adverse reactions.
Tafenoquine: (Major) Do not use penicillamine concurrently with antimalarials due to an increased risk of severe hematologic and renal adverse reactions.
Triamcinolone: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Vitamin B Complex Supplements: (Moderate) Pyridoxine, vitamin B6 excretion can be increased during the administration of penicillamine, possibly causing anemia or peripheral neuritis. Pyridoxine dosages may need to be increased during concomitant administration of penicillamine.
Penicillamine chelates heavy metals including copper, iron, lead, and mercury, forming stable complexes that can then be excreted by the kidneys. One gram of penicillamine has the potential to combine with 200 mg of copper. When administered to patients with Wilson's disease, however, a 1 gm dose of penicillamine results in excretion of only 2 mg of copper.
Penicillamine complexes with cystine, forming penicillamine-cysteine disulfide. This compound is more soluble than cysteine-cysteine disulfide (cystine), thereby reducing the levels of free urinary cystine below those considered crucial to the formation of cystine stones. Existing stones also may undergo dissolution during penicillamine therapy.
Penicillamine's antirheumatic action may be due, in part, to the drug's ability to inhibit the formation of collagen. Penicillamine also appears to depress circulating levels of IgM rheumatoid factor, but, in contrast to cytotoxic immunosuppressants, the drug does not reduce the absolute levels of serum immunoglobulins. Penicillamine depresses T-cell activity but not B-cell activity.
Penicillamine is administered orally. The distribution of penicillamine is not well known, but it is believed to cross the placenta. Protein binding is about 80%, primarily to albumin. The drug also binds to erythrocytes and macrophages. Penicillamine appears in the plasma as free penicillamine, penicillamine disulfide, and cysteine-penicillamine disulfide. A small fraction of the dose is metabolized in the liver to s-methyl-D-penicillamine. Drug excretion is primarily renal, mainly as disulfides. One study determined that, of a total dose of penicillamine, approximately 50% was excreted in the urine and 20% in the feces. Approximately 30% of the drug remained unaccounted for. When prolonged treatment is stopped, there is a slow elimination phase lasting 4-6 days.
-Route-Specific Pharmacokinetics
Oral Route
Penicillamine is rapidly absorbed from the GI tract following oral administration. Bioavailability is about 40-70%. Peak serum levels occur within 1-3 hours. The presence of food, antacids, or iron in the GI tract will slow absorption by complexing with the drug.