Penicillamine is a heavy metal antagonist that chelates copper, iron, mercury, lead, and probably other heavy metals as well as cystine and also is a disease-modifying antirheumatic drug.
Penicillamine is used to promote excretion of copper in the treatment of Wilson disease (hepatolenticular degeneration). In conjunction with penicillamine therapy, a low copper diet (less than 2 mg daily) should be maintained by excluding foods with a high copper content such as chocolate, nuts, shellfish, mushrooms, liver, molasses, broccoli, and copper-enriched cereals.103, 105, 110, 200 If the copper content of the patient's usual drinking water exceeds 100 mcg/L, distilled or demineralized water should be used.200
Wilson disease is an autosomal recessive disorder characterized by mutations in the gene encoding a copper-transporting protein; absence or reduced function of this protein results in decreased hepatocellular excretion of copper into the bile.103, 104, 105, 108, 110, 200 When the accumulation of copper exceeds the storage capacity of hepatocytes, copper is released into the blood and deposited into extrahepatic sites including the brain, kidneys, and cornea.103, 104, 105, 200 Manifestations may include hepatic (e.g., elevated liver enzymes, cirrhosis, splenomegaly, jaundice, liver failure), neurologic (e.g., tremor, incoordination, drooling, dysarthria, dystonia, spasticity), and/or psychiatric (e.g., behavioral changes, depression, anxiety, psychosis) abnormalities, which can range from asymptomatic to life-threatening (e.g., fulminant hepatic failure).103, 104, 105, 108, 110 Copper deposits in the cornea can cause Kayser-Fleischer rings, a common finding in patients with Wilson disease.103, 104, 105, 108 Less common manifestations include renal abnormalities (e.g., aminoaciduria, nephrolithiasis), skeletal abnormalities (e.g., premature osteoporosis, arthritis), cardiomyopathy, pancreatitis, hypoparathyroidism, and infertility or miscarriages.103, 104, 105, 110 Although most patients typically develop symptoms during adolescence or early adulthood, the age of onset can be highly variable.103, 104, 108, 110 Lifelong treatment of patients with Wilson disease is necessary to restore and maintain copper balance.103, 104, 105
The American Association for the Study of Liver Diseases (AASLD) recommends that initial treatment of symptomatic patients with Wilson disease include a chelating agent (i.e., penicillamine or trientine).103 Penicillamine traditionally has been used as the chelating agent of choice because of extensive experience with the drug and evidence of its efficacy; however, approximately 30% of patients experience serious adverse effects requiring discontinuance of the drug.103 Trientine may be better tolerated and should be considered in patients who cannot take penicillamine.103, 104, 105, 110 In symptomatic patients, penicillamine produces improvement of neurologic, corneal, hepatic, and psychiatric manifestations of the disease; however, noticeable improvement may not occur for 1-3 months. Neurologic symptoms may worsen in some patients during initial therapy. Although temporary interruption of therapy may improve neurologic symptoms, the drug should not be discontinued permanently; the risk of hypersensitivity may be increased when therapy is resumed. (See Cautions: Sensitivity Reactions.) Once symptoms and laboratory abnormalities have stabilized with initial chelating therapy (typically after 2-6 months, but potentially up to 5 years), patients may be continued on a lower dosage of the chelating agent or switched to zinc for maintenance therapy.103, 104, 108 Because substantial morbidity and mortality can be prevented by treating asymptomatic/presymptomatic patients, AASLD and other experts recommend that such patients also receive therapy with a chelating agent (generally at a lower dosage than that used in symptomatic patients) or zinc.103, 104, 105, 200 Treatment for Wilson disease should be continued indefinitely unless a liver transplant is performed; discontinuance of therapy is associated with high mortality and can result in clinical decompensation.103, 104, 105, 108
Penicillamine is used to reduce the excretion of cystine and prevent renal calculi development in the treatment of cystinuria and associated nephrolithiasis. Penicillamine should be reserved for cystinuric patients in whom cystine excretion exceeds 300 mg daily and who cannot be successfully treated by the conventional therapy of urine dilution and alkalinization (specific gravity below 1.010 and a pH of 7.5-8) and a low methionine diet. The drug may be administered alone or in addition to conventional therapy. The low methionine diet is not recommended in children and is probably contraindicated during pregnancy because of its low protein content. (See Cautions: Hematologic Effects.) Penicillamine maintains cystine excretion at near normal levels (40-80 mg/day), minimizing stone formation and subsequent pyelonephritis and impaired renal function.
Penicillamine is used in the treatment of rheumatoid arthritis in adults. Because the drug can cause serious adverse effects, the manufacturers state that its use should be restricted to patients who have severe disease and who fail to respond to an adequate trial of conventional therapy; the benefits versus risks of therapy should be carefully considered.199, 200 Penicillamine should be used in conjunction with other measures such as rest, physical therapy, nonsteroidal anti-inflammatory agents (NSAIAs), and corticosteroids when indicated.199, 200
Penicillamine is one of several disease-modifying antirheumatic drugs (DMARDs) that has been used in the management of rheumatoid arthritis.206, 207, 208 (For additional information on the treatment of rheumatoid arthritis, see Uses: Rheumatoid Arthritis, in Methotrexate 10:00.) Most patients with moderate to severe active rheumatoid arthritis benefit from penicillamine therapy. In patients with rheumatoid arthritis, penicillamine appears to slow the progression of the disease, improve grip strength, decrease erythrocyte sedimentation rate and rheumatoid factor, increase hemoglobin, and decrease duration of early morning stiffness. Clinical studies have shown that penicillamine is more effective than placebo for improving various measures of disease activity; however, the drug is associated with substantially higher toxicity than other DMARDs.208 Although frequently used in the past, current use of penicillamine has declined in favor of other DMARDs (e.g., methotrexate) with lower risk to benefit ratio.208, 209
When initiating penicillamine therapy, other antirheumatic drugs usually should be continued. Penicillamine may be used in conjunction with NSAIAs or systemic corticosteroids, but administration of penicillamine with DMARDs that cause blood dyscrasias or adverse renal reactions generally is contraindicated. (See Cautions: Precautions and Contraindications.) Depending upon the patient's response to penicillamine therapy, analgesics and anti-inflammatory drugs may be slowly discontinued, and attempts should be made to carefully taper the dosage of corticosteroids; many months of penicillamine therapy may be required before corticosteroids can be discontinued.199, 200 Improvement from penicillamine therapy occurs slowly and may require 1-3 months before there is clinical evidence of benefit. In patients with rheumatoid arthritis, beneficial effects may persist for 1-3 months after the drug is discontinued.
Safety and efficacy of penicillamine in the management of juvenile rheumatoid arthritis† in children have not been established. Results of preliminary studies have been encouraging, but further evaluation is needed.
Penicillamine has been used in the treatment of lead poisoning†, including that caused by alkyl lead compounds (e.g., tetraethyl lead). The oral efficacy of penicillamine may be especially advantageous if a long period of de-leading is required, although prolonged therapy may be associated with an increased risk of adverse effects, particularly iron deficiency anemia. In addition, the possibility that penicillamine (like edetate calcium disodium) may enhance absorption of lead and increase the amount of lead retained in the body should be considered. Penicillamine is not a substitute for control of the lead hazard, and patients should not be treated prophylactically with any chelating agent. The American Academy of Pediatrics (AAP) states that penicillamine typically has been used for prolonged therapy (e.g., 4-12 weeks) to reduced the total body burden of lead in patients who have received prior chelation therapy (e.g., with edetate calcium disodium and/or dimercaprol).204 However, the AAP currently states that the overall toxicity of penicillamine relegates it to a third-line agent, indicated only when unacceptable reactions have occurred following therapy with oral succimer and edetate calcium disodium (calcium EDTA) and continued therapy is considered important.204
Penicillamine has been used in the treatment of primary biliary cirrhosis† to reduce liver copper concentrations and for its possible favorable influence on the course of the disease; although several studies suggest that penicillamine therapy is beneficial, others do not, and the role of the drug in this condition remains to be clearly established. Penicillamine has been used effectively as an alternative to prednisone for maintenance therapy in patients with chronic active hepatitis†.
Penicillamine has also been used in the treatment of other heavy metal poisonings†, mercury-induced acrodynia† (pink disease), palindromic rheumatism†, macroglobulinemia†, circumscribed and diffuse scleroderma†, porphyria cutanea tarda†, and keratosis follicularis† (Darier's disease). Although the drug has appeared to be beneficial in at least some patients with these conditions, the effectiveness of penicillamine in these disease states has not been established. Available data suggest that penicillamine is ineffective in the treatment of ankylosing spondylitis and motor neuron disease.
Penicillamine is administered orally. For patients who cannot swallow capsules or tablets, the contents of a capsule may be administered in 15-30 mL of chilled pureed fruit or fruit juice. Penicillamine should be given on an empty stomach (i.e., at least 1 hour before or 2 hours after meals, and at least 1 hour apart from any other drug, food, or milk). The last dose should be given at least 3 hours after the evening meal.
Dosage of penicillamine must be individualized according to the condition being treated and the response of the patient.
For the treatment of Wilson disease, penicillamine is given 4 times daily. Dosage should be based on urinary copper excretion and serum free copper concentrations in order to produce and maintain negative copper balance. Determination of urinary copper excretion is of greatest value during the first week of penicillamine therapy; the patient will probably be in negative copper balance if the 24-hour urinary copper excretion is 0.5-1 mg. The usual initial dosage for adults and children is 250 mg 4 times daily. Alternatively, a weight-based dosage of 20 mg/kg daily given in 2-3 divided doses has been suggested for children.103 In patients who cannot tolerate 1 g/day initially, 250 mg daily may be given initially and gradually increased. Unless precluded by adverse drug reactions, penicillamine dosages ranging from 750 mg to 1.5 g daily that produce initial 24-hour cupruresis exceeding 2 mg should be continued for about 3 months. Subsequent dosage preferably should be adjusted according to serum free copper concentrations; such concentrations less than 10 mcg/dL usually are indicative of adequate maintenance dosage. Dosage greater than 2 g/day is seldom necessary.
For the treatment of cystinuria, penicillamine should be given in 4 equal doses daily. If 4 equally divided doses are not feasible, the larger dose should be given at bedtime. If adverse effects require dosage reduction, the bedtime dose should be retained. Dosage should be based on urinary cystine excretion which should be maintained at less than 100 mg daily in patients with a history of renal calculi and/or pain or at 100-200 mg daily in patients without a history of renal calculi. The usual adult dosage of penicillamine is 2 g daily (range 1-4 g daily). Initiating therapy with 250 mg daily and then gradually increasing dosage may reduce the incidence of adverse effects. Children may be given 30 mg/kg daily. In addition to receiving penicillamine, patients should maintain a high fluid intake and should drink 500 mL of water at bedtime and again during the night when urine is most concentrated and most acidic. In general, the greater the fluid intake, the lower the dosage of penicillamine required.
For the treatment of rheumatoid arthritis, the usual initial adult dosage is 125-250 mg daily. Dosage may be increased by 125-250 mg/day at 1- to 3-month intervals according to the patient's response and tolerance. Remission of symptoms is attained and maintained in many patients with 500-750 mg daily. If no improvement and no signs of potentially serious toxicity occur after 2-3 months of therapy with 500-750 mg daily, dosage may be further increased by 250 mg daily at 2- to 3-month intervals until remission or toxicity occurs. Up to 500 mg can be given as a single daily dose; larger dosages should be given in divided doses.199, 200 In patients who respond to penicillamine but in whom disease suppression is incomplete after the first 6-9 months of therapy, the daily penicillamine dosage may be increased by 125-250 mg at 3-month intervals. In the treatment of rheumatoid arthritis, the maximum dosage of penicillamine is usually 1 g daily, but up to 1.5 g daily may be required in some patients. If there is no improvement after 3-4 months of therapy with 1-1.5 g daily, the drug should be discontinued.199, 200 During penicillamine therapy, exacerbation of the disease may occur in some patients and is usually controlled by concomitant administration of nonsteroidal anti-inflammatory drugs.199, 200 If the exacerbation does not subside within 3 months, an increase in the penicillamine maintenance dosage may be considered.199, 200 Optimum duration of penicillamine therapy in patients with rheumatoid arthritis has not been determined; in patients with remission of symptoms for 6 months or longer, reduction of penicillamine maintenance dosage by 125-250 mg/day at about 3-month intervals may be attempted.199, 200
When penicillamine is used as follow-up therapy† after lead poisoning has been treated with edetate calcium disodium (calcium EDTA) and/or dimercaprol or with oral succimer, dosages of 20-30 mg/kg daily generally have been recommended.
For the treatment of primary biliary cirrhosis†, the initial adult dosage of penicillamine is 250 mg daily; this dosage is increased by 250 mg daily every 2 weeks up to a maintenance dosage of 1 g daily (i.e., 250 mg 4 times daily).
Penicillamine causes allergic reactions in about one-third of patients receiving the drug. When therapy is interrupted for even a few days, sensitivity reactions may occur when therapy is reinstituted. The most common allergic reaction is a generalized pruritic, erythematous, maculopapular, or morbilliform rash which occurs early in therapy and is often controlled by concomitant administration of an antihistamine. This early rash usually disappears within a few days after penicillamine is discontinued and seldom recurs when the drug is restarted at a lower dosage. Less commonly, late rash (usually circumscribed, scaly macular lesions on the trunk of the body) with intense pruritus may occur after 6 months or more of therapy. Late rash may persist for weeks after the drug is discontinued, is usually unresponsive to topical corticosteroids, and usually recurs if penicillamine is restarted.
Most forms of pemphigus have been reported in patients receiving penicillamine. Pemphigus vulgaris and pemphigus foliaceous have been reported most frequently and usually develop as late complications of therapy with the drug. The seborrheic characteristics of pemphigus foliaceous may obscure early diagnosis. If pemphigus is suspected, penicillamine should be discontinued. High-dose corticosteroids alone or, occasionally, combined with an immunosuppressant have been used to treat such reactions; the duration of such therapy has varied from a few weeks or months to longer than a year.
Dermatologic reactions may be accompanied by fever, arthralgia, or lymphadenopathy. Drug fever may occur, usually within 2-3 weeks after initiating penicillamine therapy. Other allergic reactions include urticaria and exfoliative dermatitis; thyroiditis has been reported very rarely.
Slight to moderate proteinuria (less than 2 g/24 hours) commonly occurs in patients receiving penicillamine and may improve spontaneously with continued therapy or if dosage is reduced. Hematuria and/or proteinuria may be warnings of an immune complex membranous glomerulopathy which can progress to nephrotic syndrome. One year or longer may be required for these urinary abnormalities to disappear after penicillamine is discontinued.
Adverse hematologic reactions of penicillamine have included leukopenia (granulocytic with or without increased eosinophils), thrombocytopenia (with normal or increased megakaryocytes in the bone marrow or, in patients with aplastic anemia, decreased or absent megakaryocytes), bone marrow depression, thrombotic thrombocytopenia purpura, hemolytic anemia, red cell aplasia, monocytosis, leukocytosis, eosinophilia, and thrombocytosis. Some fatalities have resulted from agranulocytosis, thrombocytopenia, sideroblastic anemia, and aplastic anemia. Development of a positive antinuclear antibody (ANA) test result may occur during penicillamine therapy but does not require that the drug be discontinued. It should be kept in mind that a systemic lupus erythematosus-like syndrome may occur in patients with a positive ANA test result. Migratory polyarthritis may occur and, in rheumatoid arthritis patients, is extremely difficult to distinguish from an exacerbation of their disease. Although a causal relationship to penicillamine has not been established, chronic lymphocytic leukemia has been reported in patients receiving the drug.
Iron deficiency anemia may occur rarely during penicillamine therapy, particularly in premenopausal women and in children. In patients with Wilson disease, this may partly result from the low copper diet which is also low in iron. In cystinuria, the low methionine diet may contribute to iron deficiency since this diet is low in protein. Iron therapy for iron deficiency anemia may be administered for short periods if necessary. However, at least 2 hours should elapse between administration of penicillamine and iron, since orally administered iron decreases the effect of penicillamine, probably by decreasing its absorption. In patients with Wilson disease, sulfurated potash should be discontinued when an oral iron preparation is administered. Mineral supplements (other than iron) should not be given. Sideroblastic anemia also has been reported.200, 201
Penicillamine may cause increased friability of the skin (particularly at pressure or trauma sites such as shoulders, elbows, knees, toes, and buttocks) which may progress to purpuric or vesicular ecchymoses. These ecchymoses are not progressive and apparently are not associated with bleeding elsewhere in the body or with a coagulation defect. The appearance of these lesions does not require discontinuance of therapy and occurs most frequently with daily penicillamine dosages of 2 g or more. If penicillamine dosage is reduced, these lesions may disappear. Excessive wrinkling of the skin and development of small white papules at venipuncture and surgical sites have also occurred in patients receiving penicillamine, probably as a result of the effect of the drug on collagen.
Oral ulcerations which may have the appearance of aphthous stomatitis have occurred and, rarely, cheilosis, glossitis, gingivostomatitis, and ulceration of the vulva and vagina have been reported. Oral lesions often clear when dosage is reduced but may necessitate cessation of therapy in some patients.
Lichen planus, toxic epidermal necrolysis, and anetoderma (cutaneous macular atrophy) have occurred infrequently.
Adverse GI effects of penicillamine may include anorexia, nausea, vomiting, epigastric pain, dyspepsia, occasional diarrhea, and rarely, reactivation of peptic ulcer and acute colitis.
Hepatic dysfunction, cholestatic jaundice, intrahepatic cholestasis, toxic hepatitis, and pancreatitis have occurred rarely. Penicillamine has rarely caused increased serum AST (SGOT), ALT (SGPT), alkaline phosphatase, and LDH concentrations and positive cephalin flocculation and thymol turbidity tests.
Hypogeusia (blunting or diminution of taste perception), particularly for salt or sweet, occurs frequently, and total loss of taste may occur in patients receiving penicillamine. Hypogeusia may persist for 2-3 months or longer but is usually self-limiting, even with continued penicillamine therapy, and occurs only rarely in patients with Wilson disease. Metallic taste has been reported.
Rarely, fatal glomerulonephritis and intra-alveolar hemorrhage (Goodpasture's syndrome) have occurred in patients receiving penicillamine. Myasthenia gravis syndrome has been reported rarely and, in most cases, was reversible when penicillamine was discontinued; ptosis and diplopia, with weakness of the extraocular muscles, often are early signs of the syndrome. Death has resulted from myasthenic syndrome.
Other infrequently reported adverse effects include hyperpyrexia; thrombophlebitis; loss of hair; tinnitus; optic neuritis; visual and psychic disturbances; peripheral sensory and motor neuropathies (with or without muscular weakness), including polyradiculoneuropathy (Guillain-Barré syndrome); dermatomyositis; polymyositis (occasionally fatal); neuromyotonia; myocarditis; hypocomplementemia; hypercholesterolemia; hypoglycemia associated with insulin antibodies elastosis perforans serpiginosa; obliterative bronchiolitis; interstitial pneumonitis; pulmonary fibrosis; bronchial asthma; allergic alveolitis; and fatal renal vasculitis. Hirsutism, emphysema, tingling feet, mammary hyperplasia or gynecomastia, and creaking knee joints also have been reported.
Penicillamine may cause increased excretion of heavy metals such as iron, zinc, lead, and mercury.
Precautions and Contraindications
Penicillamine should only be administered to patients under constant supervision of a physician thoroughly familiar with its toxicity and benefits. The fact that penicillamine can produce severe toxic reactions should always be kept in mind. Although the incidence of adverse effects with penicillamine is high, most reactions respond favorably to discontinuance of the drug.
Because obliterative bronchiolitis has been reported in some patients receiving penicillamine, patients should be instructed to inform their physician promptly if any pulmonary symptom such as exertional dyspnea, unexplained cough, or wheezing occurs; pulmonary function testing should be considered if such symptoms develop.
Because of the possibility of cross-sensitivity between penicillin and penicillamine, penicillamine should be administered with extreme caution, if at all, to patients who are allergic to penicillins; however, cross-sensitivity between the drugs is apparently uncommon.
In patients receiving penicillamine, skin and mucous membranes should be observed for allergic reactions. The manufacturers recommend that urinalyses, differential blood counts, leukocyte counts, hemoglobin determinations, and direct platelet counts be performed twice weekly for the first month of therapy and then every 2 weeks for the next 5 months; monitoring should continue on a monthly basis thereafter.199, 200 Patients should be observed regularly for the development of proteinuria and hematuria which may be a sign of nephrotic syndrome. When penicillamine is administered to patients with cystinuria, an annual radiograph of the kidneys is advisable because cystine stones may form rapidly, sometimes within 6 months. Liver function tests should be performed every 6 months during penicillamine therapy; a monitoring frequency of every 3 months is recommended in patients with Wilson disease, at least during the first year of therapy.199, 200 Patients should be instructed to immediately report any symptoms such as fever, sore throat, chills, or unusual bleeding or bruising which may be indications of hematologic toxicity.
If late rash occurs or if pruritus or rash are accompanied by fever, arthralgia, or lymphadenopathy, penicillamine therapy should usually be withdrawn. If pemphigus occurs, the drug should be discontinued and systemic corticosteroids administered. If drug fever occurs, penicillamine should be temporarily discontinued until fever subsides. This febrile reaction often recurs when penicillamine therapy is reinstituted. If penicillamine is reinstituted in patients with Wilson disease or cystinuria, therapy should be initiated with a small dose that is gradually increased until full dosage is achieved. Systemic corticosteroids may be required in patients who develop drug fever a second or third time. If drug fever occurs in rheumatoid arthritis patients, penicillamine should be permanently discontinued and alternative therapy initiated. Trientine therapy may be a useful alternative for patients with Wilson disease who do not tolerate penicillamine, but not for those with cystinuria or rheumatoid arthritis.
Whenever proteinuria or hematuria occurs, the physician should determine whether it is a symptom of nephrotic syndrome or unrelated to penicillamine. Since Goodpasture's syndrome has occurred rarely in patients receiving penicillamine, the drug should be discontinued if abnormal urinary findings associated with hemoptysis and pulmonary infiltrates occur. In patients with Wilson disease or cystinuria, the risks of penicillamine therapy must be weighed against the benefits if potentially serious urinary abnormalities occur. In rheumatoid arthritis patients, penicillamine should be discontinued if unexplained gross or persistent microscopic hematuria occurs. If proteinuria develops in rheumatoid arthritis patients, dosage of the drug should not be increased, but therapy may be continued cautiously if quantitative 24-hour urinary protein is determined at 1- to 2-week intervals. The manufacturers state that dosage should be reduced or the drug discontinued if proteinuria is greater than 1 g/24 hours or progressively increases in rheumatoid arthritis patients. However, some clinicians discontinue penicillamine only if proteinuria is greater than 2 g/24 hours. If the platelet count decreases to less than 100,000/mm3 (even if bleeding is not observed), the leukocyte count decreases to less than 3500-4000/mm3, or neutropenia occurs, penicillamine should be discontinued, at least temporarily. When therapy is resumed, the initial dose should be small and dosage should be increased cautiously. If the platelet or leukocyte count progressively decreases in 3 successive determinations, even if the values are within the normal range, penicillamine therapy should be at least temporarily suspended.
Because of dietary restrictions in patients with Wilson disease or cystinuria and since penicillamine increases the body's requirement for pyridoxine, these patients should receive 25-50 mg of pyridoxine hydrochloride daily during penicillamine therapy. Rheumatoid arthritis patients with impaired nutrition should receive a daily pyridoxine supplement. If a multivitamin preparation is administered to patients with Wilson disease, it must be copper-free. Some patients have experienced reversible optic neuritis, possibly related to pyridoxine deficiency, following the administration of a racemic mixture of penicillamine. However, symptoms of pyridoxine deficiency have not been reported in patients receiving d-penicillamine.
Because of penicillamine's effect on collagen and elastin, reducing the dosage to 250 mg daily should be considered prior to elective surgery. Full penicillamine therapy should not be reinstituted until wound healing is complete. However, some investigators have noted no delay in wound healing after surgery in patients receiving penicillamine.
Penicillamine is contraindicated in patients with previous penicillamine-related aplastic anemia or agranulocytosis. Concomitant administration of penicillamine with gold salts, antimalarials, immunosuppressants, or phenylbutazone is contraindicated because of the drugs' potential to cause serious adverse hematologic and/or renal reactions. Because penicillamine may cause renal damage, it is contraindicated in rheumatoid arthritis patients with renal insufficiency.
Although penicillamine and captopril are not pharmacologically related, many adverse effects (e.g., rash, taste impairment, proteinuria) of these drugs are similar. Because penicillamine and captopril contain sulfhydryl groups and are structurally related, it has been suggested that the common toxicities may in part result from the chemical and structural characteristics of the drugs; however, such a relationship has not been clearly determined.
Safety and efficacy of penicillamine as a second-line antirheumatic agent in the management of juvenile rheumatoid arthritis in children have not been established; however, results of preliminary studies have been encouraging.
One cystinuric patient treated with penicillamine throughout pregnancy delivered a child with a generalized connective tissue defect which may have been caused by penicillamine. The manufacturers state that, if possible, the drug should not be administered during pregnancy to women with cystinuria. If stones continue to form in cystinuric women, the potential benefits of penicillamine therapy must be weighed against the possible risks.
One woman with rheumatoid arthritis treated with less than 900 mg of penicillamine daily during pregnancy delivered (by cesarean section) 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. The manufacturers state that penicillamine is contraindicated in women with rheumatoid arthritis who are pregnant. The drug should not be used in women with rheumatoid arthritis who may become pregnant unless the possible benefits outweigh the risks; if pregnancy is suspected or occurs in these women during penicillamine therapy, the drug should be discontinued. Women with rheumatoid arthritis receiving penicillamine should be informed about the possible hazards of the drug to the fetus and should be advised to promptly report to their physician any missed menstrual periods or other indication of possible pregnancy.
To date, there have been no reports of serious adverse fetal effects when penicillamine was used for the treatment of Wilson disease in pregnant women. One woman with Wilson disease who received 1.5 g of penicillamine daily during pregnancy delivered an infant with loose body skin; at 9 weeks of age the infant's skin was normal. It appears that continued penicillamine therapy in these patients prevents relapse of Wilson disease and that discontinuance of the drug may be deleterious to the mother; however, dosage should be limited to 750 mg daily.199, 200 In patients with Wilson disease in whom a cesarean section is planned, dosage of penicillamine should be limited to 250 mg daily during the 6 weeks before delivery and postoperatively until wound healing is complete in order to preclude impairment of wound healing.
Although there are no studies to date using penicillamine in nursing women, the manufacturers state that nursing should not be undertaken by women receiving the drug.
Penicillamine chelates copper, iron, mercury, lead, and probably other heavy metals to form stable soluble complexes which are readily excreted by the kidneys. Copper is chelated by the combination of 2 molecules of penicillamine with one atom of the metal. In vitro, 1 g of penicillamine combines with about 200 mg of copper; however, in vivo administration of 1 g of penicillamine results in excretion of only about 2 mg of copper.
Penicillamine also combines chemically with cystine to form penicillamine-cysteine disulfide, a complex which is much more soluble than cystine (cysteine-cysteine disulfide). In cystinuric patients, penicillamine reduces the concentration of cystine in urine to less than that believed to be critical for the formation of cystine stones. In addition, existing stones may be dissolved.
The mechanism of action of penicillamine in the treatment of rheumatoid arthritis is not known but may be related to inhibition of collagen formation. Unlike cytotoxic immunosuppressants, penicillamine markedly decreases immunoglobulin M rheumatoid factor levels but does not appreciably decrease absolute levels of serum immunoglobulins. In vitro, penicillamine depresses T-cell but not B-cell activity and also depolymerizes some macroglobulins (e.g., rheumatoid factors). The relationship of these effects to the activity of the drug in rheumatoid arthritis is not known.
l-Penicillamine also inhibits pyridoxal-dependent enzymes.
Penicillamine is readily absorbed from the GI tract, and peak blood concentrations are attained in 1 hour.
Distribution data on penicillamine have not been published, but one manufacturer states that the drug crosses the placenta.
Very little information is available on the metabolism of the penicillamine that is not excreted as part of a metal or cysteine complex. The drug is believed to be metabolized in the liver and excreted in urine and feces, principally as inactive disulfides: penicillamine disulfide, penicillamine-cysteine disulfide, and small amounts of S -methyl-d-penicillamine. The manufacturers report that penicillamine is rarely excreted unchanged in urine. In one study, about 50% of a dose of penicillamine was excreted in urine, about 20% in feces, and about 30% was unaccounted for after 24 hours.
Penicillamine is a monothiol chelating agent which is a degradation product of all penicillins. Penicillamine has no antibacterial activity. Only the d-isomer of penicillamine is used clinically, and the commercially available drug is produced synthetically. Penicillamine occurs as a white or practically white, crystalline powder with a slight characteristic odor and is freely soluble in water and slightly soluble in alcohol. The drug has pKa values of 1.83, 8.03, and 10.83.
Penicillamine capsules and tablets should be stored in tight containers at 20-25°C and protected from moisture.199, 200
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Only references cited for selected revisions after 1984 are available electronically.
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