Action And Clinical Pharmacology: As a chelating agent, penicillamine removes copper from the body. In vitro studies indicate that one atom of copper combines with 2 molecules of penicillamine. It would appear that 1 g of penicillamine should be followed by the excretion of about 200 mg of copper; however, the actual amount excreted is about 1% of this.
Penicillamine also reduces excess cystine excretion in cystinuria. This is done, at least in part, by disulfide interchange between penicillamine and cystine, resulting in formation of penicillamine-cysteine disulfide, a substance that is much more soluble than cystine and is excreted readily. Penicillamine interferes with the formation of cross-links between tropocollagen molecules and cleaves them when newly formed.
The mechanism of action of penicillamine in rheumatoid arthritis is unknown although it appears to suppress disease activity. Unlike cytotoxic immunosuppressants, penicillamine markedly lowers IgM rheumatoid factor but produces no significant depression in absolute levels of serum immunoglobulins. Also, unlike cytotoxic immunosuppressants which act on both, penicillamine in vitro depresses T cell activity but not B cell activity.
In vitro, penicillamine dissociates macroglobulins (rheumatoid factor) although the relationship of the activity to its effect in rheumatoid arthritis is not known.
Indications And Clinical Uses: The treatment of Wilson’s disease, cystinuria, and in patients with severe, active rheumatoid arthritis who have failed to respond to an adequate trial of conventional therapy. Available evidence suggests that penicillamine is not of value in ankylosing spondylitis. Because of the severe toxicity of this agent, penicillamine should never be used casually.
Contra-Indications: Pregnancy: Patients with rheumatoid arthritis who are or who may become pregnant (see Precautions).
Patients with a history of penicillamine related aplastic anemia or agranulocytosis should not be restarted on penicillamine (see Precautions and Adverse Effects).
Because of its potential for causing renal damage, penicillamine should not be administered to rheumatoid arthritis patients with a history or other evidence of renal insufficiency.
Penicillamine should not be used in patients who are receiving gold therapy, antimalarial or cytotoxic drugs, oxyphenbutazone or phenylbutazone because these drugs are also associated with similar serious hematologic and renal adverse reactions.
Manufacturers’ Warnings In Clinical States: The use of penicillamine has been associated with fatalities due to certain diseases such as aplastic anemia, agranulocytosis, thrombocytopenia, Goodpasture’s syndrome, and myasthenic syndrome.
Because of the potential for serious hematological and renal adverse reactions, routine urinalysis, white and differential blood cell count, hemoglobin determination, and direct platelet count must be done every 2 weeks for the first 6 months of penicillamine therapy 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 above laboratory studies then should be promptly repeated.
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 3 500 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, 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.
Proteinuria and/or hematuria may develop during therapy and these 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. Rheumatoid arthritis patients who develop moderate degrees of proteinuria may be continued cautiously on penicillamine therapy, provided that quantitative 24 hour urinary protein determinations are obtained at intervals of 1 to 2 weeks. Penicillamine dosage should not be increased under these circumstances. Proteinuria that exceeds 1 g/24 hours, or proteinuria that is progressively increasing, requires either discontinuance of the drug or a reduction in the dosage. In some patients, proteinuria has been reported to clear following reduction in dosage.
In rheumatoid arthritis patients penicillamine should be discontinued if unexplained gross hematuria or persistent microscopic hematuria develops.
In patients with Wilson’s disease or cystinuria the risks of continued penicillamine therapy in patients manifesting potentially serious urinary abnormalities must be weighed against the expected therapeutic benefits.
When penicillamine is used in cystinuria, an annual x-ray for renal stones is advised. Cystine stones form rapidly, sometimes in 6 months.
Up to 1 year or more may be required for any urinary abnormalities to disappear after penicillamine has been discontinued.
Because of rare reports of intrahepatic cholestasis and toxic hepatitis, liver function tests are recommended every 6 months during the first 18 months of therapy.
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.
A myasthenic syndrome has been reported. In the majority of cases, symptoms of myasthenia have receded after withdrawal of penicillamine.
Pemphigoid type reactions characterized by bullous lesions clinically indistinguishable from pemphigus have occurred and have required discontinuation of penicillamine and treatment with corticosteroids.
Once instituted for Wilson’s disease or cystinuria, treatment with penicillamine should, as a rule, be continued on a daily basis. Interruptions for even a few days have been followed by sensitivity reactions after reinstitution of therapy.
Precautions: 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, because no alternative treatment is available, 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 toxic reactions develop a second or third time.
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.
The skin and mucous membranes should be observed for allergic reactions. Early and late rashes have occurred. Early rash occurs during the first few months of treatment and is more common. It is usually a generalized pruritic, erythematous, maculopapular or morbilliform rash and resembles the allergic rash seen with other drugs. Early rash usually disappears within days after stopping penicillamine and seldom recurs when the drug is restarted at a lower dosage. Pruritus and early rash often may be controlled by the concomitant administration of antihistamines. Less commonly, a late rash may be seen, usually after 6 months or more of treatment, and requires discontinuation of penicillamine. It is usually on the trunk, is accompanied by intense pruritus, and is usually unresponsive to topical corticosteroid therapy. Late rash may take weeks to disappear after penicillamine is stopped and usually recurs if the drug is restarted.
The appearance of a drug eruption accompanied by fever, arthralgia, lymphadenopathy or other allergic manifestations usually requires discontinuation of penicillamine.
Certain patients will develop a positive antinuclear antibody (ANA) test and some of these may show a lupus erythematosus like syndrome similar to drug induced lupus associated with other drugs. The lupus erythematosus like syndrome is not associated with the hypocomplementemia and may be present without nephropathy. The development of a positive ANA test does not mandate discontinuance of the drug; however, the physician should be alerted to the possibility that a lupus erythematosus like syndrome may develop in the future.
Some patients may develop oral ulcerations which in some cases have the appearance of aphthous stomatitis. The stomatitis usually recurs on rechallenge but often clears on a lower dosage. Although rare, cheilosis, glossitis and gingivo-stomatitis have also been reported. These oral lesions are frequently dose related and may preclude further increase in penicillamine dosage or require discontinuation of the drug.
Hypogeusia (a blunting or diminution in taste perception) has occurred in some patients. This may last 2 to 3 months or more and may develop into a total loss of taste; however, it is usually self limited despite continued penicillamine treatment. Such taste impairment is rare in patients with Wilson’s disease.
Patients who are allergic to penicillin theoretically may have cross-sensitivity to penicillamine. The possibility of reactions from contamination of penicillamine by trace amounts of penicillin, has been eliminated now that penicillamine is being produced synthetically rather than as a degradation product of penicillin.
Because of their dietary restrictions, patients with Wilson’s disease or cystinuria should be given 25 mg/day of pyridoxine during therapy, since penicillamine increases the requirement for this vitamin. Patients also may receive benefit from a multivitamin preparation, although there is no evidence that deficiency of any vitamin other than pyridoxine is associated with penicillamine. In Wilson’s disease, multivitamin preparations must be copper free. Rheumatoid arthritis patients whose nutrition is impaired also should be given a daily supplement of pyridoxine. Mineral supplements should not be given, since they may block the response to penicillamine.
Iron deficiency may develop, especially in children and in menstruating women.
In Wilson’s disease, this may be a result of adding the effects of the low copper diet, which is probably also low in iron, and the penicillamine to the effects of blood loss or growth. In cystinuria, a low methionine diet may contribute to iron deficiency, since it is necessarily low in protein. If necessary, iron may be given in short courses, but a period of 2 hours should elapse between administration of penicillamine and iron, since orally administered iron has been shown to reduce the effects of penicillamine.
Penicillamine causes an increase in the amount of soluble collagen. In the rat this results in inhibition of normal healing and also a decrease in tensile strength of intact skin. In man this may be the cause of increased skin friability at sites especially subject to pressure or trauma, such as shoulders, elbows, knees, toes, and buttocks. Extravasations of blood may occur and may appear as purpuric areas, with external bleeding if the skin is broken, or as vesicles containing dark blood. Neither type is progressive. There is no apparent association with bleeding elsewhere in the body and no associated coagulation defect has been found. Therapy with penicillamine may be continued in the presence of these lesions. They may not recur if dosage is reduced.
Other reported effects probably due to the action of penicillamine on collagen are excessive wrinkling of the skin and development of small, white papules at venipuncture and surgical sites.
The effects of penicillamine on collagen and elastin make it advisable to consider a reduction in dosage to 250 mg/day when surgery is contemplated. Reinstitution of full therapy should be delayed until wound healing is complete.
Long-term animal carcinogenicity studies have not been done with penicillamine. There is a report that five of ten autoimmune disease-prone NZB hybrid mice developed lymphocytic leukemia after 6 months’ intraperitoneal treatment with a dose of 400 mg/kg penicillamine 5 days per week.
Penicillamine has been shown to be teratogenic in rats when given in doses several times higher than the highest dose recommended for human use. Skeletal defects, cleft palates and fetal toxicity (resorptions) have been reported.
Pregnancy: There are no controlled studies in pregnant women with Wilson’s disease, but experience does not include any positive evidence of adverse effects on the fetus. Reported experience shows that continued treatment with penicillamine throughout pregnancy protects the mother against relapse of Wilson’s disease, and that discontinuation of penicillamine has deleterious effects on the mother. It suggests that the drug may not increase the risks of fetal abnormalities, but it does not exclude the possibility of infrequent or subtle damage to the fetus. If penicillamine is administered during pregnancy to patients with Wilson’s disease, it is recommended that the daily dosage be limited to 1 g. If cesarean section is planned, the daily dosage should be limited to 250 mg during the last 6 weeks of pregnancy and postoperatively until wound healing is complete.
If possible, penicillamine should not be given during pregnancy to women with cystinuria. There is a report of a woman with cystinuria treated with 2 g/day of penicillamine during pregnancy who gave birth to a child with a generalized connective tissue defect that may have been caused by penicillamine. If stones continue to form in these patients, the benefits of therapy to the mother must be evaluated against the risk to the fetus.
Penicillamine should not be administered to rheumatoid arthritis patients who are pregnant (see Contraindications) and should be discontinued promptly in patients in whom pregnancy is suspected or diagnosed. Penicillamine should be used in women of childbearing potential only when the expected benefits outweigh possible hazards. Women of child bearing potential should be informed of the possible hazards of penicillamine to the developing fetus and should be advised to discontinue penicillamine if they plan to become pregnant and to report promptly any missed menstrual periods or other indications of possible pregnancy while taking the drug.
There is a report that a woman with rheumatoid arthritis treated with less than 1 g a day of penicillamine during pregnancy gave birth (cesarean delivery) 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.
The efficacy of penicillamine in juvenile rheumatoid arthritis has not been established.
Adverse Reactions: Penicillamine is a drug with a high incidence of untoward reactions, some of which are potentially fatal. Therefore, it is mandatory that patients receiving penicillamine therapy remain under close medical supervision throughout the period of drug administration (see Precautions).
Reported incidences (%) for the most commonly occurring adverse reactions in rheumatoid arthritis patients are noted, based on 17 representative clinical trials reported in the literature (1 270 patients).
Allergic: Generalized pruritus, early and late rashes (5%), pemphigoid-type reactions, and drug eruptions that may be accompanied by fever, arthralgia, or lymphadenopathy have occurred (see Warnings and Precautions). Some patients may show a lupus erythematosus-like syndrome similar to that produced by other pharmacological agents (see Precautions).
Urticaria and exfoliative dermatitis have occurred.
Thyroiditis has been reported but is extremely rare.
Some patients may develop a migratory polyarthralgia, often with objective synovitis (see Dosage).
Gastrointestinal: Anorexia, epigastric pain, nausea, vomiting, or occasional diarrhea may occur (17%).
Isolated cases of reactivated peptic ulcer have occurred, as have hepatic dysfunction, cholestatic jaundice, and pancreatitis. There have been a few reports of increased serum alkaline phosphatase, lactic dehydrogenase, and positive cephalin flocculation and thymol turbidity tests.
Some patients may report a blunting, diminution, or total loss of taste perception (12%); or may develop oral ulcerations. Although rare, cheilosis, glossitis, and gingivostomatitis have been reported (see Precautions).
Gastrointestinal side effects are usually reversible following cessation of therapy.
Hematological: Penicillamine can cause bone marrow depression (see Warnings). Leukopenia (2%) and thrombocytopenia (4%) have occurred. Fatalities have been reported as a result of thrombocytopenia, agranulocytosis, and aplastic anemia.
Thrombotic thrombocytopenic purpura, hemolytic anemia, red cell aplasia, monocytosis, leukocytosis, eosinophilia, and thrombocytosis also have been reported.
Renal: Patients on penicillamine therapy may develop proteinuria (6%) and/or hematuria which, in some, may progress to the development of the nephrotic syndrome as a result of an immune complex membranous glomerulopathy (see Warnings).
CNS: Tinnitus has been reported. Reversible optic neuritis has been reported following administration of the racemic penicillamine (dl-form) and may be related to pyridoxine deficiency.
Other: Side effects that have been reported rarely include thrombophlebitis; hyperpyrexia (see Precautions); falling hair or alopecia; myasthenic syndrome (see Warnings); polymyositis; dermatomyositis; mammary hyperplasia; elastosis (cutaneous macular atrophy); and Goodpasture’s syndrome, a severe and ultimately fatal glomerulonephritis associated with intraalveolar hemorrhage (see Warnings). Allergic alveolitis and obliterative bronchiolitis have been reported in patients with severe rheumatoid arthritis, some of whom were receiving penicillamine.
Increased skin friability, excessive wrinkling of the skin, and development of small white papules at venipuncture and surgical sites have been reported (see Precautions).
The chelating action of the drug may cause increased excretion of other heavy metals such as zinc and mercury.
Dosage And Administration: 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.
Wilson’s Disease: Penicillamine should be given on an empty stomach, 4 times a day; 1/2 to 1 hour before meals, and at bedtime, at least 2 hours after the evening meal.
Optimal dosage can be determined only by measurement of urinary copper excretion. The urine must be collected in copper free glassware, and should be quantitatively analyzed for copper before, and soon after, initiation of therapy with penicillamine. Continued therapy should be monitored by doing a 24 hour urinary copper analysis every 3 months or so for the duration of therapy. Since a low copper diet should keep copper absorption down to less than 1 mg a day, the patient probably will be in negative copper balance if 0.5 to 1 mg of copper is present in a 24 hour collection of urine.
To achieve this, the suggested initial dosage of penicillamine in the treatment of Wilson’s disease is 1 g/day for children or adults. This may be increased, as indicated by the urinary copper analyses, but it is seldom necessary to exceed a dosage of 2 g/day.
In patients who cannot tolerate as much as 1 g/day initially, initiating dosage with 250 mg/day, and increasing gradually to the requisite amount, gives closer control of the effects of the drug and may help to reduce the incidence of adverse reactions.
Cystinuria: Penicillamine should be used along with conventional therapy. By reducing urinary cystine, it decreases crystalluria and stone formation. In some instances, it has been reported to decrease the size of, and even to dissolve, stones already formed.
The usual dosage of penicillamine in the treatment of cystinuria is 2 g/day for adults, with a range of 1 to 4 g/day. For children, dosage can be based on 30 mg/kg/day. The total daily amount should be divided into 4 doses. If 4 equal doses are not feasible, give the larger portion at bedtime. If adverse reactions necessitate a reduction in dosage, it is important to retain the bedtime dose.
Initiating dosage with 250 mg/day, and increasing gradually to the requisite amount, gives closer control of the effects of the drug and may help to reduce the incidence of adverse reactions.
In addition to taking penicillamine, patients should drink copiously. It is especially important to drink about a pint of fluid at bedtime and another pint once during the night when urine is more concentrated and more acid than during the day. The greater the fluid intake, the lower the required dosage of penicillamine.
Dosage must be individualized to an amount that limits cystine excretion to 100 to 200 mg/day in those with no history of stones, and below 100 mg in those who have had stone formation and/or pain. Thus, in determining dosage, the inherent tubular defect, the patient’s size, age and rate of growth, and his diet and water intake all must be taken into consideration.
Rheumatoid Arthritis: In rheumatoid arthritis, the onset of therapeutic response to penicillamine may not be seen for 2 or 3 months. In those patients who respond, however, the first evidence of suppression of symptoms such as pain, tenderness, and swelling is generally apparent within 3 months. The optimum duration of therapy has not been determined. If remissions occur, they may last from months to years, but usually require continued treatment.
In patients with rheumatoid arthritis, it is important that penicillamine be given on an empty stomach, at least 1 hour before meals and at least 1 hour apart from any other drug, food, or milk. This permits maximum absorption and reduces the likelihood of inactivation by metal binding.
When treatment with penicillamine has been interrupted because of adverse reactions or other reasons, the drug should be reintroduced cautiously by starting with a lower dosage and increasing slowly.
Initial: The recommended dosage regimen in rheumatoid arthritis begins with a single daily dose of 125 mg to 250 mg which is thereafter increased at 1 to 3 month intervals, by 125 mg to 250 mg/day, as patient response and tolerance indicates. If a satisfactory remission of symptoms is achieved, the dose associated with the remission should be continued (see Maintenance Therapy). If there is no improvement and there are signs of potentially serious toxicity after 2 to 3 months of treatment with doses of 500 to 750 mg/day, increases of 125 mg to 250 mg/day at 2 to 3 month intervals may be continued until a satisfactory remission occurs (see Maintenance Therapy) or signs of toxicity develop (see Warnings and Precautions). If there is no discernible improvement after 3 to 4 months of treatment with 1 000 to 1 500 mg of penicillamine/day, it may be assumed the patient will not respond and penicillamine should be discontinued.
Maintenance: The maintenance dosage of penicillamine must be individualized, and may require adjustment during the course of treatment. Many patients respond satisfactorily to a dosage within the 500 to 750 mg/day range. Some need less.
Changes in maintenance dosage levels may not be reflected clinically or in the erythrocyte sedimentation rate for 2 to 3 months after each dosage adjustment.
Some patients will subsequently require an increase in the maintenance dosage to achieve maximal disease suppression. In those patients who do respond, but who evidence incomplete suppression of their disease after the first 6 to 9 months of treatment, the daily dosage of penicillamine may be increased by 125 mg to 250 mg/day at 3 month intervals. It is unusual in current practice to employ a dosage in excess of 1 g/day, but up to 1.5 g/day has sometimes been required.
Exacerbations: During the course of treatment some patients may experience an exacerbation of disease activity following an initial good response. These may be self-limited and can subside within 12 weeks. They are usually controlled by the addition of nonsteroidal anti-inflammatory drugs, and only if the patient has demonstrated a true escape phenomenon (as evidenced by failure of the flare to subside within this time period) should an increase in the maintenance dose ordinarily be considered.
In the rheumatoid patient, migratory polyarthralgia due to penicillamine is extremely difficult to differentiate from an exacerbation of the rheumatoid arthritis. Discontinuance or a substantial reduction in dosage of penicillamine therapy for up to several weeks will usually determine which of these processes is responsible for the arthralgia.
The optimum duration of penicillamine therapy in rheumatoid arthritis has not been determined. If the patient has been in remission for 6 months or more, a gradual, stepwise dosage reduction in decrements of 125 mg to 250 mg/day at approximately 3 month intervals may be attempted.
Penicillamine should not be used in patients who are receiving gold therapy, antimalarial or cytotoxic drugs, oxyphenbutazone, or phenylbutazone (see Contraindications). Other measures, such as salicylates, other nonsteroidal anti-inflammatory drugs, or systemic corticosteroids, may be continued when penicillamine is initiated. After improvement commences, analgesic and anti-inflammatory drugs may be slowly discontinued as symptoms permit. Steroid withdrawal must be done gradually, and many months of penicillamine treatment may be required before steroids can be completely eliminated.
Based on clinical experience, dosages up to 500 mg/day can be given as a single daily dose. Dosages in excess of 500 mg/day should be administered in divided doses.
The standard nitroprusside cyanide test has been reported useful as a qualitative measure of the effective dose.
Availability And Storage: Each ellipsoid white, coated tablet, intagliated “37-4401” on one side and “Wallace” on other side, contains: penicillamine 250 mg. Nonmedicinal ingredients: cellulose, edetate disodium, lactose, magnesium stearate, magnesium trisilicate, polyethylene glycol, povidone, simethicone, starch and stearic acid. Energy: 2.9 kJ (0.7 kcal). Sodium: 0.21 mg. Gluten- and tartrazine-free. Bottles of 100. (Shown in Product Recognition Section)
DEPEN® Carter Horner Penicillamine Chelating Agent