Cuprimine (Penicillamine)

CUPRIMINE®

MSD

Penicillamine

Chelating Agent

Action And Clinical Pharmacology: As a chelating agent, penicillamine removes copper and lead from the body. In copper chelation, from in vitro studies which 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. The manner in which lead is chelated is not known. It may be bound in the same way as copper.

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 lgM 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, chronic lead poisoning, 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.

Wilson’s Disease: Treatment has 2 objectives: to minimize dietary intake and absorption of copper and to promote excretion of copper deposited in tissues.

For the second objective, a copper chelating agent is used. Penicillamine is the only one of these agents that is orally effective.

In symptomatic patients, this treatment usually produces marked neurologic improvement, fading of Kayser-Fleischer rings, and gradual amelioration of hepatic dysfunction and psychic disturbances.

Clinical experience to date suggests that life is prolonged with the above regimen.

Noticeable improvement may not occur for 1 to 3 months. Occasionally, neurologic symptoms become worse during the initiation of therapy with penicillamine. Despite this, the drug should not be discontinued permanently. Although temporary interruption may result in clinical improvement of the neurological symptoms, it carries an increased risk of developing a sensitivity reaction upon resumption of therapy (see Precautions).

Treatment of asymptomatic patients has been carried out for over 10 years. Symptoms and signs of the disease appear to be prevented indefinitely if daily treatment with penicillamine can be continued.

Chronic Lead Poisoning: Penicillamine should be considered adjunctive to rigorous control of environmental exposure to lead.

When used in children with chronic lead poisoning, penicillamine should be used only if the children are asymptomatic, have blood lead levels between 50 and 80 µg/deciliter (1 dL=100 mL) whole blood, and: a) have an erythrocyte protoporphyrin level greater than 400 to 500 µg/dL erythrocytes, as determined by a standard free erythrocyte protoporphyrin method (bearing in mind that values differ according to the method used). b) excrete excessive amounts of d-aminolevulinic acid (normal=up to 2 mg/mday), or of coproporphyrin (normal = 2 µg/kg/day), or both.

When using penicillamine to treat chronic lead poisoning in children, it is essential that whole blood lead levels be determined periodically during treatment.

Penicillamine is recommended for use in adults with chronic lead poisoning.

Cystinuria: Conventional treatment is directed at keeping urinary cystine diluted enough to prevent stone formation, keeping the urine alkaline enough to dissolve as much cystine as possible, and minimizing cystine production by a diet low in methionine (the major dietary precursor of cystine). Patients must drink enough fluid to keep urine specific gravity below 1.010, take enough alkali to keep urinary pH at 7.5 to 8, and maintain a diet low in methionine. This diet is not recommended in growing children and probably is contraindicated in pregnancy because of its low protein content (see Precautions).

When these measures are inadequate to control recurrent stone formation, penicillamine may be used as additional therapy. When patients refuse to adhere to conventional treatment, penicillamine may be a useful substitute. It is capable of keeping cystine excretion to near normal values, thereby hindering stone formation and the serious consequences of pyelonephritis and impaired renal function that develop in some patients.

Rheumatoid Arthritis: Because penicillamine can cause severe adverse reactions, its use in rheumatoid arthritis should be restricted to patients who have severe, active disease and who have failed to respond to an adequate trial of conventional therapy. Even then benefit-to-risk ratio should be carefully considered. Other measures, such as rest, physiotherapy, salicylates, and corticosteroids, may need to be used in conjunction with penicillamine (see Precautions).

Contra-Indications: Pregnancy: Except for the treatment of Wilson’s disease or certain cases of cystinuria, use of penicillamine during pregnancy is contraindicated (see Precautions).

Lactation: Although breast milk studies have not been reported in animals or humans, mothers on therapy with penicillamine should not nurse their infants.

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 given to patients with chronic lead poisoning when there is x-ray evidence of lead-containing substances in the gastrointestinal tract. Treatment with the drug may be instituted after the gastrointestinal tract has been cleared of these substances. Studies in animals suggest that penicillamine may be ineffective, and possibly hazardous, if excessive oral ingestion of lead continues during administration of the drug.

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. Patients who have had gold salt therapy discontinued due to a major toxic reaction may be at greater risk of serious adverse reactions with penicillamine but not necessarily of the same type.

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 myasthenia gravis.

Because of the potential for serious hematological and renal adverse reactions occurring at any time, routine urinalysis, white and differential blood cell count, hemoglobin determination, and direct platelet count must be done every 2 weeks for at least 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 should then 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 penicallamine therapy. A progressive fall in either platelet count or WBC in 3 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 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 which exceeds 1 g/24 hours, or proteinura which 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 for the duration 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.

Obliterative bronchiolitis has been reported rarely. The patient should be cautioned to report immediately pulmonary symptoms such as exertional dyspnea, unexplained cough or wheezing. Pulmonary function studies should be considered at that time.

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.

Most of the various forms of pemphigus have occurred during treatment with penicillamine. Pemphigus vulgaris and pemphigus foliaceus are reported most frequently, usually as a late complication of therapy. The seborrhea-like characteristics of pemphigus foliaceus may obscure an early diagnosis. When pemphigus is suspected, penicillamine should be discontinued. Treatment has consisted of high doses of corticosteroids alone or, in some cases, concomitantly with an immunosuppressant. Treatment may be required for only a few weeks or months, but may need to be continued for more than a year.

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.

Should drug fever occur in patients receiving penicillamine, stop the drug. In patients with Wilson’s disease, trientine HCl (where available) or zinc compounds such as zinc sulfate may be tried. In patients with cystinuria, in whom these alternative agents are inappropriate, 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 may often 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 gingivostomatitis 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 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 may theoretically 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 and 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 should also 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.

Tumorigenicity: Long-term animal carcinogenicity studies have not been done with penicillamine. There is a report that 5 of 10 autoimmune disease-prone NZB hybrid mice developed lymphocytic leukemia after 6 months intraperitoneal treatment with a dose of 400 mg/kg penicillamine 5 days/week.

Children: The efficacy of penicillamine in juvenile rheumatoid arthritis has not been established.

Pregnancy: Penicillamine has been shown to be teratogenic in rats when given in doses 6 times higher than the highest dose recommended for human use. Skeletal defects, cleft palates and fetal toxicity (resorptions) have been reported.

There are no controlled studies on the use of penicillamine in pregnant women. Although normal outcomes have been reported, characteristic congenital cutis laxa and associated birth defects have been reported in infants born of mothers who received therapy with penicillamine during pregnancy. Penicillamine should be used in women of childbearing potential only when the expected benefits outweigh the possible hazards. Women on therapy with penicillamine who are of childbearing potential should be apprised of this risk and followed closely for early recognition of pregnancy.

Wilson’s Disease: Reported experience shows that continued treatment with penicillamine throughout pregnancy protects the mother against relapse of the Wilson’s disease, and that discontinuation of penicillamine has deleterious effects on the mother.

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.

Cystinuria: If possible, penicillamine should not be given during pregnancy to women with cystinuria (see Contraindications). There are reports of women with cystinuria on therapy with penicillamine who gave birth to infants with generalized connective tissue defects who died following abdominal surgery. If stones continue to form in these patients, the benefits of therapy to the mothers must be evaluated against the risk of the fetus.

Rheumatoid Arthritis: Penicillamine should not be administered to rheumatoid arthritis patients who are pregnant and should be discontinued promptly in patients in whom pregnancy is suspected or diagnosed.

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.

Lactation: See Contraindications.

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 effects 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 which may be accompanied by fever, arthralgia, or lymphadenopathy have occurred (see Precautions). Some patients may show a lupus erythematosus-like syndrome similar to drug-induced lupus produced by other pharmacological agents (see Warnings and Precautions).

Urticaria and exfoliative dermatitis have occurred.

Thyroiditis has been reported; hypoglycemia in association with anti-insulin antibodies has been reported. These reactions are 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 and pancreatitis. Intrahepatic cholestasis and toxic hepatitis have been reported rarely. 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.

Hematologic: 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, aplastic anemia, and sideroblastic anemia.

Thrombotic thrombocytopenic purpura, hemolytic anemia, red cell aplasia, monocytosis, leukocytosis, eosinophilia, and thrombocytosis have also 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, optic neuritis and peripheral sensory and motor neuropathies (including polyradiculoneuropathy, i.e., Guillain-Barré Syndrome) have been reported. Muscular weakness may or may not occur with the peripheral neuropathies. Visual and psychic disturbances have been reported.

Neuromuscular: Myasthenia gravis: (see Precautions).

Other: Side effects that have been reported rarely include thrombophlebitis; hyperpyrexia (see Precautions); falling hair or alopecia; lichen planus (see Warnings); polymyositis; dermatomyositis; mammary hyperplasia; elastosis perforans serpiginosa; toxic epidermal necrolysis; anetoderma (cutaneous macular atrophy); and Goodpasture’s syndrome, a severe and ultimately fatal glomerulonephritis associated with intra-alveolar hemorrhage (see Warnings). Fatal renal vasculitis also reported. Allergic alveolitis and obliterative bronchiolitis, interstitial pneumonitis and pulmonary fibrosis have been reported in patients with severe rheumatoid arthritis, some of whom were receiving penicillamine. Bronchial asthma also reported.

Increased skin friability, excessive wrinkling of 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.

Symptoms And Treatment Of Overdose: Symptoms: There are no known instances of acute poisoning with penicillamine. In therapeutic doses, however, it may cause a wide variety of adverse reactions. Penicillamine may cause acute sensitivity reactions early in therapy. Cross sensitivity with penicillin may exist.

Treatment: In general, treatment is symptomatic.

Allergic Reactions: Discontinue penicillamine promptly and treat the patient with glucocorticoids, followed by reinstitution of penicillamine in small doses that are increased gradually to the desired amount.

Iron and Pyridoxine Deficiencies: Administer iron and pyridoxine supplementation.

Impairment of Taste: 5 to 10 mg of copper a day can be administered as 5 to 10 drops of a 4% solution of CuSO4 5H2O in fruit juice twice a day. (Do not give copper to patients with Wilson’s disease.)

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.

In all patients receiving penicillamine, it is important that penicillamine be given on an empty stomach, at least 1 hour before meals or 2 hours after 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.

Wilson’s Disease: Optimal dosage can be determined by measurement of urinary copper excretion and the determination of free copper in the serum. 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.

Determination of 24-hour urinary copper excretion is a greatest value in the first week of therapy with penicillamine. In the absence of any drug reaction, a dose between 0.75 and 1.5 g that results in an initial 24-hour cupruresis of over 2 mg should be continued for about 3 months, by which time the most reliable method of monitoring maintenance treatment is the determination of free copper in the serum. This equals the difference between quantitatively determined total copper and ceruloplasmin-copper. Adequately treated patients will usually have less than 10 µg free copper/dL of serum. It is seldom necessary to exceed a dosage of 2 g/day. If the patient is intolerant to therapy with penicillamine, alternative treatment is trientine HCl (where available) or zinc compounds such as zinc sulfate.

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.

Chronic Lead Poisoning: Penicillamine should be given when the gastrointestinal tract is empty of lead-containing substances. It may be given to children by dissolving the contents of the capsules no longer than 5 minutes before administration in a small amount of chilled puréed fruit or fruit juice.

Children: 30 to 40 mg/kg/day, or 600 to 750 mg/mday, not to exceed 750 mg/day, as a single dose or in 2 divided doses at least 2 hours before meals. Treatment should be continued until blood lead levels remain below 40 µg/dL whole blood for 2 consecutive months and at least one of the following is achieved: a. erythrocyte protoporphyrin level decreases to less than 3 to 5 times the average normal level. b. excretion of d-aminolevulinic acid decreases to upper limit of normal. c. excretion of coproporphyrin decreases to upper limit of normal.

Adults: 900 to 1 500 mg a day, in 3 divided doses for 1 to 2 weeks, followed by 750 mg/day in divided doses until blood lead levels are reduced to 60 µg/dL, or until urinary lead excretion remains below 500 µg/L for 2 consecutive months. All doses should be given at least 2 hours before meals.

Cystinuria: It is recommended that penicillamine 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 0.5 L of fluid at bedtime and another 0.5 L 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 dose 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.

The standard nitroprusside cyanide test has been reported useful as a qualitative measure of the effective dose. Add 2 mL of freshly prepared 5% sodium cyanide to 5 mL of a 24-hour aliquot of protein-free urine and let stand 10 minutes. Add 5 drops of freshly prepared 5% sodium nitroprusside and mix. Cystine will turn the mixture magenta. If the result is negative, it can be assumed that cystine excretion is less than 100 mg/g creatinine.

Although penicillamine is rarely excreted unchanged, it also will turn the mixture magenta. If there is any question as to which substance is causing the reaction, a ferric chloride test can be done to eliminate doubt: Add 3% ferric chloride dropwise to the urine. Penicillamine will turn the urine an immediate and quickly fading blue. Cystine will not produce any change in appearance.

Rheumatoid Arthritis: The onset of therapeutic response 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 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: 125 mg to 250 mg administered as a single daily dose 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 no 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) 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: 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 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.

Management of 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 for up to several weeks will usually determine which of these processes is responsible for the arthralgia.

Duration of Therapy: The optimum duration of 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.

Concomitant Drug Therapy: 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 treatment may be required before steroids can be completely eliminated.

Dosage Frequency: 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.

Availability And Storage: 125 mg: Each opaque, yellow and grey capsule marked MSD 672 contains: penicillamine 125 mg, supplied as a white or almost white powder. Nonmedicinal ingredients: D&C Yellow 10, gelatin, iron oxide, lactose, magnesium stearate and titanium dioxide. Gluten- and tartrazine-free. Bottles of 100.

250 mg: Each ivory colored capsule marked MSD 602 contains: penicillamine 250 mg, supplied as a white or almost white powder. Nonmedicinal ingredients: D&C Yellow 10, gelatin, lactose, magnesium stearate and titanium dioxide. Gluten- and tartrazine-free. Bottles of 100.

CUPRIMINE® MSD Penicillamine Chelating Agent

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