penicillamine

INDICATIONS Penicillamine capsules are indicated in 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 capsules are not of value in ankylosing spondylitis. Wilson’s Disease Wilson's disease (hepatolenticular degeneration) occurs in individuals who have inherited an autosomal-recessive defect that leads to an accumulation of copper far in excess of metabolic requirements. The excess copper is deposited in several organs and tissues, and eventually produces pathological effects primarily in the liver, where damage progresses to postnecrotic cirrhosis, and in the brain, where degeneration is widespread. Copper is also deposited as characteristic, asymptomatic, golden-brown Kayser-Fleischer rings in the corneas of all patients with cerebral symptomatology and some patients who are either asymptomatic or manifest only hepatic symptomatology. Two types of patients require treatment for Wilson's disease: (1) the symptomatic, and (2) the asymptomatic in whom it can be assumed the disease will develop in the future if the patient is not treated. The diagnosis, if suspected on the basis of family or individual history or physical examination, can be confirmed if the plasma copper-protein ceruloplasmin** is less than 20 mg/dL and either a quantitative determination in a liver biopsy specimen shows an abnormally high concentration of copper (greater than 250 mcg/g dry weight) or Kayser-Fleischer rings are present. Treatment has two objectives: (1) to minimize dietary intake of copper; (2) to promote excretion and complex formation (i.e., detoxification) of excess tissue copper. The first objective is attained by a daily diet that contains no more than 1 or 2 mg of copper. Such a diet should exclude, most importantly, chocolate, nuts, shellfish, mushrooms, liver, molasses, broccoli, and cereals and dietary supplements enriched with copper, and be composed to as great an extent as possible of foods with a low copper content. Distilled or demineralized water should be used if the patient's drinking water contains more than 0.1 mg/L of copper. For the second objective, a copper chelating agent is used. 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 initiation of therapy with penicillamine capsules. Despite this, the drug should not be withdrawn. Temporary interruption carries an increased risk of developing a sensitivity reaction upon resumption of therapy, although it may result in clinical improvement of neurological symptoms (see WARNINGS ). If the neurological symptoms and signs continue to worsen for a month after the initiation of penicillamine capsules therapy, several short courses of treatment with 2,3-dimercaprol (BAL) while continuing penicillamine capsules may be considered. Treatment of asymptomatic patients has been carried out for over 30 years. Symptoms and signs of the disease appear to be prevented indefinitely if daily treatment with penicillamine capsules are continued. Cystinuria Cystinuria is characterized by excessive urinary excretion of the dibasic amino acids, arginine, lysine, ornithine, and cystine, and the mixed disulfide of cysteine and homocysteine. The metabolic defect that leads to cystinuria is inherited as an autosomal-recessive trait. Metabolism of the affected amino acids is influenced by at least two abnormal factors: (1) defective gastrointestinal absorption and (2) renal tubular dysfunction. Arginine, lysine, ornithine, and cysteine are soluble substances, readily excreted. There is no apparent pathology connected with their excretion in excessive quantities. Cystine, however, is so slightly soluble at the usual range of urinary pH that it is not excreted readily, and so crystallizes and forms stones in the urinary tract. Stone formation is the only known pathology in cystinuria. Normal daily output of cystine is 40 to 80 mg. In cystinuria, output is greatly increased and may exceed 1 g/day. At 500 to 600 mg/day, stone formation is almost certain. When it is more than 300 mg/day, treatment is indicated. 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 capsules may be used as additional therapy, and when patients refuse to adhere to conventional treatment, penicillamine capsules 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. Bartter and colleagues depict the process by which penicillamine interacts with cystine to form penicillamine-cysteine mixed disulfide as: CSSC + PS' CS' + CSSP PSSP + CS' PS' + CSSP CSSC + PSSP' 2CSSP CSSC = cystine CS' = deprotonated cysteine PSSP = penicillamine disulfide PS' = deprotonated penicillamine sulfhydryl CSSP = penicillamine-cysteine mixed disulfide In this process, it is assumed that the deprotonated form of penicillamine, PS', is the active factor in bringing about the disulfide interchange. Rheumatoid Arthritis Because penicillamine capsules 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, should be used, when indicated, in conjunction with penicillamine capsules (see PRECAUTIONS ). Image Image Image

WARNINGS 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 to occur at any time, routine urinalysis, white and differential blood cell count, hemoglobin determination, and direct platelet count must be done twice weekly, together with monitoring of the patient's skin, lymph nodes, and body temperature, during the first month of therapy, every two weeks for the next 5 months, and monthly thereafter. Patients should be instructed to report promptly the development of signs and symptoms of granulocytopenia and/or thrombocytopenia such as fever, sore throat, chills, bruising, or bleeding. The 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 White Blood Cells (WBC) below 3500/mm 3 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/mm 3 , even in the absence of clinical bleeding, requires at least temporary cessation of penicillamine therapy. A progressive fall in either platelet count or WBC count 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 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 proteinuria 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 one 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. In Wilson's disease, these are recommended every three months, at least during the first year of treatment. 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. Onset of new neurological symptoms has been reported with penicillamine capsules (see ADVERSE REACTIONS ). Occasionally, neurological symptoms become worse during initiation of therapy with penicillamine capsules (see INDICATIONS ). 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 capsules 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. Pregnancy Penicillamine can cause fetal harm when administered to a pregnant woman. Penicillamine has been shown to be teratogenic in rats when given in doses six 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, advised to report promptly any missed menstrual periods or other indications of possible pregnancy, and followed closely for early recognition of pregnancy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Wilson’s Disease 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, which may be fatal. If penicillamine is administered during pregnancy to patients with Wilson's disease, it is recommended that the daily dosage be limited to 750 mg. If cesarean section is planned, the daily dose should be reduced to 250 mg, but not lower, for the last 6 weeks of pregnancy and postoperatively until wound healing is complete. 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 mother must be evaluated against the risk to the fetus. Rheumatoid Arthritis 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. There is a report that a woman with rheumatoid arthritis treated with less than 1 g/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.