FDA label 562e8b88-a39b-4318-9c19-978daa359c2c

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 five 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 five percent of patients during penicillamine therapy. Leukopenia is of the granulocytic series and may or may not be associated with an increase in eosinophils. A confirmed reduction in WBC below 3500/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 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 one to two 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 six 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 six 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 Category D Penicillamine can cause fetal harm when administered to a pregnant woman. 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, 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 the 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 six 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 one gram 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. * ** Scheinberg, I.H.; Sternlieb, I.: N. Engl. J. Med. 293: 1300-1302, Dec. 18, 1975.

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 WARNINGS and 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 (1270 patients). Allergic — Generalized pruritus, early and late rashes (5%), pemphigus (see WARNINGS ), and drug eruptions which 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 drug-induced lupus produced by other pharmacological agents (see 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 AND ADMINISTRATION ). Gastrointestinal — Anorexia, epigastric pain, nausea, vomiting, or occasional diarrhea may occur (17%). Isolated cases of reactivated peptic ulcer have occurred, as have hepatic dysfunction including hepatic failure, 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. 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, 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 ). Renal failure has been reported. Central Nervous System — 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; mental disorders; and agitation and anxiety have been reported. Neuromuscular — Myasthenia gravis (see WARNINGS ); dystonia. Other — Adverse reactions that have been reported rarely include thrombophlebitis; hyperpyrexia (see PRECAUTIONS ); falling hair or alopecia; lichen planus; 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 ). Vasculitis, including fatal renal vasculitis, has also been reported. Allergic alveolitis, 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 has been reported. Increased skin friability, excessive wrinkling of skin, and development of small white papules at venipuncture and surgical sites have been reported (see PRECAUTIONS ); yellow nail syndrome. The chelating action of the drug may cause increased excretion of other heavy metals such as zinc, mercury and lead. There have been reports associating penicillamine with leukemia. However, circumstances involved in these reports are such that a cause and effect relationship to the drug has not been established.