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/mm3 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/mm3, 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.