penicillamine
Cuprimine, Depen

Available forms
Available by prescription only
Capsules: 125 mg, 250 mg
Tablets: 250 mg

Indications and dosages
 Wilson’s disease. Adults: 250 mg P.O. q.i.d. 1/2 to 1 hour before meals and at least 2 hours after evening meal. Adjust dose to achieve urinary copper excretion of 0.5 to 1 mg daily. Doses over 2 g are seldom needed.
 Cystinuria. Adults: 250 mg P.O. daily in four divided doses; then gradually increase dosage. Usual dose is 2 g daily (range, 1 to 4 g daily). Adjust dose to achieve urinary cystine excretion of less than 100 mg daily when renal calculi are present, or 100 to 200 mg daily when no calculi are present.
 Rheumatoid arthritis, Felty’s syndrome. Adults: Initially, 125 to 250 mg P.O. daily, with increases of 125 to 250 mg daily at 1- to 3-month intervals if needed. Maximum, 1.5 g daily.
 Adjunctive treatment of heavy metal poisoning ◇. Adults: 500 to 1,500 mg P.O. daily for 1 to 2 months.
 Primary biliary cirrhosis ◇. Adults: Initially, 250 mg P.O. daily, with increases of 250 mg q 2 weeks. Maximum, 1 g daily in divided doses.

Pharmacodynamics
Antirheumatic action: Mechanism unknown; depresses circulating IgM rheumatoid factor (but not total circulating immunoglobulin levels) and depresses T-cell but not B-cell activity. Also depolymerizes some macroglobulins (for example, rheumatoid factor).
Chelating action: Forms stable, soluble complexes with copper, iron, mercury, lead, and other heavy metals that are excreted in urine; particularly useful in chelating copper in patients with Wilson’s disease. Also combines with cystine to form a complex more soluble than cystine alone, thereby reducing free cystine below the level of urinary stone formation.

Pharmacokinetics
Absorption: Well absorbed after oral administration.
Distribution: Limited data available.
Metabolism: Metabolized by liver to inactive compounds.
Excretion: Only small amounts excreted unchanged; after 24 hours, about 50% of drug excreted in urine and about 50% in feces.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug, pregnant women, patients with a history of penicillamine-related aplastic anemia or agranulocytosis, patients with significant renal or hepatic insufficiency, and patients receiving gold salts, immunosuppressants, antimalarials, or phenylbutazone because of the increased risk of serious hematologic effects.
  Use cautiously in patients allergic to penicillin (cross reaction is rare); in those who receive a second course of therapy and who may have become sensitized and are more likely to have allergic reactions; and in patients who develop proteinuria not linked to Goodpasture’s syndrome.

Interactions
Drug-drug. Antacids, iron salts: Decreases penicillamine absorption. Separate administration times.
Antimalarials, cytotoxic drugs, gold therapy, oxyphenbutazone, phenylbutazone: Causes serious hematologic and renal effects. Don’t administer together.
Digoxin: Increases serum digoxin levels. Monitor serum levels.

Adverse reactions
EENT: oral ulcerations, glossitis, cheilosis, tinnitus, optic neuritis.
GI: anorexia, nausea, vomiting, dyspepsia, alteration in taste, metallic taste, diarrhea, dysgeusia, hypogeusia, pancreatitis.
GU: proteinuria.
Hematologic: eosinophilia, leukopenia, thrombocytopenia, aplastic anemia, agranulocytosis, thrombotic thrombocytopenia purpura, hemolytic anemia or iron deficiency anemia, lupus-like syndrome, bone marrow suppression.
Hepatic: cholestatic jaundice, hepatic dysfunction.
Metabolic: thyroiditis.
Musculoskeletal: arthralgia, myasthenia gravis.
Respiratory: pneumonitis, Goodpasture’s syndrome.
Skin: pruritus; erythematous rash; intensely pruritic rash with scaly, macular lesions on trunk; pemphigoid reactions; urticaria; alopecia; exfoliative dermatitis; increased skin friability; purpuric or vesicular ecchymoses; wrinkling.
Other: lymphadenopathy, drug fever.

Effects on lab test results
• May increase liver enzyme levels.
• May increase eosinophil count. May decrease hemoglobin, hematocrit, and platelet, WBC, and granulocyte counts.

Overdose and treatment
There are no reports of significant drug overdose. Induce emesis unless unconscious or gag reflex is absent; otherwise empty stomach by gastric lavage and then administer activated charcoal and sorbitol. Thereafter, treat supportively. Treat seizures with diazepam (or pyridoxine if previously successful). Hemodialysis will remove penicillamine.

Special considerations
• Stop drug if patient has signs of hypersensitivity or drug fever, usually with other allergic signs and symptoms (if Wilson’s disease, may rechallenge), or if the following occur: rash developing 6 months or more after start of therapy, pemphigoid reaction, hematuria or proteinuria with hemoptysis or pulmonary infiltrates, gross or persistent microscopic hematuria or proteinuria greater than 2 g daily in patients with rheumatoid arthritis, platelet count below 100,000/mm³ or leukocyte count below 3,500/mm³, or if either shows three consecutive decreases (even within normal range).
• Perform kidney and liver function studies, usually every 6 months. Check routinely for proteinuria, and handle patient carefully to avoid skin damage.
 ALERT Don’t confuse penicillamine with polycillin and the various types of penicillin.
• Patients with Wilson’s disease or cystinuria may need daily pyridoxine (vitamin B₆) supplementation.
• Prescribe drug to be taken 1 hour before or 2 hours after meals or other drugs to facilitate absorption.
• For initial treatment of Wilson’s disease, 10 to 40 mg of sulfurated potash should be administered with each meal during penicillamine therapy for 6 months to 1 year, and then discontinued.
• Drug therapy may cause positive test results for antinuclear antibody with or without clinical systemic lupus erythematosus-like syndrome.
• Hemodialysis will remove penicillamine.
Breast-feeding patients
• It isn’t known if drug appears in breast milk. Safety hasn’t been established in breast-feeding women; an alternative to breast-feeding is recommended during therapy.
Pediatric patients
• Check for possible iron deficiency resulting from long-term use. Safety and efficacy for juvenile rheumatoid arthritis haven’t been established in children.
Geriatric patients
• Lower doses may be indicated. Monitor renal and hepatic function closely. Toxicity may be more common in elderly patients.

Patient education
• Provide health education for patients with Wilson’s disease, rheumatoid arthritis, or cystinuria; explain disease process and rationale for therapy and explain that results may not be evident for 3 months.
• Encourage compliance with therapy and follow-up visits.
• Stress importance of reporting immediately any fever, chills, sore throat, bruising, bleeding, or allergic reaction.
• Tell patient to take drug on an empty stomach 30 minutes to 1 hour before meals or 2 hours after ingesting food, antacids, mineral supplements, vitamins, or other drugs. Tell patient to drink large amounts of water, especially at night.
• Advise patient receiving drug for rheumatoid arthritis that an exacerbation of disease may occur during therapy. This usually can be controlled by concurrent use of NSAIDs.
• Advise patient taking drug for Wilson’s disease to maintain a low-copper (less than 2 mg daily) diet by excluding foods with high copper content, such as chocolate, nuts, liver, and broccoli. Also tell him sulfurated potash may be administered with meals to minimize copper absorption.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use