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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(pen i SIL a meen)
Generic Available (U.S.)
No
Index Terms
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Treatment of Wilson's disease, cystinuria; adjunctive treatment of rheumatoid arthritis
Use: Unlabeled/Investigational
Chelation therapy for the treatment of lead poisoning (third-line agent)
Pregnancy Risk Factor
D
Pregnancy Considerations
Birth defects, including congenital cutix laxa and associated defects, have been reported in infants following penicillamine exposure during pregnancy. Use for the treatment of rheumatoid arthritis during pregnancy is contraindicated. Use for the treatment of cystinuria only if the possible benefits to the mother outweigh the potential risks to the fetus. Continued treatment of Wilson's disease during pregnancy protects the mother against relapse. Discontinuation has detrimental maternal and fetal effects. Daily dosage should be limited to 750 mg. For planned cesarean section, reduce dose to 250 mg/day for the last 6 weeks of pregnancy, and continue at this dosage until wound healing is complete.
Lactation
Excretion in breast milk unknown/contraindicated
Contraindications
Hypersensitivity to penicillamine or any component of the formulation; renal insufficiency (in patients with rheumatoid arthritis); patients with previous penicillamine-related aplastic anemia or agranulocytosis; breast-feeding; pregnancy (in patients with rheumatoid arthritis)
Warnings/Precautions
Boxed warnings:
• Experienced physician: See “Other warnings/precautions” below.
• Toxicity symptoms: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Allergic reactions: Approximately 33% of patients will experience an allergic reaction.
• Goodpasture's syndrome: Penicillamine has been associated with fatalities due to Goodpasture's syndrome.
• Hematologic toxicities: Penicillamine has been associated with fatalities due to agranulocytosis, aplastic anemia, and thrombocytopenia.
• Hepatotoxicity: Monitor liver function tests periodically due to rare reports of intrahepatic cholestasis or toxic hepatitis.
• Penicillin cross-sensitivity: Patients with a penicillin allergy may theoretically have cross-sensitivity to penicillamine; however, the possibility has been eliminated now that penicillamine is produced synthetically and no longer contains trace amounts of penicillin.
• Proteinuria/hematuria: Proteinuria or hematuria may develop; monitor for membranous glomerulopathy which can lead to nephrotic syndrome. In rheumatoid arthritis patients, discontinue if gross hematuria or persistent microscopic hematuria develop.
• Myasthenia gravis: Penicillamine has been associated with fatalities due to myasthenia gravis.
• Toxicity symptoms: [U.S. Boxed Warning]: Patients should be warned to report promptly any symptoms suggesting toxicity (fever, sore throat, chills, bruising, or bleeding); toxicity may be dose related.
Disease-related concerns:
• Cystinuria: Once instituted for cystinuria, continue treatment on a daily basis; interruptions of even a few days have been followed by hypersensitivity with reinstitution of therapy.
• Lead poisoning: Investigate, identify, and remove sources of lead exposure prior to treatment. Penicillamine is considered to be a third-line agent for the treatment of lead poisoning in children due to the overall toxicity associated with its use; penicillamine should only be used when unacceptable reactions have occurred with edetate CALCIUM disodium and succimer. Primary care providers should consult experts in chemotherapy of lead toxicity before using chelation drug therapy.
• Wilson's disease: Once instituted for Wilson's disease, continue treatment on a daily basis; interruptions of even a few days have been followed by hypersensitivity with reinstitution of therapy.
Concurrent drug therapy issues:
• Hematopoietic-depressant drugs: Use with caution in patients on other hematopoietic-depressant drugs (eg, gold, immunosuppressants, antimalarials, phenylbutazone); hematologic and renal adverse reactions are similar.
Special populations:
• Elderly: Use with caution in the elderly.
Other warnings/precautions:
• Experienced physician: [U.S. Boxed Warning]: Should be administered under the close supervision of a physician familiar with the toxicity and dosage considerations.
Adverse Reactions
Frequency not defined, may vary by indication. Adverse effects requiring discontinuation of treatment have been reported in 20% to 30% of patients with Wilson's disease.
Cardiovascular: Vasculitis
Central nervous system: Anxiety, agitation, fever, hyperpyrexia, psychiatric disturbances; worsening neurologic symptoms (10% to 50% patients with Wilson's disease)
Dermatologic: Alopecia, cheilosis, dermatomyositis, exfoliative dermatitis, lichen planus, rash (early and late 5%), pemphigus, pruritus, skin friability increased, toxic epidermal necrolysis, urticaria, wrinkling (excessive), yellow nail syndrome
Endocrine & metabolic: Hypoglycemia, thyroiditis
Gastrointestinal: Anorexia, diarrhea (17%), epigastric pain, gingivostomatitis, glossitis, nausea, oral ulcerations, pancreatitis, peptic ulcer reactivation, taste alteration (12%), vomiting
Hematologic: Eosinophilia, hemolytic anemia, leukocytosis, leukopenia (2% to 5%), monocytosis, red cell aplasia, thrombocytopenia (4% to 5%), thrombotic thrombocytopenia purpura, thrombocytosis
Hepatic: Alkaline phosphatase increased, hepatic failure, intrahepatic cholestasis, toxic hepatitis
Local: Thrombophlebitis, white papules at venipuncture and surgical sites
Neuromuscular & skeletal: Arthralgia, dystonia, myasthenia gravis, muscle weakness, neuropathies, polyarthralgia (migratory, often with objective synovitis), polymyositis
Ocular: Diplopia, extraocular muscle weakness, optic neuritis, ptosis, visual disturbances
Otic: Tinnitus
Renal: Goodpasture's syndrome, hematuria, nephrotic syndrome, proteinuria (6%), renal failure, renal vasculitis
Respiratory: Asthma, interstitial pneumonitis, pulmonary fibrosis, obliterative bronchiolitis
Miscellaneous: Allergic alveolitis, anetoderma, elastosis perforans serpiginosa, lupus-like syndrome, lactic dehydrogenase increased, lymphadenopathy, mammary hyperplasia, positive ANA test
Drug Interactions
Antacids: May decrease the serum concentration of Penicillamine. Risk D: Consider therapy modification
Digoxin: Penicillamine may decrease the serum concentration of Digoxin. Risk C: Monitor therapy
Iron Salts: May decrease the absorption of Penicillamine. Only oral iron salts are a concern. Exceptions: Ferric Gluconate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Risk D: Consider therapy modification
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid or limit ethanol.
Food: Penicillamine serum levels may be decreased if taken with food. Do not administer with milk.
Storage
Store in tight, well-closed containers.
Mechanism of Action
Chelates with lead, copper, mercury and other heavy metals to form stable, soluble complexes that are excreted in urine; depresses circulating IgM rheumatoid factor, depresses T-cell but not B-cell activity; combines with cystine to form a compound which is more soluble, thus cystine calculi are prevented
Pharmacodynamics/Kinetics
Onset of action: Rheumatoid arthritis: 2-3 months; Wilson's disease: 1-3 months
Absorption: 40% to 70%
Protein binding: 80% to albumin and ceruloplasmin
Metabolism: Hepatic (small amounts metabolized to s-methyl-d-penicillamine)
Half-life elimination: 1.7-7 hours
Time to peak, serum: 1-3 hours
Excretion: Urine (>80% as unchanged drug)
Dosage
Oral:
Rheumatoid arthritis:
Children (unlabeled use): Initial: 3 mg/kg/day (≤250 mg/day) for 3 months, then 6 mg/kg/day (≤500 mg/day) in divided doses twice daily for 3 months to a maximum of 10 mg/kg/day in 3-4 divided doses; maximum dose: 750 mg/day
Adults: 125-250 mg/day, may increase dose at 1- to 3-month intervals up to 1-1.5 g/day; maximum in older adults: 750 mg/day
Wilson's disease: Note: Decrease dose for surgery and during last trimester of pregnancy
Children (unlabeled): AASLD guidelines: 20 mg/kg/day in 2-3 divided doses, round off to the nearest 250 mg dose
Adults: 750-1500 mg/day in divided doses (dose that results in an initial 24-hour urinary copper excretion >2 mg/day should be continued for ~3 months; maintenance dose defined by amount resulting in <10 mcg serum free copper/dL); maximum dose: 2000 mg/day. Note: Therapy in elderly patients should be initiated at low end of dosing range and titrated upward cautiously.
AASLD guidelines recommend to increase tolerability, therapy may be initiated at 250-500 mg/day then titrated upward 250 mg every 4-7 days; usual maintenance dose: 750–1000 mg/day in 2 divided doses; maximum: 1000-1500 mg/day in 2-4 divided doses (Roberts, 2008)
Cystinuria: Note: Adjust dose to limit cystine excretion to 100-200 mg/day (<100 mg/day with history of stone formation)
Children: 30 mg/kg/day in 4 divided doses
Adults: 1-4 g/day in 4 divided doses; usual dose: 2 g/day
Lead poisoning (unlabeled use): Children: 20-30 mg/kg/day, administered in 3-4 divided doses; initiating treatment at 25% of this dose and gradually increasing to the full dose over 2-3 weeks may minimize adverse reactions. Doses of 15 mg/kg/day may also be effective and have less adverse effects (Shannon 2000). Note: For the treatment of high blood lead concentrations in children, the CDC recommends chelation treatment when blood lead concentrations are >45 mcg/dL (CDC, 2002). Children with blood lead concentrations >70 mcg/dL or symptomatic lead poisoning should be treated with parenteral agents (AAP, 2005).
Dosing adjustment/comments in renal impairment: Clcr <50 mL/minute: Avoid use
Hemodialysis: Dialyzable; a dosing decrease from 250 mg/day to 250 mg 3 times/week after dialysis has been suggested in the treatment of rheumatoid arthritis.
Administration: Oral
For patients who cannot swallow, contents of capsules may be administered in 15-30 mL of chilled puréed fruit or fruit juice. Give on an empty stomach (1 hour before meals and at bedtime).
Cystinuria: If administering 4 equal doses is not feasible, administer the larger dose at bedtime.
Rheumatoid arthritis: Doses ≤500 mg/day may be given as a single dose; >500 mg administer in divided doses
Monitoring Parameters
Urinalysis, CBC with differential, platelet count, skin, lymph nodes, and body temperature twice weekly during the first month of therapy, then every 2 weeks for 5 months, then monthly; LFTs every 6 months
Cystinuria: Urinary cystine, annual X-ray for renal stones
Lead poisoning: Serum lead concentration (baseline and 7-21 days after completing chelation therapy); hemoglobin or hematocrit, iron status, free erythrocyte protoporphyrin or zinc protoporphyrin; neurodevelopmental changes
Wilson's disease: Serum non-ceruloplasmin bound copper, 24-hour urinary copper excretion, LFTs every 3 months during the first year of treatment; periodic ophthalmic exam
CBC: WBC <3500/mm3 indicate need to stop therapy immediately; platelet counts <100,000/mm3 indicate need to stop therapy until numbers of platelets increase
Urinalysis: Monitor for proteinuria and hematuria. A quantitative 24-hour urine protein at 1- to 2-week intervals initially (first 2-3 months) is recommended if proteinuria develops; in patients with rheumatoid arthritis, discontinue or decrease dose with proteinuria >1 g/24 hours, progressively increasing proteinuria or hematuria.
Reference Range
Wilson's disease: 24-hour urinary copper excretion: 200-500 mcg (3-8 micromoles)/day
Dietary Considerations
Should be taken at least 1 hour before a meal on an empty stomach. Iron may decrease drug action. Patients with Wilson's disease or cystinuria should receive pyridoxine supplementation 25 mg/day. For Wilson's disease, decrease copper in diet to <1-2 mg/day and omit chocolate, nuts, shellfish, mushrooms, liver, raisins, broccoli, copper-enriched cereal, multivitamins with copper, and molasses. For lead poisoning, decrease calcium in diet. For cystinuria, increase daily fluid intake including 1 pint of fluid prior to bedtime and 1 additional pint during the night.
Patient Education
Capsules may be opened and contents mixed in 15-30 mL of chilled fruit juice or puree; do not take with milk or milk products. Avoid or limit alcohol and excess intake of vitamin A. It is preferable to take penicillamine on empty stomach, 1 hour before or 2 hours after meals. Maintain adequate hydration, unless instructed to restrict fluid intake. For Wilson's disease, avoid chocolate, shellfish, nuts, mushrooms, liver, broccoli, and molasses. For lead poisoning, decrease dietary calcium. For cystinuria, take with large amounts of water. You may experience anorexia, taste alteration, nausea, vomiting, or diarrhea. Report persistent fever or chills; unhealed sores; white spots or sores in mouth or vaginal area; extreme fatigue; signs of infection; breathlessness, respiratory difficulty, or unusual cough; unusual bruising/bleeding; blood in urine, stool, mouth, or vomitus; swollen face or extremities; skin rash or itching; muscle pain or cramping; or pain on urination.
Geriatric Considerations
Close monitoring of elderly is necessary; since steady-state serum/tissue concentrations rise slowly, “go slow” with dose increase intervals; steady-state concentrations decline slowly after discontinuation suggesting extensive tissue distribution. Skin rashes and taste abnormalities occur more frequently in the elderly than in young adults; leukopenia, thrombocytopenia, and proteinuria occur with equal frequency in both younger adults and elderly. Since toxicity may be dose related, it is recommended not to exceed 750 mg/day in the elderly.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Oral ulcerations, glossitis, gingivostomatitis, and taste alteration.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause anxiety, agitation, visual and psychic disturbances
Mental Health: Effects on Psychiatric Treatment
May cause aplastic anemia; use caution with clozapine and carbamazepine. May cause dystonia. May cause thrombocytopenia; monitor in patients receiving valproate.
Nursing: Physical Assessment/Monitoring
Monitor for an allergic reaction. Teach patient actions to take if an allergic reaction should occur.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, oral:
Cuprimine®: 250 mg
Tablet, oral:
Depen®: 250 mg [scored]
Pricing: U.S. (www.drugstore.com)
Capsules (Cuprimine)
250 mg (30): $201.98
Tablets (Depen Titratabs)
250 mg (30): $139.99
Extemporaneously Prepared
A 50 mg/mL oral suspension may be made with capsules. Mix the contents of sixty 250 mg capsules with 3 g carboxymethylcellulose, 150 g sucrose, 300 mg citric acid, and parabens (methylparaben 120 mg, propylparaben 12 mg). Add quantity of propylene glycol sufficient to make 100 mL, then add quantity of purified water sufficient to make 300 mL. Cherry flavor may be added. Label "shake well" and "refrigerate". Stable for 30 days refrigerated.
DeCastro FJ, Jaeger RQ, and Rolfe UT, "An Extemporaneously Prepared Penicillamine Suspension Used to Treat Lead Intoxication," Hosp Pharm, 1977, 2:446-8.
References
Adelman HM, Winters PR, Mahan CS, et al, “D-Penicillamine-Induced Myasthenia Gravis; Diagnosis Obscured by Coexisting Chronic Obstructive Pulmonary Disease,” Am J Med Sci, 1995, 309(4):191-3.
Albert C, Aynard B, Terbe V, et al, “D-Penicillamine Induced Rapidly Progressive Glomerulonephritis With Membranous Nephropathy in a Patient With Rheumatoid Arthritis,” Clin Exp Rheumatol, 1994, 12(Suppl 11):108.
American Academy of Pediatrics Committee on Environmental Health, “Lead Exposure in Children: Prevention, Detection, and Management,” Pediatrics, 2005, 116(4):1036-46.
Andonopoulos AP, Terzis E, and Tsibri E, “D-Penicillamine Induced Myasthenia Gravis in Rheumatoid Arthritis: An Unpredictable Common Occurrence?” Clin Rheumatol, 1994, 13(4):586-8.
Aronow R and Fleschmann LE, “Mercury Poisoning in Children,” Clin Pediatr (Phila), 1976, 15(10):936-45.
Centers for Disease Control and Prevention (CDC), Managing Elevated Blood Lead Levels Among Young Children: Recommendations from the Advisory Committee on Childhood Lead Poisoning Prevention, Atlanta: CDC; 2002.
Cullen NM, Wolf LR, and St Clair D, “Pediatric Arsenic Ingestion,” Am J Emerg Med, 1995, 13(4):432-5.
Gracia RC and Snodgrass WR, “Lead Toxicity and Chelation Therapy," Am J Health Syst Pharm, 2007, 64(1):45-53.
Hryhorczuk DO, Meyers L, and Chen G, “Treatment of Mercury Intoxication in a Dentist With N-Acetyl-D,L-Penicillamine,” J Toxicol Clin Toxicol, 1982, 19(4):401-8.
Kandola L, Swannell AJ, and Hunter A, “Acquired Sideroblastic Anaemia Associated With Penicillamine Therapy for Rheumatoid Arthritis,” Ann Rheum Dis, 1995, 54(6):529-30.
Kosnett MJ, Wedeen RP, Rothenberg SJ, et al, “Recommendations for Medical Management of Adult Lead Exposure,” Environ Health Perspect, 2007, 115(3):463-71.
Lifshitz M and Levy J, “Efficacy of D-Penicillamine in Reducing Lead Concentrations in Children: A Prospective, Uncontrolled Study,” J Pharm Technol, 2000, 16(3):98-101.
Lyle WH, “Penicillamine in Metal Poisoning,” J Rheumatol Suppl, 1981, 7:96-9.
Multz CV, “Cholestatic Hepatitis Caused by Penicillamine,” JAMA, 1981, 246(6):674-5.
Negishi M, Matsuda A, Kaga S, et al, “A Case of Agranulocytosis Which Occurred Several Hours After the Readministration of D-Penicillamine Accompanied by Shivering-Chillness,” Arerugi, 1995, 44(2):96-9.
Oga M, Matsui N, Anai T, et al, “Copper Disposition of the Fetus and Placenta in a Patient With Untreated Wilson's Disease,” Am J Obstet Gynecol, 1993, 169(1):196-8.
Piomelli S, “Childhood Lead Poisoning,” Pediatr Clin North Am, 2002, 49(6):1285-304.
Roberts EA and Schilsky ML, “Diagnosis and Treatment of Wilson Disease: An Update. American Association for Study of Liver Diseases (AASLD),” Hepatology, 2008, 47(6):2089-111.
Rosa FW, “Teratogen Update. Penicillamine,” Teratology, 1986, 33(1):127-31.
Rosenberg AM. “Advanced Drug Therapy for Juvenile Rheumatoid Arthritis,” J Pediatr, 1989, 114(2):171-8.
Shannon M and Townsend MK, “Adverse Effects of Reduced-Dose d-Penicillamine in Children With Mild to Moderate Lead Poisoning,” J Toxicol Clin Toxicol, 1999, 37(5):625.
Smith DB and Gallagher BB, “The Effect of Penicillamine on Seizure Threshold. The Role of Pyridoxine,” Arch Neurol, 1970, 23(1):59-62.
Stein HB, Patterson AC, Offer RC, et al, “Adverse Effects of D-Penicillamine in Rheumatoid Arthritis,” Ann Intern Med, 1980, 92:24-9.
Swarup A, Sachdeva N, and Schumacher Jr HP, “Dosing of Antirheumatic Drugs in Renal Disease and Dialysis,” J Clin Rheumatol, 2004, 10(4):190-204.
International Brand Names
Lexi-Comp.com
Last full review/revision April 2011
Content last modified April 2011
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