Penicillamine

Class
Chelating agents
Subclass
Copper chelators
Substance name
penicillAMINE, D-penicillamine
Brand names
Cuprimine®, Depen®
Common formulations
Capsule, Tablet
Dosage and administration
Adults patients
Cystinuria
•
Start at: 250 mg PO daily
•
Maintenance: 1,000-4,000 mg PO daily, in 4 divided doses
Taken at least 1 hour before or 2 hours after meals. Administered in combination with conventional therapy and generous fluid intake. Individualize dose to limit cystine excretion to 100-200 mg per day in patients with no history of stones, and below 100 mg per day in patients with stones and/or pain.
Rheumatoid arthritis • Severe, not responding to conventional therapy
•
Start at: 125-250 mg PO daily
•
Maintenance: 500-1,500 mg PO daily, in divided doses
•
Maximum: 1,500 mg per day
Taken at least 1 hour before or 2 hours after meals. Titrate in 125-250 mg increments at 1-3-month intervals based on response and tolerance. Consider further titrating in 250 mg increments at 2-3-month intervals if there is no improvement and no serious toxicity after 2-3 months. Discontinue after 3-4 months if there is no improvement on a daily dose of 1,000-1,500 mg.
Wilson's disease
•
Start at: 250 mg PO daily, titrated gradually if an initial daily dose of 1,000 mg is not tolerated
•
Maintenance: 750-1,500 mg PO daily, in divided doses, for 3 months followed by a dose based on serum free copper levels
•
Maximum: 2,000 mg per day
Taken at least 1 hour before or 2 hours after meals.
Indications for use
Labeled indications
Adults
•
Treatment of Wilson's disease
•
Treatment of cystinuria
•
Treatment of rheumatoid arthritis (severe, not responding to conventional therapy)
Children
•
Treatment of JIA
Safety risks
Boxed warnings
Penicillamine toxicity
•
Maintain a high level of suspicion, as penicillamine has been associated with toxicity. Familiarize with penicillamine toxicity, special dosage considerations, and therapeutic benefits before initiation. Do not use penicillamine casually. Ensure that the patient is constantly under the close supervision of the physician. Instruct patients to report any symptoms suggesting toxicity.
Contraindications
Hypersensitivity to penicillamine or its components
History of penicillamine-related aplastic anemia or agranulocytosis
Concomitant use of gold therapy, antimalarial drugs, cytotoxic drugs, oxyphenbutazone, or phenylbutazone
Warnings and precautions
Blood dyscrasias
•
Maintain a high level of suspicion, as penicillamine has been associated with an increased risk of thrombocytopenia, leukopenia, agranulocytosis, and aplastic anemia. Monitor hemoglobin and CBC twice weekly for the first month, then every 2 weeks for the next 5 months, and monthly thereafter. Additionally, check skin, lymph nodes, and body temperature during these intervals.
Bronchiolitis obliterans
•
Maintain a high level of suspicion, as penicilliamine has been rarely associated with obliterative bronchiolitis.
Fever, skin rash, oral ulcers, reduced sense of taste
•
Maintain a high level of suspicion, as penicillamine has been associated with drug fever, early and late rash, oral ulcers, sometimes resembling aphthous stomatitis, and hypogesia.
Goodpasture syndrome
•
Maintain a high level of suspicion, as penicillamine has been rarely associated with Goodpasture syndrome. Discontinue penicillamine if abnormal urinary findings, hemoptysis, or pulmonary infiltrates on X-ray develop.
Intrahepatic cholestasis, toxic hepatitis
•
Maintain a high level of suspicion, as penicillamine has been rarely associated with drug-induced liver injury. Monitor LFTs every 6 months, and every 3 months in patients with Wilson's disease, at least during the first year of treatment.
Membranous nephropathy
•
Maintain a high level of suspicion, as penicillamine is associated with an increased risk of proteinuria and hematuria, which are signs of membranous glomerulopathy that can progress to nephrotic syndrome. Discontinue penicillamine in patients with rheumatoid arthritis developing gross hematuria or persistent microscopic hematuria.
Myasthenia gravis
•
Maintain a high level of suspicion, as penicillamine has been associated with an increased risk of myasthenic syndrome progressing to myasthenia gravis.
Pemphigus vulgaris, pemphigus foliaceus
•
Maintain a high level of suspicion, as penicillamine has been associated with an increased risk of pemphigus vulgaris and pemphigus foliaceus.
Positive ANA, lupus-like symptoms
•
Maintain a high level of suspicion, as penicillamine has been associated with positive ANA, somtimes leading to a lupus-like syndrome.
Vitamin B6 deficiency
•
Maintain a high level of suspicion, as penicillamine increases the requirement for pyridoxine. Administer pyridoxine supplements in patients with Wilson's disease, cystinuria, or rheumatoid arthritis with impaired nutrition.
Specific populations
Renal impairment
eGFR 0-90 mL/min/1.73 m²
•
Use with caution. Do not use in patients with rheumatoid arthritis and a history or evidence of renal impairment.
Renal replacement therapy
Continuous renal replacement
•
No guidance available.
Intermittent hemodialysis
•
No guidance available.
Peritoneal dialysis
•
No guidance available.
Hepatic impairment
Any severity
•
No guidance available.
Pregnancy and breastfeeding
Pregnancy
All trimesters • Australia Category: D
•
Avoid use. Evidence of fetal harm in humans. Do not use penicillamine for rheumatoid arthritis during pregnancy. Avoid using penicillamine for cystinuria during pregnancy. Continue penicillamine for Wilson's disease during pregnancy, limiting the dose to 1,000 mg daily and reducing to 250 mg daily during the last 6 weeks of pregnancy and postpartum if a C-section is planned.
Breastfeeding
Do not use during breastfeeding.
Unknown amount excreted in breastmilk.
Unknown drug levels in breastfed infants.
Adverse reactions
Very common > 10%
•
Loss of appetite, nausea, vomiting, diarrhea, epigastric pain, mouth ulcers, reduced sense of taste
Common 1-10%
•
↓ WBC count, ↓ platelet count, ↑ urine protein, skin rash, generalized pruritus
Unknown frequency
•
Acute liver failure, acute pancreatitis, peptic ulcer disease, intrahepatic cholestasis, toxic hepatitis, aplastic anemia, agranulocytosis, ↑ serum ALP, ↓ serum LDH, asthma, bronchiolitis obliterans syndrome, dermatomyositis and polymyositis, exfoliative dermatitis, thyroiditis, goodpasture syndrome, hemolytic anemia, interstitial lung disease, ↑ liver enzymes, lichen planus, vasculitis, nephrotic syndrome, optic neuritis, Guillain-Barré syndrome, myasthenia gravis, pemphigus vulgaris, pemphigus foliaceus, anetoderma, pulmonary fibrosis, pulmonary hemorrhage, renal failure, fever, arthralgia, lymphadenopathy, lupus-like symptoms, urticaria, ↓ blood glucose, synovitis, ↑ blood eosinophil count, ↑ WBC count, hair loss, hematuria, muscle weakness, peripheral neuropathy, tinnitus, agitation, visual disturbances, anxiety, dystonia, sideroblastic anemia, stomatitis, gingivitis, glossitis, cheilosis, thrombotic thrombocytopenic purpura, thrombophlebitis, toxic epidermal necrolysis, yellow nails
Interactions
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