D-Penicillamine Dosing and Treatment Protocol
For Wilson disease, start D-penicillamine at 250-500 mg/day and titrate by 250 mg increments every 4-7 days to a maximum of 1,000-1,500 mg/day in 2-4 divided doses, with maintenance typically at 750-1,000 mg/day in 2 divided doses. 1
Dosing Regimen
Initial Dosing
- Adults: Begin with 250-500 mg/day, increase by 250 mg increments every 4-7 days until reaching 1,000-1,500 mg/day 1
- Children: 20 mg/kg/day rounded to nearest 250 mg, given in 2-3 divided doses 1
- Administration timing: 1 hour before or 2 hours after meals (food reduces absorption by ~50%) 1
- Closer proximity to meals is acceptable if it ensures compliance 1
Maintenance Dosing
- Target dose: 750-1,000 mg/day in 2 divided doses 1
- Maximum: 1,000-1,500 mg/day in divided doses 1
- Critical warning: Doses ≥1,500 mg/day given at once may cause rapid, irreversible neurological deterioration 1
Mandatory Supplementation
- Pyridoxine (Vitamin B6): 25-50 mg daily throughout treatment 1
- Required because penicillamine interferes with pyridoxine action 1
Monitoring Treatment Adequacy
Primary Monitoring Parameters
- 24-hour urinary copper excretion: Should be 200-500 μg/day (3-8 μmol/day) on treatment 1
- Non-ceruloplasmin-bound copper: Should normalize with effective treatment 1
- Compliance check: After 2 days off penicillamine, urinary copper should be ≤1.6 μmol/24h; values >1.6 μmol/24h suggest non-adherence 1
Expected Clinical Response Timeline
- Hepatic disease: Recovery of synthetic function and improvement in jaundice/ascites typically occurs within 2-6 months, with continued improvement through first year 1
- Neurologic disease: Improvement is slower, may take up to 3 years 1
- Serum ceruloplasmin: Tends to decrease after treatment initiation; may remain low or increase as hepatic function recovers 1
Critical Adverse Effects Requiring Immediate Discontinuation
Early Reactions (First 1-3 Weeks)
- Fever and cutaneous eruptions 1
- Lymphadenopathy 1
- Neutropenia or thrombocytopenia 1
- Proteinuria 1
- Action: Discontinue immediately; do NOT attempt prednisone co-treatment 1
Late Reactions
- Nephrotoxicity: Proteinuria or cellular elements in urine—discontinue immediately 1
- Severe bone marrow toxicity: Severe thrombocytopenia or total aplasia 1
- Lupus-like syndrome: Hematuria, proteinuria, positive ANA 1
- Goodpasture syndrome (with higher doses) 1
Very Late Reactions
- Myasthenia gravis 1
- Polymyositis 1
- Severe allergic response upon restarting after discontinuation 1
- Hepatotoxicity and hepatic siderosis 1
Dermatologic Toxicities
- Elastosis perforans serpiginosa 1
- Pemphigus or pemphigoid lesions 1
- Cutis laxa (with long-term high-dose use) 2
- Lichen planus, aphthous stomatitis 1
Common Pitfalls and Caveats
Neurologic Worsening
- 10-50% of patients experience worsening neurologic symptoms during initial treatment 1
- In recent series, 13.8% had neurologic deterioration with penicillamine (highest among all Wilson disease treatments) 1
- Mitigation: Start with incremental doses (125-250 mg/day) and increase slowly 1
Overall Discontinuation Rate
- 20-30% of patients require discontinuation due to severe side effects 1
- Long-term studies show only 30-40% still taking drug at 2 years 3
Non-Compliance Consequences
- Failure to comply leads to significant liver disease progression and liver failure within 1-12 months 1
- May result in death or necessitate liver transplantation 1