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Penicillamine

Editor: Kamleshun Ramphul Updated: 3/27/2023 8:59:56 PM

Indications

Penicillamine has FDA approval as a treatment in adults for Wilson disease and cystinuria, and severe rheumatoid arthritis that has failed to respond to conventional therapies.[1][2] It is considered a conventional disease-modifying antirheumatic drug (DMARD). In pediatric patients, it is used to treat cystinuria and off-label to treat Wilson disease.[3][4] As a chelating agent, it has sometimes been used to treat other heavy metal toxicities.[5][6][7]

Mechanism of Action

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Mechanism of Action

Penicillamine can chelate heavy metals such as copper, lead, and mercury and form a soluble complex that is renally excreted in the urine. It also can combine and form disulfide bonds with cysteine resulting in a more soluble compound that facilitates the excretion in urine; this also helps prevent the formation of cystine calculi. 

In rheumatoid arthritis, it can depress T cell activity, although its precise mechanism of action remains unknown.

It has a plasma peak time of 1 to 3 hours and a peak plasma concentration of 1 to 2 mg/L for the 250 mg dose. The drug's half-life is 4 to 6 days. More than 80% is protein-bound, and it is excreted in the urine.[8]

Administration

Penicillamine is available in 250 mg tablets and 125 mg and 250 mg capsules.

Wilson Disease

  • Adult dosing: 750 to 1500 mg/day divided three or four times daily. The dose that gives an initial 24-hour urinary copper excretion of more than 2 mg/day should be kept constant for three months; dose adjustments are made on the 24-hour urinary copper excretion and free serum copper levels. The maintenance dose should give a free copper serum level of less than 10 mcg/dL.
  • Pediatric dosing: The recommended off-label dosing for pediatric cases of Wilson disease is 20 mg/kg/day divided into 2 to 3 doses. The maximum dose is 1000 mg per day. As with adults, dose adjustments are made on the 24-hour urinary copper excretion and free serum copper levels. 

Cystinuria

  • Adult dosing: 500 mg by mouth daily; start with 250 mg daily, increase the dose gradually. The maximum dose is 4000 mg daily.
  • Pediatric dosing: 30 mg/kg/day by mouth divided into two or three doses daily. The maximum dose is 4000 mg per day. The initial dose is usually 250 mg/day, gradually titrated upward to reduce the risk of adverse effects. The goal is to limit the excretion rate of cysteine to 100 to 200 mg/day.

Rheumatoid Arthritis (RA)

  • Adult dosing: The typical maintenance dose is 500 to 750 mg daily in divided dosages; some patients may require up to 1500 mg daily to obtain a therapeutic benefit. Start with 125 to 250 mg daily for the initial four weeks, increasing by the same amount every 4 to 12 weeks until achieving remission. The minimum maintenance dose for symptomatic suppression should be used, and therapy should be discontinued if the patient shows insufficient benefit within 12 months.[9]
  • Pediatric dosing: Typical maintenance dosing is 15 to 20mg/kg/day. Start at a lower dose of 2.5 to 5mg/kg/day and increase every four weeks over three to six months.

 Lead Poisoning

  • It can be a treatment for lead poisoning if no other preferred chelating agents are available. For adults, the daily oral dose is between 1000 and 1500 mg daily in divided doses until the urinary lead stabilizes at less than 0.5 mg/day.[7]

Penicillamine should be administered on an empty stomach, at least 1 hour before meals or 2 hours after meals. Some protocols recommend taking the drug at least 2 hours before meals in cases of lead poisoning. It is also advisable to take the medication at least 1 hour apart from other medications or zinc-containing products and if the patient is consuming milk or antacids. It is a strong recommendation to supplement the patient with pyridoxine. In patients with Wilson disease, 25 to 50 mg/day of pyridoxine is advised. A multivitamin regimen without copper can also be an option. In patients with rheumatoid arthritis or cystinuria, the recommendation is to take 25 mg of pyridoxine per day. The last dose of the day should be taken at least 3 hours after dinner. It is recommended to administer penicillamine with pyridoxine dosed at 25 mg per day for both adults and children, especially in patients with nutritional deficiencies.[10]

Dosing should be decreased if the patient is having surgery and maintained at the reduced dose until wound healing is complete.

Renal and hepatic dosing: For rheumatoid arthritis patients, penicillamine is contraindicated in renal impairment. For other indications in patients with renal impairment, if creatinine clearance is greater than 50, caution is advised, and if creatinine clearance is below 50, penicillamine use should be avoided. The drug should also not be used in cases of peritoneal or hemodialysis. Hepatic dosing is undefined.

Adverse Effects

Most Common Adverse Effects 

  • Diarrhea
  • Dysgeusia

Less Common Adverse Effects 

  • Skin rash
  • Proteinuria
  • Thrombocytopenia
  • Leukopenia

Rare Adverse Effects

  • Local thrombophlebitis, vasculitis
  • Anxiety, agitation, dystonia, Guillain-Barre syndrome, myasthenia (including extraocular muscles), myasthenia gravis, neuropathy, psychiatric disturbance
  • Agranulocytosis, aplastic anemia, pure red cell aplasia, sideroblastic anemia, positive ANA titer, thrombotic thrombocytopenic purpura
  • Increased serum alkaline phosphatase, hepatic failure, intrahepatic cholestasis
  • Lupus-like syndrome
  • Diplopia, optic neuritis, visual disturbance
  • Tinnitus, renal failure, asthma, interstitial pneumonitis, pulmonary fibrosis
  • Breast disease (mammary hyperplasia), Goodpasture syndrome, hematuria, nephrotic syndrome
  • Dermatomyositis, polymyositis[11]
  • Polyarthralgia (migratory, often with objective synovitis)

Contraindications

Penicillamine is contraindicated in the following conditions:

  • Patients with a previous history of penicillamine-related aplastic anemia
  • Penicillin allergy, discontinue if an immune reaction
  • Renal insufficiency and rheumatoid arthritis
  • Pregnancy risk factor D (It has correlations with multiple congenital disabilities such as congenital cutix laxa)
  • Concurrency with antimalarials, immunosuppressants

Pregnancy: Penicillamine is contraindicated in pregnancy for rheumatoid arthritis. Use during pregnancy should be avoided for cystinuria. For Wilson disease, the clinician must weigh the risk vs. benefits and limit dosing to 750 mg daily in capsule form and 1,000 mg daily in tablet form. If the patient is to have a cesarean delivery, dosing should be limited to 250 mg daily for the six weeks prior to the delivery procedure.[12]

Breastfeeding: The presence of the drug in breast milk is unknown and not documented, but avoidance is recommended based on conflicting human data.[13] The manufacturer advises against breastfeeding.

Monitoring

Given the adverse effects, recommendations are to monitor for the following:

  • Allergic Reactions: 33% of patients can present with an allergic reaction to the drug. It often presents with a rash that heals on stopping the drug. The patient should stop the medication if the patient presents with fever, arthralgia, and lymphadenopathy.[14]
  • Pulmonary: Patients presenting with dyspnea should undergo a pulmonary function test. It also is associated with obliterative bronchiolitis.[15]
  • Dermatologic: Patients can present with a drug-induced lupus-like rash and other dermatologic changes. It also has been associated with pemphigus[16], and the recommendations to stop the drug and start treatment on high-dose corticosteroids.
  • Gastrointestinal: Patients can present with multiple gastrointestinal side effects such as taste alteration, oral ulceration, and gingivostomatitis. These may require discontinuation of the drug based on severity.
  • Renal: Penicillamine has shown correlations with multiple renal side effects such as Goodpasture syndrome, proteinuria, and hematuria. Proper renal function tests should be done in patients experiencing such complaints or having risk factors.[17][18][19]
  • Hepatic: Periodic liver function tests should also be done as penicillamine correlates with intrahepatic cholestasis, hepatitis, and increased alanine aminotransferase and aspartate aminotransferase levels.

The drug should be used with caution in the elderly as they are more at risk of developing a skin rash and gastrointestinal side effects.

Penicillamine also interacts with the following drugs:

Major Interactions

  • Aluminum hydroxide
  • Calcium carbonate
  • Carbonyl iron
  • Copper
  • Ferrous fumarate
  • Digoxin
  • Ferrous gluconate
  • Ferrous sulfate
  • Iron dextran
  • Magnesium citrate
  • Magnesium hydroxide
  • Magnesium oxide
  • Magnesium sulfate
  • Pyridoxine
  • Peramivir
  • Polysaccharide iron
  • Promazine
  • Sodium bicarbonate
  • Sodium citrate/citric acid
  • Tenofovir

The following drugs decrease the levels of penicillamine:

  • Aluminum hydroxide
  • Calcium carbonate 
  • Carbonyl iron copper
  • Ferrous fumarate
  • Iron dextran complex
  • Magnesium chloride
  • Magnesium citrate
  • Magnesium hydroxide
  • Magnesium oxide
  • Sodium bicarbonate
  • Digoxin

The following drugs increase levels of penicillamine:

  • Peramivir
  • Promazine

During the first month of therapy, it is advisable to check the blood cell levels with a complete blood count, platelet count, and urinalysis and properly monitor for any changes in the skin, lymph nodes, and body temperature twice weekly. From the second month until the fifth month, the laboratory and physical findings should be checked every two weeks, and from the sixth month onwards, it should receive testing every month.[20]

Toxicity

Clinicians need to be familiar with the toxicity of penicillamine, understand special dosing considerations, and never use the drug casually. Patients should be under close clinical supervision and understand to report any symptoms suggesting toxicity, such as fever, bleeding, bruising, and chills. Gold sodium thiomalate can cause the toxicity of penicillamine and should be avoided.[21][22]

Enhancing Healthcare Team Outcomes

Members of the interprofessional healthcare team, including clinicians (MDs, DOs, NPs, PAs), who prescribe penicillamine, should be familiar with its pharmacology. Because the agent can bind many drugs and minerals, regular monitoring of the patient is necessary. Nursing staff can counsel the patient on the drug and assist with monitoring. The pharmacist should educate the patient not to take the other medications at the same time as penicillamine, watch for drug-drug interactions, and verify dosing is appropriate for the condition being treated and the patient's age and health status. All interprofessional team members need to participate in close monitoring of therapy to prevent adverse events and therapeutic failure. Finally, before prescribing this agent, always ask if the patient has any allergies; nearly 30% of patients develop some type of allergic reaction to penicillamine.[23][24] This interprofessional team dynamic will optimize therapeutic results while minimizing adverse events with penicillamine therapy, improving patient outcomes. [Level 5]

References


[1]

. Treatment guidelines for lead exposure in children. American Academy of Pediatrics Committee on Drugs. Pediatrics. 1995 Jul:96(1 Pt 1):155-60     [PubMed PMID: 7596706]

Level 1 (high-level) evidence

[2]

Hedera P. Clinical management of Wilson disease. Annals of translational medicine. 2019 Apr:7(Suppl 2):S66. doi: 10.21037/atm.2019.03.18. Epub     [PubMed PMID: 31179303]


[3]

Socha P, Czlonkowska A, Janczyk W, Litwin T. Wilson's disease- management and long term outcomes. Best practice & research. Clinical gastroenterology. 2022 Feb-Mar:56-57():101768. doi: 10.1016/j.bpg.2021.101768. Epub 2021 Oct 12     [PubMed PMID: 35331405]


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Das MC, Sen Sarma M, Srivastava A, Yachha SK, Poddar U. Effect of chelation therapy in pediatric Wilson's disease: Liver and endoscopic outcome. Journal of hepato-biliary-pancreatic sciences. 2021 Apr:28(4):336-345. doi: 10.1002/jhbp.812. Epub 2020 Aug 28     [PubMed PMID: 32745371]


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Seetharaman J, Sarma MS. Chelation therapy in liver diseases of childhood: Current status and response. World journal of hepatology. 2021 Nov 27:13(11):1552-1567. doi: 10.4254/wjh.v13.i11.1552. Epub     [PubMed PMID: 34904029]


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. Chelating Agents. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 2012:():     [PubMed PMID: 31643849]


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Vahabzadeh M, Balali-Mood M, Banagozar Mohammadi A, Moshiri M. Efficacy and expenses of succimer vs. d-penicillamine plus garlic in the treatment of lead poisoning: a retrospective cross-sectional study. Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences. 2021 Dec:29(2):477-481. doi: 10.1007/s40199-021-00407-7. Epub 2021 Jul 27     [PubMed PMID: 34313939]

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Perrett D. The metabolism and pharmacology of D-penicillamine in man. The Journal of rheumatology. Supplement. 1981 Jan-Feb:7():41-50     [PubMed PMID: 7014876]


[9]

Negrei C, Bojinca V, Balanescu A, Bojinca M, Baconi D, Spandidos DA, Tsatsakis AM, Stan M. Management of rheumatoid arthritis: Impact and risks of various therapeutic approaches. Experimental and therapeutic medicine. 2016 Apr:11(4):1177-1183     [PubMed PMID: 27073419]


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Lheureux P, Penaloza A, Gris M. Pyridoxine in clinical toxicology: a review. European journal of emergency medicine : official journal of the European Society for Emergency Medicine. 2005 Apr:12(2):78-85     [PubMed PMID: 15756083]

Level 3 (low-level) evidence

[11]

Levy RS, Fisher M, Alter JN. Penicillamine: review and cutaneous manifestations. Journal of the American Academy of Dermatology. 1983 Apr:8(4):548-58     [PubMed PMID: 6222087]


[12]

Mussi MCL,Nardelli MJ,Santos BC,Abreu ES,Osório FMF,Cançado GGL,Ferrari TCA,Faria LC,Couto CA, Pregnancy Outcomes in Wilson's Disease Women: Single-Center Case Series. Fetal and pediatric pathology. 2021 Aug 5;     [PubMed PMID: 34350816]

Level 2 (mid-level) evidence

[13]

. Penicillamine. Drugs and Lactation Database (LactMed®). 2006:():     [PubMed PMID: 30000118]


[14]

Hsu HL, Huang FC, Ni YH, Chang MH. Steroids used to desensitize penicillamine allergy in Wilson disease. Acta paediatrica Taiwanica = Taiwan er ke yi xue hui za zhi. 1999 Nov-Dec:40(6):448-50     [PubMed PMID: 10927964]

Level 3 (low-level) evidence

[15]

Bruguera-Àvila N, Sánchez-Martínez E, Garcia-Olivé I, Pérez-Ochoa JF, Martínez-Barenys C, Ruiz-Manzano J. Obliterating bronchiolitis in a patient treated with (D)-penicillamine. Archivos de bronconeumologia. 2013 Sep:49(9):411-2. doi: 10.1016/j.arbres.2013.02.002. Epub 2013 Apr 10     [PubMed PMID: 23582262]

Level 3 (low-level) evidence

[16]

Khashoggi M, Machet L, Perrinaud A, Brive D, Machet MC, Maruani A, Vaillant L. [D-penicillamine-induced pemphigus: changes in anti-32-2B immunostaining patterns]. Annales de dermatologie et de venereologie. 2013 Aug-Sep:140(8-9):531-4. doi: 10.1016/j.annder.2013.04.073. Epub 2013 May 21     [PubMed PMID: 24034638]

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[17]

Bienaimé F, Clerbaux G, Plaisier E, Mougenot B, Ronco P, Rougier JP. D-Penicillamine-induced ANCA-associated crescentic glomerulonephritis in Wilson disease. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2007 Nov:50(5):821-5     [PubMed PMID: 17954295]

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Nanke Y, Akama H, Terai C, Kamatani N. Rapidly progressive glomerulonephritis with D-penicillamine. The American journal of the medical sciences. 2000 Dec:320(6):398-402     [PubMed PMID: 11149553]

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Karpinski J, Jothy S, Radoux V, Levy M, Baran D. D-penicillamine-induced crescentic glomerulonephritis and antimyeloperoxidase antibodies in a patient with scleroderma. Case report and review of the literature. American journal of nephrology. 1997:17(6):528-32     [PubMed PMID: 9426850]

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[20]

Kumar V, Singh AP, Wheeler N, Galindo CL, Kim JJ. Safety profile of D-penicillamine: a comprehensive pharmacovigilance analysis by FDA adverse event reporting system. Expert opinion on drug safety. 2021 Nov:20(11):1443-1450. doi: 10.1080/14740338.2021.1956460. Epub 2021 Jul 26     [PubMed PMID: 34259127]

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[21]

Sehgal S, Fazal ZZ, Gupta L, Sheeran T. Progressive dermopathy akin to pseudoxanthoma elasticum after D-penicillamine use in a patient with cystinuria. Rheumatology (Oxford, England). 2022 Oct 6:61(10):e324. doi: 10.1093/rheumatology/keac117. Epub     [PubMed PMID: 35212711]


[22]

Pitman SK, Huynh T, Bjarnason TA, An J, Malkhasyan KA. A case report and focused literature review of d-penicillamine and severe neutropenia: A serious toxicity from a seldom-used drug. Clinical case reports. 2019 May:7(5):990-994. doi: 10.1002/ccr3.2125. Epub 2019 Apr 9     [PubMed PMID: 31110732]

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[23]

Vajdi T, Lee WW, Paravar T. Penicillamine-associated cutis laxa and milia en plaque - case report and review of cutaneous changes associated with penicillamine. Dermatology online journal. 2016 May 15:22(5):. pii: 13030/qt47p4d8zv. Epub 2016 May 15     [PubMed PMID: 27617526]

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[24]

Xu SQ, Li XF, Zhu HY, Liu Y, Fang F, Chen L. Clinical efficacy and safety of chelation treatment with typical penicillamine in cross combination with DMPS repeatedly for Wilson's disease. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban. 2013 Oct:33(5):743-747. doi: 10.1007/s11596-013-1190-z. Epub 2013 Oct 20     [PubMed PMID: 24142730]