Penicillamine

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]