Penicillamine
- Article Author:
- Stephanie Mejias
- Article Editor:
- Kamleshun Ramphul
- Updated:
- 8/24/2020 11:02:01 PM
- For CME on this topic:
- Penicillamine CME
- PubMed Link:
- Penicillamine
Indications
Penicillamine has FDA approval as a treatment for Wilson disease and cystinuria. It also is used as an off-label treatment option for lead poisoning in children.[1]
Mechanism of Action
Penicillamine can chelate heavy metals such as lead, copper, and mercury and form a soluble complex that is renally excreted in the urine. It also can combine and form disulfide bonds with cysteine and facilitates the excretion in urine. This helps to prevent the formation of cystine calculi.
In rheumatoid arthritis, it can depress T cell activity.
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. More than 80% is protein-bound, and it is excreted in the urine.[2]
Administration
It usually exists as 250 mg tablets and 125 mg or 250 mg capsules.
- Wilson Disease: In Wilson disease in adults, the usual recommended dose is 750 mg to 1,500 mg per day in divided doses. A maximum dose of 2,000 mg per day is allowed, and the most often used dosage is 250 mg, four times per day. The dose that gives an initial 24-hour copper excretion of more than 2 mg/day in the urine should be kept constant for three months. The maintenance dose should give a free copper level of less than 10 mcg/dL in the serum. The recommended off-label dosing for pediatric cases of Wilson disease is 20 mg/kg/day divided into 2 to 3 doses.
- Cystinuria: In cystinuria among adults, the recommended oral daily dose of 1 to 4 g per day in divided doses. The initial dose is usually 250 mg/day, gradually titrated up to reduce the risk of adverse effects. The aim is to limit the excretion rate of cysteine to 100 to 200 mg/day. Children suffering from cystinuria should receive an oral dose of 30 mg/kg/day in 4 divided doses.
- Juvenile Rheumatoid Arthritis: In juvenile rheumatoid arthritis, the dose for the first two months is 5 mg/kg per day, then 10 mg/kg per day for the next four months.
- Rheumatoid Arthritis: In rheumatoid arthritis, an initial dose of 125 to 250 mg/day is the oral dose. The dosage then can increase by 125 to 250 mg/day over the next 1 to 3 months to reach 500 to 750 mg/day, depending on the response.
- Lead Poisoning: It can be a treatment for lead poisoning at a dose of 1 to 1.5 g per day orally.
Penicillamine should be taken 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 drugs 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.
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[3]
- 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 birth defects such as congenital cutix laxa)
- Concurrency with antimalarials, immunosuppressants
Breastfeeding: The presence of the drug in breast milk is unknown and not documented. There is a manufacturer's advice against breastfeeding.
Monitoring
Given the adverse effects, recommendations are to monitor and watch out 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.[4]
- Pulmonary: Patients presenting with dyspnea should undergo a pulmonary function test. It also is associated with obliterative bronchiolitis.[5]
- Dermatologic: Patients can present with a drug-induced lupus-like rash and other dermatologic changes. It also has been associated with pemphigus[6], 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.[7][8][9]
- Hepatic: Periodic liver function tests also should be done as penicillamine has correlations 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 as well as to 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.
Toxicity
Patients should understand to report any symptoms suggesting toxicity such as fever, bleeding, bruising, and chills. Gold sodium thiomalate can cause toxicity of penicillamine and should be avoided.
Enhancing Healthcare Team Outcomes
Healthcare workers, including the nurse practitioner, 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. The pharmacist should educate the patient not to take the other medications at the same time as penicillamine. Finally, before prescribing this agent, always ask if the patient has any allergies. Nearly 30% of patients do develop some type of allergic reaction to penicillamine.[10][11]