Cuprimine

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Cuprimine

Classes

Antidotes, Systemic
Chelating Agents
Cystinuria Agents
Other Specific Antirheumatics

Administration
Oral Administration

Penicillamine is administered orally at least 1 hour before or 2 hours after meals and at least 1 hour before or after any other drug, food, or milk. Give last dose 3 hours after the evening meal. Food decreases the oral absorption by about 52%.
For patients with difficulty swallowing capsules or tablets, the contents of a capsule may be mixed in 15—30 ml of chilled pureed fruit or fruit juice and administered. Alternatively, a 50 mg/ml elixir may be prepared by dissolving forty-eight 250-mg capsules in 100 ml of water, then filter and stir in 100 ml of cherry syrup plus 30 ml of alcohol. Bring the total volume to 240 ml with water. Shake well and store in the refrigerator.

Adverse Reactions
Severe

proteinuria / Delayed / 6.0-6.0
pemphigus / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
hemolytic anemia / Delayed / Incidence not known
aplastic anemia / Delayed / Incidence not known
thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
pancytopenia / Delayed / Incidence not known
red cell aplasia / Delayed / Incidence not known
sideroblastic anemia / Delayed / Incidence not known
bronchiolitis obliterans / Delayed / Incidence not known
nephrotic syndrome / Delayed / Incidence not known
nephrotoxicity / Delayed / Incidence not known
vasculitis / Delayed / Incidence not known
glomerulonephritis / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
peptic ulcer / Delayed / Incidence not known
Guillain-Barre syndrome / Delayed / Incidence not known
optic neuritis / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
lupus-like symptoms / Delayed / Incidence not known
new primary malignancy / Delayed / Incidence not known

Moderate

thrombocytopenia / Delayed / 0-5.0
leukopenia / Delayed / 0-5.0
lymphadenopathy / Delayed / Incidence not known
synovitis / Delayed / Incidence not known
phlebitis / Rapid / Incidence not known
thrombocytosis / Delayed / Incidence not known
bleeding / Early / Incidence not known
eosinophilia / Delayed / Incidence not known
hemolysis / Early / Incidence not known
wheezing / Rapid / Incidence not known
dyspnea / Early / Incidence not known
hematuria / Delayed / Incidence not known
nephrolithiasis / Delayed / Incidence not known
hemoptysis / Delayed / Incidence not known
stomatitis / Delayed / Incidence not known
glossitis / Early / Incidence not known
oral ulceration / Delayed / Incidence not known
myasthenia / Delayed / Incidence not known
peripheral neuropathy / Delayed / Incidence not known
hypoglycemia / Early / Incidence not known
hepatitis / Delayed / Incidence not known
cholestasis / Delayed / Incidence not known

Mild

nausea / Early / 17.0-17.0
anorexia / Delayed / 17.0-17.0
diarrhea / Early / 17.0-17.0
vomiting / Early / 17.0-17.0
dysgeusia / Early / 12.0-12.0
rash / Early / 5.0-5.0
fever / Early / Incidence not known
pruritus / Rapid / Incidence not known
maculopapular rash / Early / Incidence not known
myalgia / Early / Incidence not known
urticaria / Rapid / Incidence not known
ecchymosis / Delayed / Incidence not known
chills / Rapid / Incidence not known
leukocytosis / Delayed / Incidence not known
pharyngitis / Delayed / Incidence not known
cough / Delayed / Incidence not known
cheilitis / Delayed / Incidence not known
ptosis / Delayed / Incidence not known
diplopia / Early / Incidence not known
vitamin B6 deficiency / Delayed / Incidence not known
weakness / Early / Incidence not known
tinnitus / Delayed / Incidence not known
anxiety / Delayed / Incidence not known
agitation / Early / Incidence not known
alopecia / Delayed / Incidence not known
lichen planus-like eruption / Delayed / Incidence not known
nail discoloration / Delayed / Incidence not known
arthralgia / Delayed / Incidence not known
breast enlargement / Delayed / Incidence not known

Boxed Warning
Fever, penicillamine hypersensitivity, penicillin hypersensitivity, requires an experienced clinician, serious rash

Administration of penicillamine requires an experienced clinician who is familiar with the toxicities, special dosage considerations, and therapeutic benefits. Never use penicillamine casually. Closely and constantly supervise each patient, and instruct patients to promptly report any possible toxicity symptoms. Toxicities include hematologic, renal, neuromuscular, and allergic reactions, some of which have been fatal. Penicillamine is contraindicated in patients with a prior history of penicillamine hypersensitivity. In addition, there is a possibility of cross-sensitivity between penicillin and penicillamine. Penicillamine should be used cautiously in patients known to have a penicillin hypersensitivity. Synthetic penicillamine is less likely to be contaminated with trace amounts of penicillin than drug produced as a degradation product of penicillin. Some patients may experience drug fever, a marked febrile response to penicillamine, usually in the second to third week following initiation of therapy. Drug fever may sometimes be accompanied by a macular cutaneous eruption. In the case of drug fever in patients with Wilson's disease or cystinuria, penicillamine should be temporarily discontinued until the reaction subsides. Then penicillamine should be reinstituted with a small dose that is gradually increased until the desired dosage is attained. Systemic steroid therapy may be necessary, and is usually helpful, in such patients in whom drug fever and rash develop several times. Rheumatoid arthritis patients who have developed fever during prior administration of penicillamine should not be retreated because experience suggests that febrile reactions will recur; alternative treatments are available for rheumatoid arthritis. A serious rash, such as the appearance of toxic epidermal necrolysis (TEN), necessitates penicillamine discontinuation.

Common Brand Names

Cuprimine, Depen

Dea Class

Rx

Description

Oral chelating agent; breakdown product of penicillin that has no antibacterial properties; D-isomer is prepared synthetically which reduces the incidence of hypersensitivity reactions
Used in the treatment of patients with Wilson's disease, cystinuria
Used historically for refractory rheumatoid arthritis, but myelosuppression, proteinuria and risk for autoimmune disease limits use

Dosage And Indications
For the treatment of Wilson's disease (hepatolenticular degeneration). Oral dosage Adults

250 mg PO 4 times daily, initially. To enhance tolerability, may also start with 250 to 500 mg/day PO, increased by 250 mg increments every 4 to 7 days, to a maximum of 1,000 to 1,500 mg/day, given in 2 to 4 divided doses. Maintenance dose is usually 750 to 1,000 mg/day given in 2 divided doses; doses exceeding 2,000 mg/day are rarely necessary. Adequate maintenance dose is a 24-hour urinary copper excretion of 200 to 500 mcg (3 to 8 micromol/L). In addition, adequate maintenance can be monitored by determination of free copper in serum. Patients should have a serum free copper level of less than 10 mcg/dL.

Pregnant Adult and Adolescent patients

Do not exceed a total dose of 750 mg/day PO. If a cesarean delivery is planned in advance, reduce dose to 250 mg PO daily for the last 6 weeks of pregnancy and postoperatively until wound healing is complete.

Infants†, Children†, and Adolescents†

10 to 20 mg/kg/day (Max: 1,500 mg/day) PO, rounded to the nearest 250-mg increment, given in 2 to 3 divided doses. Adequate maintenance dose is a 24-hour urinary copper excretion of 200 to 500 mcg (3 to 8 micromol/L). In addition, adequate maintenance can be monitored by determination of free copper in serum. Patients should have a serum free copper level of less than 10 mcg/dL.

For the treatment of cystinuria. Oral dosage Adults

Initially, 250 mg PO daily. Increase gradually to 1 to 4 grams PO per day, given in 4 divided doses (doses greater than 500 mg/day should be given as divided doses), and adjust to achieve urinary cystine excretion of less than 100 mg/day in patients with a history of renal calculi or pain, or 100 to 200 mg/day in patients with no history of renal calculi. Dosage should be accompanied by a high fluid intake; penicillamine requirements are lower the higher the fluid intake.

Infants, Children, and Adolescents

30 mg/kg/day PO in 4 divided doses (doses greater than 500 mg/day should be given as divided doses). If 4 equal doses are not feasible, the larger dose should be given at bedtime. Dosage should be adjusted to achieve urinary cystine excretion of less than 100 mg daily when renal calculi are present, or 100 to 200 mg daily when renal calculi are not present. Maximum: 4 grams/day.

For the treatment of arsenic toxicity. Oral dosage Adults

250 mg PO up to 4 times per day, not to exceed 1 g/day PO.

For the treatment of rheumatoid arthritis. For the treatment of juvenile rheumatoid arthritis (JRA)/juvenile idiopathic arthritis (JIA)†. Oral dosage Children

Initially, 3 mg/kg (250 mg/day or less) PO for 3 months, then 6 mg/kg (500 mg/day or less) PO in 2 divided doses for 3 months. Continue to a maximum of 10 mg/kg/day PO in 3 to 4 divided doses.

Oral dosage Adults

The recommended initial dose is 125 to 250 mg PO once daily. This dose can be increased at 1 to 3 month intervals by 125 to 250 mg/day according to patient response and tolerance (NOTE: Doses greater than 500 mg/day should be given as divided doses). If no response is evident after 2 to 3 months at a daily dose of 500 to 750 mg PO, the dosage may be increased by 250 mg/day at 2 to 3 monthly intervals until remission or intolerance occurs. If there is no improvement at a dose of 1 to 1.5 g/day after 3 to 4 months, assume there will not be a response and penicillamine therapy should be discontinued. The typical maintenance dosage usually ranges 500 to 750 mg PO daily.

For the treatment of lead toxicity†. Oral dosage Adults

1 to 1.5 g/day PO, divided every 8 to 12 hours for 4 to 12 weeks.

Children

30 to 40 mg/kg/day PO or 600 to 750 mg/m2/day PO in 2 to 3 divided doses for 4 to 12 weeks. Maximum dose is 1.5 g/day.

For the treatment of rapidly progressive scleroderma (systemic sclerosis)†. Oral dosage Adults

The effects of penicillamine were studied prospectively in 69 patients with rapidly progressing scleroderma of recent onset in an uncontrolled study. Treatment was initiated with a dose of 250 mg PO once daily and increased by 250 mg every 6 weeks (every 4 weeks for cases of fulminant progression) to a dose of 750 to 1500 mg/day (NOTE: Doses greater than 500 mg/day should be given as divided doses). Sixty patients received at least 750 mg/day of penicillamine for at least 6 months. Of these 60 patients, 58 experienced an arrest in the progression of skin sclerosis, followed by a regression characterized by skin softening, increased pliability and the reappearance of sweating and hair. The total body surface of sclerotic skin also improved considerably with therapy. In patients receiving treatment for at least 6 months, scleroderma-related renal disease was uncommon and pulmonary involvement was not progressive. The period of follow-up was variable and ranged from 10 to 171 months. The overall survival in the treatment group was 88%. Of the 9 patients that did not complete 6 months of therapy, 8 died of scleroderma-related causes. The incidence of adverse effects was high; 27 of 69 patients experienced adverse effects that necessitated a reduction in dose, or discontinuation. Two patients died from adverse reactions related to therapy.

†Indicates off-label use

Dosing Considerations
Hepatic Impairment

Penicillamine is metabolized in the liver and may require a dosage adjustment; however, specific guidelines for dosage adjustments in hepatic impairment are not available.

Renal Impairment

Penicillamine is primarily excreted in the urine, but specific guidelines for dosage adjustments in renal impairment are not available.

Drug Interactions

Aluminum Hydroxide: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Antacids: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Antimalarials: (Major) Do not use penicillamine concurrently with antimalarials due to an increased risk of severe hematologic and renal adverse reactions.
Antithymocyte Globulin: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Auranofin: (Contraindicated) Gold compounds have adverse reactions similar to those of penicillamine. Concomitant use of these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Basiliximab: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Calcium Carbonate: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Calcium Carbonate; Magnesium Hydroxide: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Calcium Carbonate; Simethicone: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Calcium; Vitamin D: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Corticosteroids: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Digoxin: (Moderate) Decreased serum digoxin concentrations have been reported in patients who received digoxin and penicillamine. Measure serum digoxin concentrations before initiating penicillamine. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary.
Foscarnet: (Moderate) The risk of renal toxicity may be increased if foscarnet is used in conjunction with other nephrotoxic agents such as penicillamine.
Gold: (Contraindicated) Gold compounds have adverse reactions similar to those of penicillamine. Concomitant use of these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
Iron: (Major) In general, oral mineral supplements should not be given since they may block the oral absorption of penicillamine. However, iron deficiency may develop, especially in children and menstruating or pregnant women, or as a result of the low copper diet recommended for Wilson's disease. If necessary, iron may be given in short courses, but since iron and penicillamine each inhibit oral absorption of the other, 2 hours should elapse between administration of penicillamine and iron doses.
Magnesium Hydroxide: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Magnesium Sulfate; Potassium Sulfate; Sodium Sulfate: (Major) Administer penicillamine at least 2 hours before or 6 hours after administration of magnesium sulfate; potassium sulfate; sodium sulfate. The absorption of penicillamine may be reduced by chelation with magnesium sulfate.
Omeprazole; Sodium Bicarbonate: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Polyethylene Glycol; Electrolytes: (Major) Administer penicillamine at least 2 hours before or 6 hours after administration of magnesium sulfate; potassium sulfate; sodium sulfate. The absorption of penicillamine may be reduced by chelation with magnesium sulfate.
Polyethylene Glycol; Electrolytes; Ascorbic Acid: (Major) Administer penicillamine at least 2 hours before or 6 hours after administration of magnesium sulfate; potassium sulfate; sodium sulfate. The absorption of penicillamine may be reduced by chelation with magnesium sulfate.
Pyridoxine, Vitamin B6: (Moderate) Pyridoxine, vitamin B6 excretion can be increased during the administration of penicillamine, possibly causing anemia or peripheral neuritis. Pyridoxine dosages may need to be increased during concomitant administration of penicillamine.
Sodium Bicarbonate: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Major) Penicillamine may chelate with the magnesium in sodium picosulfate; magnesium oxide; anhydrous citric acid solution. Therefore, penicillamine should be taken at least 2 hours before and not less than 6 hours after the administration of sodium picosulfate; magnesium oxide; anhydrous citric acid solution.

How Supplied

Cuprimine/Penicillamine Oral Cap: 250mg
Depen/Penicillamine Oral Tab: 250mg

Maximum Dosage
Adults

2 g/day PO for Wilson's disease; 1.5 g/day PO for rheumatoid arthritis and lead toxicity; 1 g/day PO for arsenic toxicity; 4 g/day PO for cystinuria.

Geriatric

2 g/day PO for Wilson's disease; 1.5 g/day PO for rheumatoid arthritis and lead toxicity; 1 g/day PO for arsenic toxicity; 4 g/day PO for cystinuria.

Adolescents

1.5 g/day PO for Wilson's disease and lead toxicity; 4 g/day PO for cystinuria; 10 mg/kg/day PO for JRA.

Children

1.5 g/day PO for Wilson's disease and lead toxicity; 4 g/day PO for cystinuria; 10 mg/kg/day PO for JRA.

Infants

30 mg/kg/day PO.

Mechanism Of Action

Mechanism of Action: Penicillamine chelates heavy metals including copper, iron, lead, and mercury, forming stable complexes that can then be excreted by the kidneys. One gram of penicillamine has the potential to combine with 200 mg of copper. When administered to patients with Wilson's disease, however, a 1 gm dose of penicillamine results in excretion of only 2 mg of copper.Penicillamine complexes with cystine, forming penicillamine-cysteine disulfide. This compound is more soluble than cysteine-cysteine disulfide (cystine), thereby reducing the levels of free urinary cystine below those considered crucial to the formation of cystine stones. Existing stones also may undergo dissolution during penicillamine therapy.Penicillamine's antirheumatic action may be due, in part, to the drug's ability to inhibit the formation of collagen. Penicillamine also appears to depress circulating levels of IgM rheumatoid factor, but, in contrast to cytotoxic immunosuppressants, the drug does not reduce the absolute levels of serum immunoglobulins. Penicillamine depresses T-cell activity but not B-cell activity.

Pharmacokinetics

Penicillamine is administered orally. The distribution of penicillamine is not well known, but it is believed to cross the placenta. Protein binding is about 80%, primarily to albumin. The drug also binds to erythrocytes and macrophages. Penicillamine appears in the plasma as free penicillamine, penicillamine disulfide, and cysteine-penicillamine disulfide. A small fraction of the dose is metabolized in the liver to s-methyl-D-penicillamine. Drug excretion is primarily renal, mainly as disulfides. One study determined that, of a total dose of penicillamine, approximately 50% was excreted in the urine and 20% in the feces. Approximately 30% of the drug remained unaccounted for. When prolonged treatment is stopped, there is a slow elimination phase lasting 4—6 days.

Oral Route

Penicillamine is rapidly absorbed from the GI tract following oral administration. Bioavailability is about 40—70%. Peak serum levels occur within 1—3 hours. The presence of food, antacids, or iron in the GI tract will slow absorption by complexing with the drug.

Pregnancy And Lactation
Pregnancy

Penicillamine can cause fetal harm when administered to a pregnant woman. Use during pregnancy is contraindicated except in the treatment of Wilson's disease and certain patients with cystinuria. In women with Wilson's disease, drug discontinuation during pregnancy may be fatal; continued treatment throughout pregnancy protects the mother against disease relapse. If penicillamine is administered to pregnant patients with Wilson's disease, a maximum daily dosage of 750 mg is recommended. Further dosage adjustments are required in women undergoing caesarean section. If caesarean section is planned the daily dose should be reduced to 250 mg, but not lower, for the last 6 weeks of pregnancy and postoperatively until wound healing is complete. Penicillamine should be used in females of childbearing potential for the treatment of Wilson's disease or certain patients with cystinuria only when the expected benefits outweigh the possible hazards; women should be apprised of the fetal risk and advised to report immediately any missed menstrual periods or other indications of possible pregnancy, and followed closely for early recognition of pregnancy. If penicillamine is used during pregnancy, or if a patient becomes pregnant while taking penicillamine, warn the patient of the potential hazard to the fetus. Prompt discontinuation is recommended for pregnant patients taking penicillamine for rheumatoid arthritis. Avoidance of penicillamine use during pregnancy to women with cystinuria is also recommended. If stones continue to develop in women with cystinuria, weigh the benefits of continued therapy to the mother against the fetal risks. Although adequate human studies have not been carried out, studies in animals have shown adverse fetal effects (i.e., skeletal defects, cleft palates, and fetal toxicity). Characteristic congenital cutis laxa and associated birth defects have been reported in infants whose mothers received penicillamine during pregnancy. Further, a woman with rheumatoid arthritis treated with less than one gram per day during pregnancy gave birth to an infant with growth retardation, flattened face with broad nasal bridge, low set ears, short neck with loose skin folds, and unusually lax body skin. Reports exist of women with cystinuria on penicillamine who gave birth to infants with generalized connective tissue defects who died following abdominal surgery.