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  • CLASSES

    Antidotes, Systemic
    Chelating Agents
    Other Specific Antirheumatics

    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.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral chelating agent used in the treatment of patients with Wilson's disease, cystinuria, and resistant cases of rheumatoid arthritis. Identified as a breakdown product of penicillin metabolism. Has no antibacterial properties. D-isomer used clinically and is prepared synthetically, thereby reducing the incidence of penicillin hypersensitivity reactions.

    COMMON BRAND NAMES

    Cuprimine, D-PENAMINE, Depen

    HOW SUPPLIED

    Cuprimine Oral Cap: 250mg
    Depen/D-PENAMINE Oral Tab: 125mg, 250mg

    DOSAGE & INDICATIONS

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

    250 mg PO 4 times per day. To maintain a negative free copper balance, dosage should be adjusted to achieve a urinary copper excretion of 0.5 to 1 mg/day. Except in the case of adverse response, penicillamine therapy 0.75 to 1.5 g per day that results in cupriuresis greater than 2 mg in an initial 24-hour period should be administered for 3 months (NOTE: doses greater than 500 mg/day should be given as divided doses). 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. If pregnant, do not exceed a total dose of 500 to 750 mg PO daily. 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.

    Children and Infants†

    20 mg/kg/day PO in 2 to 4 daily doses. Maximum daily dose is 1 g/day.

    For the treatment of cystinuria.
    Oral dosage
    Adults

    Initially, 250 mg PO daily. Increase gradually to 1 to 2 g PO daily 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.

    Children

    30 mg/kg/day PO, administered 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 dose is 4 g/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

    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; 5 g/day PO for cystinuria; 500—750 mg/day PO if pregnant. For planned cesarean section, reduce dose to 250 mg PO daily for the last 6 weeks of pregnancy and postoperatively until wound healing is complete.

    Elderly

    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; 5 g/day PO for cystinuria.

    Adolescents

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

    Children

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

    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.

    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.

    STORAGE

    Cuprimine:
    - Storage information not listed
    Depen:
    - Avoid exposure to heat
    - Protect from light
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    D-PENAMINE:
    - Protect from extreme heat
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store below 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    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.

    Agranulocytosis, aplastic anemia, bone marrow suppression, hematological disease, neutropenia

    Penicillamine should not be used in patients with previous penicillamine-induced agranulocytosis or aplastic anemia. Use is associated with a high incidence of adverse hematological reactions because of bone marrow suppression. The use of penicillamine has been associated with fatalities due to certain diseases such as aplastic anemia, agranulocytosis (severe neutropenia), and thrombocytopenia. Any patient with a history of hematological disease could experience a severe and possibly fatal reaction. A complete blood count, in addition to hemoglobin and direct platelet count should be performed twice a week, together with monitoring of patients skin, lymph nodes, and body temperature during the first month of therapy, every 2 weeks for the next 5 months, and monthly thereafter. Patients should be instructed to report promptly the development of signs and symptoms of granulocytopenia and/or thrombocytopenia such as fever, sore throat, chills, bruising or bleeding; the prescriber should promptly repeat laboratory testing.  Leukopenia and thrombocytopenia have been reported to occur in up to 5% of patients during penicillamine therapy. Leukopenia is of the granulocytic series and may or may not be associated with an increase in eosinophils. A confirmed reduction in WBC below 3500/mm3 mandates discontinuance of penicillamine therapy. Thrombocytopenia may be on an idiosyncratic basis, with decreased or absent megakaryocytes in the marrow, when it is part of an aplastic anemia. In other cases the thrombocytopenia is presumably on an immune basis since the number of megakaryocytes in the marrow has been reported to be normal or sometimes increased. The development of a platelet count below 100,000/mm3, even in the absence of clinical bleeding, requires at least temporary cessation of penicillamine therapy. A progressive fall in either platelet count or WBC in three successive determinations, even though values are still within the normal range, likewise requires at least temporary cessation.

    Pemphigus vulgaris

    Penicillamine should not be used in patients with various forms of pemphigus because this is a common adverse reaction to penicillamine therapy, and the condition can be exacerbated. Pemphigus vulgaris and pemphigus foliaceus are most frequent.

    Hematuria, nephrolithiasis, nephrotoxicity, proteinuria, renal failure, renal impairment

    Penicilliamine use is associated with nephrotoxicity, including kidney damage and use is contraindicated in patients with rheumatoid arthritis and a history or other evidence of renal insufficiency, including renal impairment, or renal failure. Proteinuria and/or hematuria may develop during therapy and may be warning signs of membranous glomerulopathy which can progress to a nephrotic syndrome. Close observation of these patients is essential. In some patients the proteinuria disappears with continued therapy; in others, penicillamine must be discontinued. When a patient develops proteinuria or hematuria the physician must ascertain whether it is a sign of drug-induced glomerulopathy or is unrelated to penicillamine. If the drug is used to treat rheumatoid arthritis (RA) patients with mild or moderate proteinuria, continue to monitor the urine-protein concentration and do not increase the dosage. Quantitative 24-hour urinary protein determinations are recommended every 1 to 2 weeks. Proteinuria that exceeds 1 gram/24 hours or proteinuria that is progressively increasing, requires either penicillamine discontinuance or dosage reduction. Proteinuria may resolve with dosage reduction. If unexplained gross hematuria or persistent microscopic hematuria develops in a patient with RA, discontinue penicillamine. For patients with Wilson's disease or cystinuria who have renal defects, the benefit of therapy must be weighed against the risk of exacerbating the underlying renal disease. An annual radiograph (X-ray) for kidney stones (nephrolithiasis) is advised if penicillamine is used for cystinuria. Cystine stones form rapidly, and up to 1 year or more may be required for any urinary abnormalities to disappear after penicillamine discontinuation. Goodpasture's syndrome, a potentially fatal reaction, has been reported in association with penicillamine. Goodpasture's syndrome has occurred rarely. The development of abnormal urinary findings associated with hemoptysis and pulmonary infiltrates on X-ray requires immediate cessation of penicillamine.

    Caesarean section, 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.

    Breast-feeding

    Although insufficient data are available on the administration of penicillamine while breast-feeding, the manufacturers recommend that alternative feeding methods be implemented if use of the drug is continued. According to the manufacturer, use during pregnancy is contraindicated, except for the treatment of patients with Wilson's disease or certain patients with cystinuria.

    Diabetes mellitus, hypoglycemia

    Penicillamine should be used cautiously in patients with diabetes mellitus. Nighttime hypoglycemia has occurred in 2 insulin dependent diabetic patients started on penicillamine. These patients required reductions in their insulin dosages. Also, penicillamine has been implicated in the formation of anti-insulin antibodies in 2 non-diabetic patients.

    Cholestasis, hepatitis, hepatotoxicity, jaundice

    Because of rare reports of hepatotoxicity, such as intrahepatic cholestasis, jaundice, and toxic hepatitis, liver function tests (LFTs) are recommended every 6 months for the duration of penicillamine therapy. In patients with Wilson's disease, LFTs are recommended every 3 months, at least during the first year of treatment.

    Geriatric

    Clinical studies of penicillamine did not include sufficient numbers of geriatric patients (>= 65 years) to adequately determine whether they respond differently from younger subjects. Review of reported clinical trials suggest greater risk in the elderly than in younger patients for overall skin rash and abnormality of taste. In general, dose selection for an elderly patient should be cautious, starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drugs. Penicillamine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and careful monitoring of renal function is recommended.

    Children

    The efficacy of penicillamine in children with juvenile rheumatoid arthritis (JRA) has not been established.

    Myasthenia gravis

    Onset of new neurological symptoms has been reported with penicillamine. Occasionally, neurological symptoms become worse during initiation of therapy. Myasthenic syndrome sometimes progressing to myasthenia gravis has been reported. Ptosis and diplopia, with weakness of the extraocular muscles, are often early signs of myasthenia. In the majority of cases, symptoms of myasthenia have receded after withdrawal of penicillamine.

    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

    DRUG INTERACTIONS

    Afatinib: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Aldesleukin, IL-2: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Alemtuzumab: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Altretamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    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: (Severe) Antimalarials have adverse reactions similar to those of penicillamine. Concomitant use is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
    Antineoplastic Agents: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    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.
    Arsenic Trioxide: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Auranofin: (Severe) 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.
    Axitinib: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Azacitidine: (Major) Do not use penicillamine with antineoplastic agents due to 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.
    Belinostat: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Bendamustine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Bevacizumab: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Bexarotene: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Bleomycin: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Bortezomib: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Bosutinib: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Busulfan: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Cabazitaxel: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Cabozantinib: (Major) Do not use penicillamine with antineoplastic agents due to 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; 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; Risedronate: (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.
    Capecitabine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Carboplatin: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Carmustine, BCNU: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Ceritinib: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Cetuximab: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Chlorambucil: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Cisplatin: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Cladribine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Clofarabine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Cobimetinib: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    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.
    Crizotinib: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Cyclophosphamide: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Cytarabine, ARA-C: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Dacarbazine, DTIC: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Dactinomycin, Actinomycin D: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Dasatinib: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Daunorubicin Liposomal: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Daunorubicin Liposomal; Cytarabine Liposomal: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Daunorubicin: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Decitabine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Denileukin Diftitox: (Major) Do not use penicillamine with antineoplastic agents due to 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.
    Docetaxel: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Doxorubicin Liposomal: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Doxorubicin: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Efalizumab: (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.
    Epirubicin: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Eribulin: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Erlotinib: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Estramustine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Etoposide, VP-16: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Floxuridine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Fludarabine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Fluorouracil, 5-FU: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Foscarnet: (Moderate) The risk of renal toxicity may be increased if foscarnet is used in conjunction with other nephrotoxic agents such as penicillamine.
    Gefitinib: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Gemcitabine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Gold Sodium Thiomalate: (Severe) 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.
    Gold: (Severe) 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.
    Hydroxychloroquine: (Severe) Concomitant use of penicillamine with hydroxychloroquine is contraindicated. Hydroxychloroquine used concurrently with penicillamine can increase penicillamine plasma concentrations, possibly causing serious adverse hematological, renal, or skin reactions.
    Hydroxyurea: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Ibritumomab Tiuxetan: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Idarubicin: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Ifosfamide: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Imatinib: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Interferon Alfa-2a: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Interferon Alfa-2b: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Interferon Alfa-2b; Ribavirin: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Irinotecan: (Major) Do not use penicillamine with antineoplastic agents due to 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.
    Ixabepilone: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Lapatinib: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    L-Asparaginase Escherichia coli: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Lenvatinib: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Lomustine, CCNU: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    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.
    Mechlorethamine, Nitrogen Mustard: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Melphalan: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Mercaptopurine, 6-MP: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Methotrexate: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Methoxsalen: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Mitomycin: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Mitoxantrone: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Muromonab-CD3: (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.
    Nanoparticle Albumin-Bound Paclitaxel: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Nelarabine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Nilotinib: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Olaparib: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Omacetaxine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    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.
    Osimertinib: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Oxaliplatin: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Paclitaxel: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pazopanib: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pegaspargase: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pemetrexed: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentostatin: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Plicamycin: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Ponatinib: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Porfimer: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Procarbazine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    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.
    Rituximab: (Moderate) The concomitant use of rituximab with other disease modifying anti-rheumatic drugs (DMARDs), such as penicillamine, may result in additive immunosuppression and an increased risk of infection. Monitor patients closely for signs or symptoms of infection.
    Rituximab; Hyaluronidase: (Moderate) The concomitant use of rituximab with other disease modifying anti-rheumatic drugs (DMARDs), such as penicillamine, may result in additive immunosuppression and an increased risk of infection. Monitor patients closely for signs or symptoms of infection.
    Romidepsin: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Ruxolitinib: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    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.
    Sorafenib: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Streptozocin: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Sunitinib: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Telbivudine: (Moderate) The risk of myopathy may be increased if penicillamine is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Temozolomide: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Teniposide: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Thioguanine, 6-TG: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Thiotepa: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Topotecan: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Tositumomab: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Trametinib: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Trastuzumab: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Tretinoin, ATRA: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Vemurafenib: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Vinblastine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Vincristine Liposomal: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Vincristine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Vinorelbine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Vorinostat: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.

    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.

    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.