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PENICILLAMINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Penicillamine is a degradation product of penicillin and acts as a chelator of heavy metals.

Specific Substances

    1) 3-mercaptovaline
    2) Alpha amino beta methyl beta mercaptobutyric acid
    3) Beta, beta-dimethylcysteine
    4) Beta mercaptovaline
    5) Beta thiovaline
    6) D-3-mercaptovaline
    7) D-beta-thiovaline
    8) DMC
    9) D-mercaptovaline
    10) Dimethylcysteine
    11) D-valine, 3-mercapto-
    12) Metalcaptase
    13) PCA
    14) NIOSH/RTECS YV 9425000
    15) Valine, 3-mercapto-,D-
    16) Molecular Formula: C5-H11-N-O2-S
    17) CAS 52-67-5 (penicillamine)
    18) CAS 2219-30-9 (penicillamine hydrochloride)
    1.2.1) MOLECULAR FORMULA
    1) C5-H11-N-O2-S

Available Forms Sources

    A) FORMS
    1) Penicillamine is available as 125 mg and 250 mg capsules, and as 250 mg tablets (Prod Info DEPEN(R) titratable oral tablets, 2009; Prod Info CUPRIMINE(R) oral capsules, 2007).
    B) USES
    1) Penicillamine is a heavy metal chelator of copper, lead, and mercury. It promotes the excretion of these metals in the urine and has been used to treat cystinuria, Wilson's disease, and heavy metal poisoning. The drug has also been very successful for rheumatoid arthritis patients (Prod Info DEPEN(R) titratable oral tablets, 2009; Prod Info CUPRIMINE(R) oral capsules, 2007).
    2) In rodent models of thallium intoxication, D-penicillamine combined with Prussian blue decreased mortality and tissue levels of thallium without causing redistribution to brain (Rios & Monroy-Noyola, 1992; Barroso-Moguel et al, 1994). D-penicillamine alone caused redistribution of thallium to brain and increased mortality (Rios & Monroy-Noyola, 1992; Barroso-Moguel et al, 1994).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Penicillamine is a heavy metal chelator of copper, lead, and mercury. It promotes the excretion of these metals in the urine and has been used to treat cystinuria, Wilson's disease, and heavy metal poisoning. Penicillamine has also been used to treat patients with severe, active rheumatoid arthritis.
    B) PHARMACOLOGY: Penicillamine is a degradation product of penicillin and acts as a chelator of heavy metals. It chelates copper, lead, and mercury. Although in vitro studies indicate copper binding at 1 gram penicillamine to 200 mg copper, only about 2 mg of copper are excreted by 1 gram of penicillamine for a 2% efficiency. Penicillamine is also used to treat cystinuria by forming a soluble urinary complex thus reducing the formation risk of renal stones. It also chelates iron and probably other heavy metals to form stable, soluble complexes that are readily excreted in the urine. The mechanism of action of penicillamine in rheumatoid arthritis is not known, but may involve improvement of lymphocyte function. It markedly reduces IgM rheumatoid factor and immune complexes in serum and synovial fluid, but does not significantly lower absolute concentrations of serum immunoglobulins.
    C) TOXICOLOGY: The L isomer and racemic mixture are more toxic than the D isomer. The N-acetylated form of DL-penicillamine has shown less toxicity than the DL mixture itself, and more similar to that of penicillamine.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) The following adverse effects have been reported following the therapeutic use of penicillamine: anorexia, nausea, vomiting, loss of taste, abdominal pain, optic neuritis, retinopathy, photophobia, lacrimation, conjunctival inflammation, proteinuria, nephrotic syndrome, glomerulonephritis, disturbance in copper and zinc metabolism, hypersensitivity reactions, thrombocytopenia, thrombotic thrombocytopenic purpura, leukopenia, polycythemia, aplastic anemia, lymphopenia, agranulocytosis, rashes, alveolitis, pulmonary hemorrhage, bronchial asthma, pleurisy, hemoptysis, bronchiolitis obliterans, and bilateral infiltrate, seizures, neuropathies, dystonia and various autoimmune responses (eg, polymyositis, myasthenia gravis, SLE, Goodpasture's syndrome, thyroiditis). In some studies, adverse effects occurred in as high as 62% of patients, with 36% experiencing symptoms which necessitated discontinuation of therapy. Most of these toxic side effects occur with chronic administration. The relationship to dose is unclear, as even patients taking small doses may develop toxicity. Although penicillamine has a structure very similar to penicillin, there does not appear to be extensive crossreactivity even though skin testing may show crossreactivity.
    F) WITH POISONING/EXPOSURE
    1) Overdose data are limited. In general, overdose effects are anticipated to be an extension of adverse effects at therapeutic doses. Occupational asthma has been reported in a pharmaceutical company worker after chronic exposure to penicillamine.
    0.2.20) REPRODUCTIVE
    A) Connective tissue defects including congenital cutis hyperelastia has been seen in a number of children born to mothers taking D-penicillamine. Other abnormalities reported include hydrocephalus, cerebral palsy, webbing of the fingers and toes, and arthrogryposis multiplex.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status in symptomatic patients.
    C) Monitor CBC with differential and platelet count, renal function, liver enzymes, and serum electrolytes in symptomatic patients.
    D) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.
    E) Patients on long term penicillamine therapy: Consider monitoring renal function, urinalysis, complete blood count with differential and platelets every 2 weeks for the first 4 to 6 months and monthly thereafter, copper and zinc levels, liver enzymes, and pyridoxine concentrations.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Myelosuppression has been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg, filgrastim, sargramostim). Transfusions may be required for severe thrombocytopenia or bleeding. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Pemphigus has been treated with anti-immune drugs such as prednisone or azathioprine. In some cases, the administration of pyridoxine has decreased the neurologic toxicity of penicillamine.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not recommended because of the potential for persistent seizures and subsequent aspiration.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain their airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe respiratory distress, persistent seizures, or severe allergic reactions.
    E) ANTIDOTE
    1) None.
    F) MYELOSUPPRESSION
    1) Severe neutropenia: filgrastim 5 mcg/kg/day IV or SubQ or sargramostim 250 mcg/m(2)/day IV infused over 4 hours. Monitor serial CBC with differential. Transfusions may be required for severe thrombocytopenia or bleeding.
    G) ENHANCED ELIMINATION
    1) Hemodialysis is unlikely to be of value because of the high degree of protein binding (greater than 80%).
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    I) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered.
    J) PHARMACOKINETICS
    1) Tmax: 3 hours. Absorption ranges from 40% to 70% and is not dose dependent. Protein binding: More than 80%. Excretion: Penicillamine is eliminated primarily by the kidney, but it also undergoes some hepatic metabolism. About 30% to 60% of penicillamine given in a single dose was recovered in the urine in the first 48 hours. Elimination half-life: Penicillamine has a biphasic half-life. When tested in patients with rheumatoid arthritis, the initial rapid phase was 1.6 hours and the slow phase was 4 to 6 days.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression, hepatotoxicity, or dystonia.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) TOXICITY: Limited data are available. No specific acute toxic dose has been established. Toxic effects generally occur in those patients taking penicillamine chronically. The relationship to dose is unclear, as even patients on small doses may develop toxicity. THERAPEUTIC DOSE: ADULT: CYSTINURIA: 2 g/day but may range from 1 to 4 g/day. RHEUMATOID ARTHRITIS: Initial dose, 125 to 250 mg daily, increased at 1 to 3 month intervals by 125 to 250 mg daily; a frequent maintenance dose is 500 to 750 mg/day. WILSON'S DISEASE: Initial dose, 0.75 to 1.5 g/day that results in cupriuresis of over 2 mg/day, continued for about 3 months; may be increased gradually up to 2 g/day. PEDIATRIC: CYSTINURIA: 30 mg/kg/day, divided into 4 doses. RHEUMATOID ARTHRITIS: Safety and efficacy in the pediatric or adolescent population have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Penicillamine is a heavy metal chelator of copper, lead, and mercury. It promotes the excretion of these metals in the urine and has been used to treat cystinuria, Wilson's disease, and heavy metal poisoning. Penicillamine has also been used to treat patients with severe, active rheumatoid arthritis.
    B) PHARMACOLOGY: Penicillamine is a degradation product of penicillin and acts as a chelator of heavy metals. It chelates copper, lead, and mercury. Although in vitro studies indicate copper binding at 1 gram penicillamine to 200 mg copper, only about 2 mg of copper are excreted by 1 gram of penicillamine for a 2% efficiency. Penicillamine is also used to treat cystinuria by forming a soluble urinary complex thus reducing the formation risk of renal stones. It also chelates iron and probably other heavy metals to form stable, soluble complexes that are readily excreted in the urine. The mechanism of action of penicillamine in rheumatoid arthritis is not known, but may involve improvement of lymphocyte function. It markedly reduces IgM rheumatoid factor and immune complexes in serum and synovial fluid, but does not significantly lower absolute concentrations of serum immunoglobulins.
    C) TOXICOLOGY: The L isomer and racemic mixture are more toxic than the D isomer. The N-acetylated form of DL-penicillamine has shown less toxicity than the DL mixture itself, and more similar to that of penicillamine.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) The following adverse effects have been reported following the therapeutic use of penicillamine: anorexia, nausea, vomiting, loss of taste, abdominal pain, optic neuritis, retinopathy, photophobia, lacrimation, conjunctival inflammation, proteinuria, nephrotic syndrome, glomerulonephritis, disturbance in copper and zinc metabolism, hypersensitivity reactions, thrombocytopenia, thrombotic thrombocytopenic purpura, leukopenia, polycythemia, aplastic anemia, lymphopenia, agranulocytosis, rashes, alveolitis, pulmonary hemorrhage, bronchial asthma, pleurisy, hemoptysis, bronchiolitis obliterans, and bilateral infiltrate, seizures, neuropathies, dystonia and various autoimmune responses (eg, polymyositis, myasthenia gravis, SLE, Goodpasture's syndrome, thyroiditis). In some studies, adverse effects occurred in as high as 62% of patients, with 36% experiencing symptoms which necessitated discontinuation of therapy. Most of these toxic side effects occur with chronic administration. The relationship to dose is unclear, as even patients taking small doses may develop toxicity. Although penicillamine has a structure very similar to penicillin, there does not appear to be extensive crossreactivity even though skin testing may show crossreactivity.
    F) WITH POISONING/EXPOSURE
    1) Overdose data are limited. In general, overdose effects are anticipated to be an extension of adverse effects at therapeutic doses. Occupational asthma has been reported in a pharmaceutical company worker after chronic exposure to penicillamine.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Visual disturbance has been reported with penicillamine use (Prod Info CUPRIMINE(R) oral capsules, 2010).
    2) OPTIC NEURITIS: Optic neuritis has been reported with penicillamine use (Prod Info CUPRIMINE(R) oral capsules, 2010). Axial optical neuritis has been reported as a side effect when DL-penicillamine was used to treat Wilson's disease (Gosselin et al, 1984).
    a) In one case, the symptoms reversed when the dosage was reduced and the patient was given pyridoxine (Tu et al, 1963; Goldstein et al, 1966).
    b) Optic neuritis was also seen in a patient using penicillamine, who had partial optic atrophy from infancy. His condition improved when pyridoxine was given (Damaske & Althoff, 1972).
    3) RETINOPATHY has been reported in several patients taking therapeutic doses (Dingle & Havener, 1978; Klepach & Wray, 1981).
    4) MYOPIA: Gradual changes in refraction and increasing myopia has been seen with therapeutic doses (Michiels et al, 1962).
    5) IRRITATION: Photophobia and lacrimation, as well as conjunctival inflammation have been seen as side effects of penicillamine therapy (Ishak & Abbas, 2013; McDonald & Henneman, 1965; Sternlieb & Scheinberg, 1964). This included chalazion in the eyelids of two patients with blepharo-conjunctivitis (Scheinberg, 1964).
    6) DIPLOPIA may occur with therapeutic use of penicillamine (Ishak & Abbas, 2013).
    7) OCULAR MYASTHENIA GRAVIS has been reported in more than 20 articles. Effects include diplopia and ptosis. It seems to be most frequently associated with rheumatoid arthritis patients who have been taking penicillamine for several months (Drosos et al, 1993; Raynauld et al, 1993; Adelman et al, 1995).
    a) Patients with Wilson's disease are much less susceptible to this side effect (Grant, 1986; Atcheson & Ward, 1978; Kimbrough et al, 1981).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) TINNITUS has been reported with penicillamine use (Prod Info CUPRIMINE(R) oral capsules, 2010).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) RHINITIS may occur following exposures.
    2) CASE REPORT: A 76-year-old patient who had been taking penicillamine 125 mg three times a day for 2 months developed blocked nasal passages due to edema, and then a constant nasal discharge. Short courses of 1% ephedrine nasal drops and xylometazoline nasal drops were not beneficial, nor were steroids. The condition stopped when the penicillamine was discontinued (Presley, 1988).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PERIPHERAL ISCHEMIA
    1) WITH THERAPEUTIC USE
    a) ARTERIAL DAMAGE: It is well known that long term penicillamine therapy may cause changes in the elastic tissues of the skin. One study showed morphologically specific elastic tissue alterations in systemic arteries as well (Price & Prentice, 1986).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PNEUMONIA
    1) WITH THERAPEUTIC USE
    a) Interstitial pneumonitis has been reported with penicillamine use (Prod Info CUPRIMINE(R) oral capsules, 2010).
    b) ALVEOLITIS: A patient who was started on 150 mg/day and increased to 450 mg/day developed symptoms of fibrosing alveolitis including dyspnea, and cough after 12 months of treatment. When the penicillamine was discontinued, the dyspnea improved within a week, and by 3 months pulmonary function studies were normal (Eastmond, 1976).
    c) BRONCHIOLITIS OBLITERANS: Obliterative bronchiolitis was reported in 4 of 3,356 patients receiving penicillamine as therapy for a variety of illnesses (Lyle, 1977).
    B) PULMONARY HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) Pulmonary hemorrhage has been reported in a few patients taking 1 to 3.5 grams per day for 2 to 3 years for the treatment of Wilson's disease. Effects included weakness, pleurisy, hemoptysis, and bilateral infiltrates (Sternlieb et al, 1975; Louie et al, 1986).
    C) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Tanphaichitr (1980) reported a case of reversible airway obstruction and angioedema in a patient whose penicillamine dose had been slowly raised to 250 mg three times a day over an 8 week period (Tanphaichitr, 1980).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Occupational asthma has been reported in a pharmaceutical company worker. The symptoms of sneezing, wheezing, and dyspnea started after 7 years of exposure. Symptoms were initiated almost immediately on exposure during the day, and persisted into the evening hours at home. Laboratory tests indicated that the asthma was not IgE medicated (Lagier et al, 1989).
    D) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea may develop after many months of therapy (Kay, 1986).
    b) Penicillamine-induced bronchoalveolitis with severe dyspnea may occur in patients receiving penicillamine (Ishak & Abbas, 2013).
    E) PLEURAL EFFUSION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A case of pleural effusion has been reported in a patient that had been receiving penicillamine 1.5 g/day for approximately 13 years for the treatment of Wilson's disease (Karkos et al, 1996).
    F) EXTRINSIC ALLERGIC ALVEOLITIS
    1) WITH THERAPEUTIC USE
    a) Allergic alveolitis has been reported with penicillamine use (Prod Info CUPRIMINE(R) oral capsules, 2010).
    b) Penicillamine-induced bronchoalveolitis with severe dyspnea may occur in patients receiving penicillamine (Ishak & Abbas, 2013).
    G) ASTHMA
    1) WITH THERAPEUTIC USE
    a) Bronchial asthma has been reported with penicillamine use (Prod Info CUPRIMINE(R) oral capsules, 2010).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Occupational asthma has been reported in a pharmaceutical company worker. The symptoms of sneezing, wheezing, and dyspnea started after 7 years of exposure. Symptoms were initiated almost immediately on exposure during the day, and persisted into the evening hours at home. Laboratory tests indicated that the asthma was not IgE medicated (Lagier et al, 1989).
    H) FIBROSIS OF LUNG
    1) WITH THERAPEUTIC USE
    a) Pulmonary fibrosis has been reported with penicillamine use (Prod Info CUPRIMINE(R) oral capsules, 2010).
    I) OBLITERATIVE BRONCHIOLITIS
    1) WITH THERAPEUTIC USE
    a) Obliterative bronchiolitis has been reported with penicillamine use (Prod Info CUPRIMINE(R) oral capsules, 2010).
    b) Obliterative bronchiolitis was reported in 4 of 3,356 patients receiving penicillamine as therapy for a variety of illnesses (Lyle, 1977).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) MUSCLE WEAKNESS
    1) WITH THERAPEUTIC USE
    a) MYASTHENIA GRAVIS occurs in under 1% of patients who are taking penicillamine for rheumatoid arthritis. Autoimmune myasthenia gravis and this penicillamine induced variety have similar pathophysiology, including the presence of an anti-acetylcholine receptor antibody, serum induced blockage of anti-acetylcholine receptors, and antibody mediated accelerated degradation of these receptors. The net result is a reduction in the junctional anti-acetylcholine receptors (Kuncl et al, 1986; Dawkins et al, 1987).
    b) Effects include diplopia, ptosis, difficulty swallowing, slurred speech, difficulty walking, dyspnea and respiratory failure (Drosos et al, 1993; Raynauld et al, 1993; Jones et al, 1993; Adelman et al, 1995).
    B) SEIZURE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 25-year-old woman treated with 4 grams per day for 11 months developed psychomotor status epilepticus that did not respond to 450 mg of phenobarbital over 12 hours, but did respond to 100 mg of pyridoxine IV. The authors suggested the seizures were due to pyridoxine deficiency (Smith & Gallagher, 1970).
    C) NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) Peripheral sensory or motor neuropathy has been reported with penicillamine use. Muscular weakness may or may not be present (Prod Info CUPRIMINE(R) oral capsules, 2010).
    b) CASE REPORT: A 55-year-old woman developed a symmetrical, rapidly progressive motor and sensory neuropathy while receiving 500 to 750 mg of penicillamine per day. Her condition improved when given 50 mg per day of pyridoxine (Pool et al, 1981).
    D) POLYRADICULONEUROPATHY
    1) WITH THERAPEUTIC USE
    a) Polyradiculoneuropathy (ie, Guillain-Barre syndrome) has been reported with penicillamine use (Prod Info CUPRIMINE(R) oral capsules, 2010).
    E) DYSTONIA
    1) WITH THERAPEUTIC USE
    a) Dystonia has been reported with penicillamine use (Prod Info CUPRIMINE(R) oral capsules, 2010).
    b) CASE REPORT: A 37-year-old man with Wilson's disease and neurologic symptoms, developed severe generalized dystonia with superimposed painful spasms of the limbs and trunk after taking penicillamine (up to 1250 mg/day) for approximately 4 weeks. After approximately 2 weeks, he developed hypotension, hypoglycemia, sinus tachycardia (100 to 140 beats/min), fever, leukocytosis (25 x 109/L), rhabdomyolysis, metabolic acidosis (pH 7.25), and a renal failure with a urea of 16.3 mmol/L and myoglobinuria. Despite all measures, he developed oliguria and died after 3 weeks of status dystonicus (Svetel et al, 2001).
    c) CASE SERIES: Three cases of acute generalized dystonia and akinetic rigid syndrome have been reported following initial therapy with penicillamine (125 to 500 mg/day) for Wilson's disease. Brain MRI revealed lesions in the thalamus and brainstem. Brain lesions resolved following continuation of penicillamine or replacement with zinc sulfate. Dystonia improved following the disappearance of the brain lesions (Huang & Chu, 1998).
    d) The mechanism of penicillamine associated dystonia in patients with Wilson's disease is believed to be mobilization of copper to the brain from the liver following decopperization by penicillamine (Huang & Chu, 1998).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SEIZURES
    a) RATS given doses of the racemic mixture exhibited running fits, excessive salivation, and seizures. Deaths occurred within 3 to 12 hours.

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) LOSS OF TASTE
    1) WITH THERAPEUTIC USE
    a) TASTE ABNORMALITIES: Therapeutic administration of penicillamine (usually with 400 milligrams or more per day) is often associated with loss of taste perception (Kay, 1986). This is associated with depressed serum ceruloplasmin concentrations.
    b) Blunting, reduced, and total loss of taste have been reported in 12% of patients treated with penicillamine. It is reported to last 2 to 3 months and may progress to complete loss of taste. It is usually self-limiting despite ongoing penicillamine therapy. Loss of taste occurs rarely in patients with Wilson disease (Prod Info CUPRIMINE(R) oral capsules, 2010).
    c) Discontinuation of the penicillamine, or administration of copper sulfate in a dose of 5 to 15 mg/day, usually returns the taste to normal in 1 to 4 months (Jaffe, 1968; Vogel et al, 1974).
    B) COLITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 61-year-old woman who was receiving 375 mg of penicillamine per day for rheumatoid arthritis developed profuse diarrhea containing blood and mucous. The colitis was associated with considerable abdominal pain (Hickling & Fuller, 1979).
    C) GASTROENTERITIS
    1) WITH THERAPEUTIC USE
    a) Anorexia, epigastric pain, nausea, vomiting, or occasional diarrhea have been reported in 17% of patients with rheumatoid arthritis who received penicillamine therapy in 17 clinical trials (n=1270) (Prod Info CUPRIMINE(R) oral capsules, 2010).
    b) Nausea, vomiting, diarrhea, and epigastric discomfort occurred in 14% to 39% of individuals taking penicillamine therapeutically (Metcalf et al, 1980; Ishak & Abbas, 2013). Other effects included dyspepsia and anorexia (Ishak & Abbas, 2013).
    D) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) Isolated cases of pancreatitis have been reported with penicillamine use (Prod Info CUPRIMINE(R) oral capsules, 2010).
    E) GINGIVITIS
    1) WITH THERAPEUTIC USE
    a) Buccal ulceration is estimated to occur in 7 to 13% of those taking the drug therapeutically. It generally takes 3 to 4 weeks for the condition to clear after the drug has been discontinued (Metcalf et al, 1980).
    b) CASE REPORT: Gingivitis was seen in a 19-year-old who took a dose of 1 gram per day. The lesions healed within three days of drug discontinuation (Bennett & Harbilas, 1967).
    F) INFLAMMATORY DISEASE OF MUCOUS MEMBRANE
    1) WITH THERAPEUTIC USE
    a) Buccal ulceration is estimated to occur in 7 to 13% of those taking the drug therapeutically. It generally takes 3 to 4 weeks for the condition to clear after the drug has been discontinued (Metcalf et al, 1980).
    b) CASE REPORT: Stomatitis was seen in a 19-year-old who took a dose of 1 gram per day. The lesions healed within three days of drug discontinuation (Bennett & Harbilas, 1967).
    G) CHEILITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Cheilosis were seen in a 19-year-old who took a dose of 1 gram per day. The lesions healed within three days of drug discontinuation (Bennett & Harbilas, 1967).
    H) PEPTIC ULCER
    1) WITH THERAPEUTIC USE
    a) Isolated cases of reactivated peptic ulcer have been reported with penicillamine use (Prod Info CUPRIMINE(R) oral capsules, 2010).
    I) ULCER OF MOUTH
    1) WITH THERAPEUTIC USE
    a) Oral ulcerations with the appearance of aphthous stomatitis have been reported in patients receiving penicillamine therapy. This effect is dose-related (Prod Info CUPRIMINE(R) oral capsules, 2010).
    J) CHEILOSIS
    1) WITH THERAPEUTIC USE
    a) Cheilosis has been reported rarely with penicillamine therapy. This effect is dose-related (Prod Info CUPRIMINE(R) oral capsules, 2010).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) CHOLESTATIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Toxic hepatitis and intrahepatic cholestasis have been rarely reported with penicillamine use (Prod Info CUPRIMINE(R) oral capsules, 2010).
    b) CASE REPORT: Cholestasis has been reported in one patient who died (Barzilai, 1978).
    c) CASE REPORT: Upper right quadrant pain, nausea, and elevated liver enzymes were seen in a patient who was first given 750 mg/day and later only 250 mg/day. The condition cleared between the two dosage schedules, during which time the penicillamine had been discontinued (Langan & Thomas, 1987).
    d) Numerous other authors have reported cholestasis as a complication of penicillamine therapy (Barzilai, 1978; McLeod & Kinsella, 1979; Seibold et al, 1981; Multz, 1981).
    e) CASE REPORT: Cholestatic hepatitis developed in a 37-year-old woman with rheumatoid arthritis who received penicillamine 125 milligrams/day for 10 days. Hepatitis progressed to hepatic fibrosis despite discontinuation of penicillamine and therapy with prednisone and ursodeoxycholic acid (Jacobs et al, 1994).
    B) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) ELEVATED TRANSAMINASE LEVELS: Mild persistent elevations in aspartate aminotransferase and alanine aminotransferase developed in two children being treated with penicillamine for Wilson's disease. These resolved when zinc sulfate was substituted and recurred when penicillamine was reintroduced (Menara & Zancan, 1992).
    C) HEPATIC FAILURE
    1) WITH THERAPEUTIC USE
    a) Isolated cases of hepatic failure have been reported with penicillamine use (Prod Info CUPRIMINE(R) oral capsules, 2010).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) PROTEINURIA
    1) WITH THERAPEUTIC USE
    a) Proteinuria (6%) and hematuria may develop in patients treated with penicillamine, especially those with rheumatoid arthritis (Ishak & Abbas, 2013; Prod Info CUPRIMINE(R) oral capsules, 2010; Kay, 1986; Hall et al, 1988).
    b) INCIDENCE: Proteinuria has been reported in 6% of patients with rheumatoid arthritis who received penicillamine therapy in 17 clinical trials (n=1270) (Prod Info CUPRIMINE(R) oral capsules, 2010). Proteinuria developed in 14% of patients on long term therapy in one series (Halverson et al, 1978).
    1) One study reported proteinuria in 4% to 33% of patients receiving penicillamine and 70% or more of those patients developed nephrotic syndrome (Ishak & Abbas, 2013).
    c) PREDISPOSING CONDITIONS: There seems to be a relationship between various HLA markers and the development of proteinuria (Stockman et al, 1986). This may be useful in an acute setting as a predictor of whether a patient is likely to develop proteinuria.
    1) Another predictor for the risk of developing proteinuria appears to be impaired sulfoxidation (Emery et al, 1984; Emery, 1987).
    B) GLOMERULONEPHRITIS
    1) WITH THERAPEUTIC USE
    a) Hall et al (1988) discussed the natural course of penicillamine-induced nephropathy in a series of 33 patients with rheumatoid arthritis. Proteinuria generally occurred within 2 to 75 months with doses of 125 to 1250 mg/day. Membranous glomerulonephritis was observed on renal biopsy of a number of these patients (Hall et al, 1988).
    b) Glomerulonephritis has been reported in a number of other patients on penicillamine therapy. Effects may include proteinuria, hematuria, elevated serum creatinine, peripheral edema and hypertension (Devogelaer et al, 1987; Almirall et al, 1993; Donnelly et al, 1993; Jones & Major, 1992).
    C) ACUTE RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) Renal failure has been reported with penicillamine use (Prod Info CUPRIMINE(R) oral capsules, 2010).
    b) Acute reversible renal failure with nephrotic syndrome and tubulointerstitial nephritis has also been seen (Feehally et al, 1987).
    D) URINARY INCONTINENCE
    1) WITH THERAPEUTIC USE
    a) ENURESIS developed in 3 of 84 (4%) children receiving penicillamine for lead poisoning (Shannon et al, 1988).
    E) NEPHROTIC SYNDROME
    1) WITH THERAPEUTIC USE
    a) Nephrotic syndrome has been reported with penicillamine use as a result of an immune complex membranous glomerulopathy (Prod Info CUPRIMINE(R) oral capsules, 2010).
    b) In some patients, nephrotic syndrome with membranous glomerulopathy, anti-neutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis, or Goodpasture-like syndrome may occur (Ishak & Abbas, 2013).
    F) KIDNEY STONE
    1) WITH THERAPEUTIC USE
    a) Cystine stones have been reported in patients receiving penicillamine for cystinuria (Prod Info CUPRIMINE(R) oral capsules, 2010).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) HEMATOLOGICAL EFFECTS are more common with rheumatoid arthritis patients than with Wilson's disease or cystinuria patients (Camp, 1981), and there seems to be an association between various HLA markers in rheumatoid arthritis patients and the development of thrombocytopenia in this group (Stockman et al, 1986).
    b) Penicillamine use has been associated with aplastic anemia, agranulocytosis, and thrombocytopenia, some resulting in fatalities (Prod Info CUPRIMINE(R) oral capsules, 2010).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia was reported in 4% of patients with rheumatoid arthritis receiving penicillamine therapy in 17 clinical trials (n=1270) (Prod Info CUPRIMINE(R) oral capsules, 2010).
    b) Thrombocytopenia is the most common hematological side effect seen with penicillamine therapy, occurring in about 8% of all patients. This effect is most often associated with raising a dose too rapidly or too high. The decrease in platelets is generally gradual and may be transient (Shannon et al, 1988).
    C) HEMOLYTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Hemolytic anemia has been reported with penicillamine use (Prod Info CUPRIMINE(R) oral capsules, 2010).
    D) ERYTHROCYTOSIS
    1) WITH THERAPEUTIC USE
    a) Polycythemia has been reported as a rare side effect of penicillamine therapy (Camp, 1981).
    E) APLASTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Cases of aplastic anemia, including fatalities, have been reported with penicillamine use (Prod Info CUPRIMINE(R) oral capsules, 2010; Ishak & Abbas, 2013).
    b) Aplastic anemia was reported as a toxic side effect of therapy in a woman who was given penicillamine 150 mg/day initially and then increased over the next 3 months to 600 mg/day. The bone marrow showed no sign of recovery at any time (McAllister & Vale, 1976).
    F) PANCYTOPENIA
    1) WITH THERAPEUTIC USE
    a) PANMYELOPHTHISIS was noted in a 50-year-old woman who was treated with a total dose of 200 grams of penicillamine over seven months. The woman was also noted to receive gold therapy prior to the penicillamine therapy, but the drug had been discontinued due to side effects (Baier, 1973).
    G) SIDEROBLASTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Cases of sideroblastic anemia, including fatalities, have been reported with penicillamine use (Prod Info CUPRIMINE(R) oral capsules, 2010).
    b) One study reported a case of sideroblastic anemia after aplastic anemia which eventually was fatal (Ramselaar et al, 1987).
    H) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia including bone marrow aplasia has been reported as a rare side effect of penicillamine therapy (Ishak & Abbas, 2013; Prod Info CUPRIMINE(R) oral capsules, 2007; Camp, 1981; Oliver et al, 1972; Corocos et al, 1964; Kay, 1986).
    b) Leukopenia may resolve despite continued penicillamine administration (Shannon et al, 1988).
    c) Doses of 600 to 900 mg/day may result in depressed lymphocyte counts (Brandt & Svensson, 1975).
    I) AGRANULOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) Cases of agranulocytosis, including fatalities, have been reported with penicillamine use (Prod Info CUPRIMINE(R) oral capsules, 2010; Ishak & Abbas, 2013).
    b) CASE REPORT: A 26-year-old man who was treated with a dose of 750 mg/day for 22 days for lead poisoning developed agranulocytosis. He was also receiving antazoline, so it is difficult to determine whether the toxic effect was due to the penicillamine or to the antazoline (Selander & Cramer, 1965).
    J) LEUKEMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Acute lymphoblastic leukemia has been reported in a 15-year-old girl with Wilson's disease following 37 months of high dose penicillamine therapy (5 g for 10 months, 10 g for 6 months, 20 g for 16 months, and 28 g for 5 months) (Gilman & Holtzman, 1992).
    K) THROMBOTIC THROMBOCYTOPENIC PURPURA
    1) WITH THERAPEUTIC USE
    a) Thrombotic thrombocytopenic purpura has been reported with penicillamine use (Prod Info CUPRIMINE(R) oral capsules, 2010).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) NAIL FINDING
    1) WITH THERAPEUTIC USE
    a) NAIL CHANGES: Penicillamine has been known to cause nail dystrophy and yellow nail beds (Ellenhorn & Barceloux, 1988; Ishak & Abbas, 2013).
    B) BULLOUS ERUPTION
    1) WITH THERAPEUTIC USE
    a) PEMPHIGUS: Various types of pemphigus have been associated with the use of penicillamine (Brown & Dubin, 1987; Walton et al, 1987; Jones et al, 1993).
    1) Some of these cases have been fatal (Kohn, 1986)
    C) ELASTOSIS PERFORANS SERPIGINOSA
    1) WITH THERAPEUTIC USE
    a) Elastic fiber abnormalities such as elastosis perforans serpiginosa (EPS), acquired cutis laxa, anetoderma, and pseudo-pseudo-xanthoma elasticum (PPXE) have been reported following penicillamine therapy (Ishak & Abbas, 2013).
    b) Elastosis perforans serpiginosa is unlikely to be an effect seen in acute overdose. It is a rare skin disorder associated with the long term use of penicillamine (Ratnavel & Norris, 1994; Ishak & Abbas, 2013). Histological examination of the skin shows characteristic "lumpy-bumpy" elastic fibers. The skin of the neck, face, and flexural areas are most commonly affected (Price & Prentice, 1986).
    2) WITH POISONING/EXPOSURE
    a) Elastosis perforans serpiginosa is unlikely to be an effect seen in acute overdose. It is a rare skin disorder associated with the long term use of penicillamine (Ratnavel & Norris, 1994).
    D) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Various rashes have been reported with penicillamine use, including urticaria, exanthema, papulohemorrhagic skin lesions, erythema, lichen planus, psoriasiform dermatitis, pseudoxanthoma elasticum, vesicles, and purpura (Ishak & Abbas, 2013; Van Hecke et al, 1981; Seehafer et al, 1981; Lang et al, 1972; Machtey, 1971; Katz, 1967; Coulson & Marsden, 1985; Gilman & Holtzman, 1992; Narron et al, 1992).
    E) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) Toxic epidermal necrolysis has been reported with penicillamine use (Prod Info CUPRIMINE(R) oral capsules, 2010).
    F) CONTACT DERMATITIS
    1) WITH THERAPEUTIC USE
    a) ALLERGIC CONTACT DERMATITIS resulting in vesicles, swollen eyelids and conjunctiva has been reported after penicillamine eye drops (Coenraads et al, 1990; (De Moor et al, 1993).
    b) Exfoliative dermatitis has been reported with penicillamine use (Prod Info CUPRIMINE(R) oral capsules, 2010).
    c) Acute hypersensitivity reactions such as morbilliform and urticarial eruptions have been reported following penicillamine therapy (Ishak & Abbas, 2013).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MYOSITIS
    1) WITH THERAPEUTIC USE
    a) POLYMYOSITIS: Penicillamine has been reported to cause polymyositis in patients treated with penicillamine in doses as low as 400 to 600 mg/day for as short a period as 1 month (Lenden & Liabelius, 1985) (Morgan et al, 1981; Cucher & Goldman, 1976; Ostensen et al, 1980).
    1) Penicillamine therapy was associated with the onset of polymyositis or dermatomyositis in 14 patients. Two of these cases were fatal due to cardiac involvement (Doyle et al, 1983).
    b) Myositis or myelopathy may occur following penicillamine use (Ishak & Abbas, 2013).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) LARGE BREAST
    1) WITH THERAPEUTIC USE
    a) Several cases of breast enlargement have occurred in men and women who were taking penicillamine chronically (Ishak & Abbas, 2013; Kahl et al, 1985; Passas & Weinstein, 1978; Reid et al, 1982).
    B) AUTOIMMUNE THYROIDITIS
    1) WITH THERAPEUTIC USE
    a) Autoimmune thyroiditis may occur following penicillamine use (Ishak & Abbas, 2013).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) PENICILLIN ALLERGY: Penicillamine is a product of the metabolism of penicillin and because of this has been the subject of concern when used in patients with penicillin allergy. There have been tests showing some crossreactivity in skin testing done on penicillin-sensitive patients.
    b) Bell and Graziano (1983) tested 40 patients with histories of immediate systemic reaction to penicillin by using either a skin test or an intradermal injection of penicillin followed by intradermal injections of penicillamine. They concluded the risk of an immediate allergic reaction to penicillamine in patients with a history of penicillin reactions is quite low (Bell & Graziano, 1983).
    B) IMMUNE SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) INSULIN AUTOANTIBODIES: 21 adults treated with penicillamine for rheumatoid arthritis were monitored for the onset of insulin autoantibodies. Titers of insulin autoantibodies were elevated in 9 (42.9%) patients, with an inverse correlation between their concentration and the time interval since the last drug administration (Vardi et al, 1992).
    C) MUSCLE WEAKNESS
    1) WITH THERAPEUTIC USE
    a) MYASTHENIA GRAVIS may occur in patients receiving penicillamine (Ishak & Abbas, 2013).
    b) Autoimmune myasthenia gravis and this penicillamine-induced variety have similar pathophysiology, including the presence of an anti-acetylcholine receptor antibody, serum-induced blockage of anti-acetylcholine receptors, and antibody mediated accelerated degradation of these receptors. The net result is a reduction in the junctional anti-acetylcholine receptors (Kuncl et al, 1986; Dawkins et al, 1987).
    D) DRUG-INDUCED LUPUS ERYTHEMATOSUS
    1) WITH THERAPEUTIC USE
    a) SYSTEMIC LUPUS ERYTHEMATOSUS: SLE is an autoimmune disease that has been reported as a side effect of penicillamine treatment of rheumatoid arthritis (Weinstein et al, 1986; Donnelly et al, 1993; Ishak & Abbas, 2013).
    E) BULLOUS ERUPTION
    1) WITH THERAPEUTIC USE
    a) AUTOIMMUNE PEMPHIGUS: Such as pemphigus vulgaris and pemphigus foliaceus have been seen with doses of 1 gram or more per day when used for a month or more. These conditions have been reported most frequently in patients taking penicillamine for rheumatoid arthritis (Trunnell et al, 1981; Benveniste et al, 1975; Cairns, 1976; Tan & Rowell, 1976).
    b) Acute hypersensitivity reactions such as morbilliform and urticarial eruptions have been reported following penicillamine therapy (Ishak & Abbas, 2013).
    c) These lesions differ histologically and immunologically from the naturally occurring lesions, and are generally considered to be less severe (Troy et al, 1981; Santa Cruz et al, 1981).

Reproductive

    3.20.1) SUMMARY
    A) Connective tissue defects including congenital cutis hyperelastia has been seen in a number of children born to mothers taking D-penicillamine. Other abnormalities reported include hydrocephalus, cerebral palsy, webbing of the fingers and toes, and arthrogryposis multiplex.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) FDA pregnancy category D (Briggs et al, 1998).
    B) SKELETAL MALFORMATION
    1) CASE REPORT - A mother who had taken 2,000 mg daily throughout pregnancy for cystinuria produced a child with "bloodhound" facies, with dysplastic ears and micrognathia, and generalized cutis laxis.
    a) There was, in addition, an interrupted aortic arch and hypoplastic left ventricle. Biopsies showed normal collagen bundles, but no elastic fibers (Beck et al, 1981).
    2) CASE REPORT - A mother who was being treated with 1,200 mg per day for Wilson's disease (she also received 250 mg of pyridoxine per day) had a child with micrognathia, low ears, inguinal hernia, loose folds of skin in the neck and axillae, and abnormally lax skin on other areas of the body.
    a) The infant's zinc level at birth was 85 micrograms/deciliter (110 to 130 is normal) and its copper level was 19.7 micrograms/deciliter (normal 212 to 368).
    b) The child was given zinc supplementation and at 4 months of age appear to have normal skin (Harpey et al, 1983).
    3) CASE SERIES - Rosa (1986) summarizes four additional cases where children developed (1) hydrocephalus, (2) cerebral palsy, (3) arthrogryposis multiplex and (4) webbing of the fingers and toes.
    C) SKIN DISORDER
    1) A mother who had been taking 2,000 mg per day throughout pregnancy for cystinuria produced a child with connective tissue defects which included lax skin, fragility of veins, and hyperflexibility of joints (Mjolnerod, 1971).
    D) GROWTH RETARDED
    1) CASE REPORT - Solomon et al (1977) reported a case of growth retardation, flat face, low ears, flexion contractures, inguinal hernia, and lax skin. This child's mother had taken 900 mg of D-penicillamine for rheumatoid arthritis daily for the first 16 weeks of pregnancy, and then again in the last trimester.
    E) LACK OF EFFECT
    1) CASE REPORT - A case of successful pregnancy in a 29-year-old woman with Wilson's disease treated with D-penicillamine and zinc sulfate (for 3 years before and during pregnancy) has been reported (Hartard & Kunze, 1994).
    F) ANIMAL STUDIES
    1) MICE fed 4 g of D-penicillamine per gram of diet throughout pregnancy and lactation produced offspring with often severe and varied neurological and aortic abnormalities.
    a) Neurological abnormalities included neuronal degeneration in the cerebral cortex, thalamic nuclei, and spinal ganglion on the 14th and 21st days, but not on the 7th postnatal day. Aortas developed with dissecting aneurysms and breaks in the elastic lamellae.
    b) These abnormalities in offspring were not seen in another group fed the same diet only with copper sulfate (5 x 10 (-3)) added to the formula (Irino et al, 1982).
    c) These facts led the authors to propose that the reason for the abnormalities was a copper deficiency induced by the D-penicillamine chelating the dietary copper, especially postnatally.
    2) MICE - Myint (1984) showed that cleft palate could occur in mice whose mothers received D-penicillamine.
    3) RATS given at least 25mg/kg/day of D-penicillamine developed cutis laxis, abdominal herniation, incomplete diaphragms, and reduced ossification of phalanges and tail vertebrae, which were associated with reductions in maternal copper levels (Keen et al, 1983).
    a) When similarly treated animals were given 50 to 100 mg/kg of copper in their diet, malformations and resorptions were prevented (Mark-Savage et al, 1981).
    4) RATS - Kilburn & Hare (1982) found that D-penicillamine added to a low copper diet in rats produced tracheobronchomegally.
    3.20.3) EFFECTS IN PREGNANCY
    A) SKIN DISORDER
    1) Linares et al (1979) reported a case of transient cutis laxis in a mother who had taken 1,500 mg of D-penicillamine throughout pregnancy for Wilson's disease.
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) ANIMAL STUDIES
    1) MICE - In study by Irino et al (1982) the authors showed both neurologic and aortic abnormalities in offspring of mice fed diets containing 4 g of D-penicillamine/g of diet during the mother's pregnancy and lactating period.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS52-67-5 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed

Genotoxicity

    A) Penicillamine induces chromosome aberrations and sister-chromatid exchanges in cultivated mammalian cells at concentrations from 400 micrograms/mL upward.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status in symptomatic patients.
    C) Monitor CBC with differential and platelet count, renal function, liver enzymes, and serum electrolytes in symptomatic patients.
    D) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.
    E) Patients on long term penicillamine therapy: Consider monitoring renal function, urinalysis, complete blood count with differential and platelets every 2 weeks for the first 4 to 6 months and monthly thereafter, copper and zinc levels, liver enzymes, and pyridoxine concentrations.
    4.1.2) SERUM/BLOOD
    A) For patients on long term penicillamine therapy, consider monitoring renal function, urinalysis, complete blood count with differential and platelets every 2 weeks for the first 4 to 6 months and monthly thereafter, copper and zinc levels, liver function, and pyridoxine levels.
    B) Patients taking the drug for 12 months are still at risk for the development of any of the described adverse effects (Taylor & Samanta, 1992).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status in symptomatic patients.
    C) Monitor CBC with differential and platelet count, renal function, liver enzymes, and serum electrolytes in symptomatic patients.
    D) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.
    E) Patients on long term penicillamine therapy: Consider monitoring renal function, urinalysis, complete blood count with differential and platelets every 2 weeks for the first 4 to 6 months and monthly thereafter, copper and zinc levels, liver enzymes, and pyridoxine concentrations.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not recommended because of the potential for persistent seizures and subsequent aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Myelosuppression has been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg, filgrastim, sargramostim). Transfusions may be required for severe thrombocytopenia or bleeding. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Pemphigus has been treated with anti-immune drugs such as prednisone or azathioprine. In some cases, the administration of pyridoxine has decreased the neurologic toxicity of penicillamine.
    B) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs and mental status in symptomatic patients.
    3) Monitor CBC with differential and platelet count, renal function, liver enzymes, and serum electrolytes in symptomatic patients.
    4) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.
    5) Patients on long term penicillamine therapy: Consider monitoring renal function, urinalysis, complete blood count with differential and platelets every 2 weeks for the first 4 to 6 months and monthly thereafter, copper and zinc levels, liver enzymes, and pyridoxine concentrations.
    C) PEMPHIGUS
    1) Pemphigus has been treated with anti-immune drugs such as prednisone or azathioprine. Walton et al (1987) reported a case of pemphigus resistant to drug therapy and discontinuation of the penicillamine that responded to four exchange transfusions over a 2-week period (Walton et al, 1987).
    D) PYRIDOXINE HYDROCHLORIDE
    1) In some cases, the administration of pyridoxine has decreased the neurologic toxicity of penicillamine. In one case, 100 mg given IV to a 25-year-old terminated a seizure, and some cases of neuropathy improved when given 50 mg/day orally (Pool et al, 1981; Smith & Gallagher, 1970).
    E) CHOLESTYRAMINE
    1) The amount of binding was dependent on the concentrations of the resin, the pH, and the concentration of other chemicals, such as bile salts. When 150 mg of penicillamine was combined with 4 to 8 g of cholestyramine, about 10% was absorbed. When 10 millimoles/liter of bile salts were present, only 1.3% was absorbed (Allgayer et al, 1982).
    F) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    G) MYELOSUPPRESSION
    1) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.
    2) Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or hemorrhage.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is unlikely to be of value because of the high degree of protein binding (greater than 80%).

Abstracts

Case Reports

    A) ADVERSE EFFECTS
    1) Halverson et al (1978) noted a 62% adverse reaction rate, with 36% experiencing symptoms which necessitated discontinuation of their therapy. Common complaints included proteinuria (14%), hematologic adverse effects (11%), mucocutaneous toxic reactions (28%), and gastrointestinal symptoms (12%) (Halverson et al, 1978a).

Range Of Toxicity

Summary

    A) TOXICITY: Limited data are available. No specific acute toxic dose has been established. Toxic effects generally occur in those patients taking penicillamine chronically. The relationship to dose is unclear, as even patients on small doses may develop toxicity. THERAPEUTIC DOSE: ADULT: CYSTINURIA: 2 g/day but may range from 1 to 4 g/day. RHEUMATOID ARTHRITIS: Initial dose, 125 to 250 mg daily, increased at 1 to 3 month intervals by 125 to 250 mg daily; a frequent maintenance dose is 500 to 750 mg/day. WILSON'S DISEASE: Initial dose, 0.75 to 1.5 g/day that results in cupriuresis of over 2 mg/day, continued for about 3 months; may be increased gradually up to 2 g/day. PEDIATRIC: CYSTINURIA: 30 mg/kg/day, divided into 4 doses. RHEUMATOID ARTHRITIS: Safety and efficacy in the pediatric or adolescent population have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) CYSTINURIA
    1) 2 g/day but may range from 1 to 4 g/day (Prod Info CUPRIMINE(R) oral capsules, 2010; Prod Info DEPEN(R) titratable oral tablets, 2009)
    B) RHEUMATOID ARTHRITIS
    1) Initial dose, 125 to 250 mg daily, increased at 1 to 3 month intervals by 125 to 250 mg daily;a frequent maintenance dose is 500 to 750 mg/day (Prod Info CUPRIMINE(R) oral capsules, 2010; Prod Info DEPEN(R) titratable oral tablets, 2009)
    C) WILSON'S DISEASE
    1) Initial dose, 0.75 to 1.5 g/day that results in cupriuresis of over 2 mg/day, continued for about 3 months; may be increased gradually up to 2 g/day (Prod Info CUPRIMINE(R) oral capsules, 2010; Prod Info DEPEN(R) titratable oral tablets, 2009)
    7.2.2) PEDIATRIC
    A) CYSTINURIA
    1) 30 mg/kg/day, divided into 4 doses (Prod Info CUPRIMINE(R) oral capsules, 2010; Prod Info DEPEN(R) titratable oral tablets, 2009)
    B) RHEUMATOID ARTHRITIS
    1) Safety and efficacy in the pediatric or adolescent population have not been established (Prod Info CUPRIMINE(R) oral capsules, 2010; Prod Info DEPEN(R) titratable oral tablets, 2009).

Maximum Tolerated Exposure

    A) No specific acute toxic dose has been established.

Workplace Standards

    A) ACGIH TLV Values for CAS52-67-5 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS52-67-5 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS52-67-5 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS52-67-5 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Penicillamine is a degradation product of penicillin and acts as a chelator of heavy metals. It chelates copper, lead, and mercury. Although in vitro studies indicate copper binding at 1 gram penicillamine to 200 mg copper, only about 2 mg of copper are excreted by 1 gram of penicillamine for a 2% efficiency. Penicillamine is also used to treat cystinuria by forming a soluble urinary complex thus reducing the formation risk of renal stones. It also chelates iron and probably other heavy metals to form stable, soluble complexes that are readily excreted in the urine. The mechanism of action of penicillamine in rheumatoid arthritis is not known, but may involve improvement of lymphocyte function. It markedly reduces IgM rheumatoid factor and immune complexes in serum and synovial fluid, but does not significantly lower absolute concentrations of serum immunoglobulins (Ishak & Abbas, 2013; Prod Info CUPRIMINE(R) oral capsules, 2010).
    B) D-penicillamine substitues a sulfhydryl radical in amino acids, and is therefore useful in solubilizing cysteine in the treatment of cystinuria (Crawhill, 1981).

Toxicologic Mechanism

    A) D-penicillamine alters the condensation of elastin and collagen crosslinks by compressing free lysine-derived aldehydes (Rosa, 1986).
    B) This compound catalyzes disulfide-sulfhydryl exchange reactions (Gosselin et al, 1984).
    C) The L isomer appears to be more toxic possibly due to the specific inhibitory effect on pyridoxine metabolism in mammals (Gosselin et al, 1984).

Physicochemical

Physical Characteristics

    A) D-penicillamine has a slightly bitter taste and a characteristic odor (S Sweetman , 2001).
    B) A fine, white crystalline powder (S Sweetman , 2001).

Ph

    A) 4.5-5.5 (1% solution) (S Sweetman , 2001)

Molecular Weight

    A) 149.2 (S Sweetman , 2001)

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