Penicillamine(D-) (penicillamine)

Dosage of penicillamine must be individualized according to the condition being treated and the response of the patient.

Penicillamine is administered orally. For patients who cannot swallow capsules or tablets, the contents of a capsule may be administered in 15-30 mL of chilled pureed fruit or fruit juice. Penicillamine should be given on an empty stomach (i.e., at least 1 hour before or 2 hours after meals, and at least 1 hour apart from any other drug, food, or milk). The last dose should be given at least 3 hours after the evening meal.

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Penicillamine/Antimalarial Agents

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent use may result in additive or synergistic effects on the blood and kidneys(1) or increased penicillamine levels.(2)

CLINICAL EFFECTS: Concurrent use of penicillamine with antimalarials may result in serious hematologic or renal toxicity(1,2) or elevated levels of penicillamine.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of penicillamine states that penicillamine should not be used in patients receiving concurrent therapy with antimalarial agents.(1)

DISCUSSION: In patients with rheumatoid arthritis, concurrent chloroquine increased penicillamine plasma concentrations by 34% when compared to penicillamine alone.(2) In a 2-year controlled, double-blind trial of penicillamine, hydroxychloroquine, or combination therapy, patients on combination therapy did not do as well as patients receiving penicillamine alone.(3) Because antimalarial agents are associated with hematologic and renal toxicity, the manufacturer of penicillamine states that penicillamine should not be used in patients receiving concurrent antimalarials.(1)

Penicillamine/Gold Salts

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Both agents have similar hematologic and renal adverse effects.(1)

CLINICAL EFFECTS: Concurrent use may result in hematologic and/or renal toxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of penicillamine(1) and aurothioglucose(2) state that penicillamine and gold salts should not be used simultaneously.

DISCUSSION: Because penicillamine and the gold salts have similar hematologic and renal adverse effects, the manufacturers of penicillamine(1) and aurothioglucose(2) state that penicillamine and gold salts should not be used simultaneously. Penicillamine has been shown not to chelate gold to a significant extent.(3-5)

Penicillamine/Oxyphenbutazone; Phenylbutazone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent use may result in additive or synergistic effects on the blood and kidneys.(1)

CLINICAL EFFECTS: Concurrent use of penicillamine and oxyphenbutazone or phenylbutazone may result in serious hematologic or renal toxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of penicillamine states that penicillamine should not be used in patients receiving concurrent oxyphenbutazone or phenylbutazone.(1)

DISCUSSION: Because oxyphenbutazone and phenylbutazone are associated with hematologic and renal toxicity, the manufacturer of penicillamine states that penicillamine should not be used in patients receiving concurrent oxyphenbutazone or phenylbutazone.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)

Selected Myelosuppressive Agents/Clozapine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clozapine and other myelosuppressive agents may be associated with neutropenia or agranulocytosis.(2)

CLINICAL EFFECTS: Moderate neutropenia, even if due to combination therapy, may require abrupt discontinuation of clozapine resulting in decompensation of the patient's psychiatric disorder (e.g. schizophrenia). The disease treated by the myelosuppressive agent may be compromised if myelosuppression requires dose reduction, delay, or discontinuation of the myelosuppressive agent. Undetected severe neutropenia or agranulocytosis may be fatal.

PREDISPOSING FACTORS: Low white blood counts prior to initiation of the myelosuppressive agent may increase risk for clinically significant neutropenia.

PATIENT MANAGEMENT: If a patient stabilized on clozapine therapy requires treatment with a myelosuppressive agent, the clozapine prescriber should consult with prescriber of the myelosuppressive agent (e.g. oncologist) to discuss treatment and monitoring options.(2) More frequent absolute neutrophil count (ANC) monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. The U.S. Food and Drug Administration (FDA) recommends that prescribers monitor patients' ANC according to the monitoring frequencies described in the prescribing information. Severe neutropenia remains a serious, potentially fatal risk that is greatest in the first several months of clozapine treatment. ANC monitoring can help identify neutropenia early to allow for timely intervention.(1-2) Australia, Canada, and U.K.: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing. For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(2)

DISCUSSION: Concurrent use of clozapine and selected myelosuppressive agents may require more frequent ANC monitoring or consideration of treatment alternatives secondary to neutropenic episodes. Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(3-26)

Selected Myelosuppressive Agents/Deferiprone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1)

CLINICAL EFFECTS: Concurrent use of deferiprone and myelosuppressive agents may result in severe neutropenia or agranulocytosis, which may be fatal.

PREDISPOSING FACTORS: Agranulocytosis may be less common in patients receiving deferiprone for thalassemia, and more common in patients treated for other systemic iron overload conditions (e.g. myelodysplastic syndromes, sickle cell disease).(2,3) Inadequate monitoring appears to increase the risk for severe outcomes. Manufacturer post market surveillance found that in all fatal cases of agranulocytosis reported between 1999 and 2005, data on weekly white blood count (WBC) monitoring was missing. In three fatal cases, deferiprone was continued for two to seven days after the detection of neutropenia or agranulocytosis.(2)

PATIENT MANAGEMENT: If possible, discontinue one of the drugs associated with risk for neutropenia or agranulocytosis. If alternative therapy is not available, documentation and adherence to the deferiprone monitoring protocol is essential. Baseline absolute neutrophil count (ANC) must be at least 1,500/uL prior to starting deferiprone. Monitor ANC weekly during therapy. If infection develops, interrupt deferiprone therapy and monitor ANC more frequently. If ANC is less than 1,500/uL but greater than 500/uL, discontinue deferiprone and any other drugs possibly associated with neutropenia. Initiate ANC and platelet counts daily until recovery (i.e. ANC at least 1,500/uL). If ANC is less than 500/uL, discontinue deferiprone, evaluate patient and hospitalize if appropriate. Do not resume deferiprone unless potential benefits outweigh potential risks.(1)

DISCUSSION: Drugs linked to this monograph have an FDA Boxed Warning for risk of neutropenia, agranulocytosis, or pancytopenia, or have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(1-25) In pooled clinical studies submitted to the FDA, 6.1% of deferiprone patients met criteria for neutropenia and 1.7% of patients developed agranulocytosis.(1) The time to onset of agranulocytosis was highly variable with a range of 65 days to 9.2 years (median, 161 days).(3)

Selected Myelosuppressive Agents/Dipyrone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of dipyrone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1-29)

CLINICAL EFFECTS: Concurrent use of dipyrone with agents that cause bone marrow depression, including myelosuppressives, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding. Undetected severe neutropenia or agranulocytosis may be fatal.(1-29)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of dipyrone and myelosuppressive agents should be avoided. The European Medicines Agency states dipyrone is contraindicated in patients with a prior medical history of dipyrone-induced agranulocytosis (or from other pyrazolones/pyrazolidines), impaired bone marrow function or diseases of the hematopoietic system.(3) International labeling for dipyrone and methotrexate state that co-administration may increase the hematotoxicity of methotrexate, especially in elderly patients, and therefore should be avoided.(1-2) The European Medicines Agency advises if agranulocytosis is suspected with dipyrone, a complete blood count (including differential blood count) should be performed immediately, and treatment must be stopped while waiting for the results. If confirmed, treatment must not be reintroduced.(1-3)

DISCUSSION: A retrospective cohort study analyzed new users of dipyrone (n=444,972), non-steroidal anti-inflammatory drugs (n=3,814,367) which served as a reference cohort, and opioids-paracetamol (n=3,129,221) which was the negative control. During continuous treatment over a median of 37-40 days, 26 cases of hospitalized agranulocytosis occurred. With the assumption that agranulocytosis onset was 7 days prior to admission, the hazard ratio of agranulocytosis associated with dipyrone was 4.40 [0.90-21.57] compared to NSAIDs and 2.45 [0.68-8.83] compared to opioid-paracetamol. HR of neutropenia from dipyrone was 2.98 [1.57-5.65] compared to NSAIDs and not statistically significant compared to opioids-paracetamol. In a sensitivity analysis assuming that the onset of agranulocytosis was the date of hospitalization, the HR of dipyrone-induced agranulocytosis was 7.20 [95% confidence interval: 1.92-26.99] compared to NSAIDs and 3.31 [1.17-9.34] compared to opioids-paracetamol. Agranulocytosis was very rare but more than 4 times more common with dipyrone than other analgesics.(4) In a review of 1,448 reports of agranulocytosis attributed to dipyrone, patients with fatal outcomes were older and more often had also received methotrexate compared to those with non-fatal outcomes (odds ratio: 5.18; 95% confidence interval: 3.06-8.78).(5) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(2,6-26)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Penicillamine, Oral/Polyvalent Cations

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Penicillamine chelates with polyvalent cations such as aluminum, calcium, iron, magnesium, and zinc in the GI tract reducing the absorption of the penicillamine.

CLINICAL EFFECTS: Reduced (to 30% of fasting) bioavailability of penicillamine with decreased pharmacologic response.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: In order to assure systemic absorption and maximal effectiveness from penicillamine, counsel patient to separate penicillamine by at least 1 hour before or 1 hours after any medications or products containing polyvalent cations such as antacids or mineral supplements. Monitor clinical status for decreased effectiveness and adjust the penicillamine dose if necessary.

DISCUSSION: Clinical studies with polyvalent cations have not been conducted. Multivitamins with low doses of cations including iron and zinc may decrease penicillamine absorption so insure patient is aware of the risks.

Penicillamine/Digoxin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown.

CLINICAL EFFECTS: Serum digoxin concentrations may be decreased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor serum digoxin concentrations and observe the patient for a decrease in pharmacologic activity when concurrent treatment with penicillamine is started or stopped. Adjust the dose of digoxin accordingly. The dosage of digoxin may need to be increased by 20% to 40%.

DISCUSSION: Penicillamine administration to adults or children has been shown to decrease serum concentrations. The decrease occurred whether digoxin was given orally or intravenously.

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• Agranulocytosis
• Aplastic anemia
• Aplastic anemia secondary to drugs
• Kidney disease with reduction in glomerular filtration rate (GFr)

• Bronchiolitis
• Glomerulonephritis
• Hematuria
• Leukopenia
• Lupus-like syndrome
• Myasthenia gravis
• Pemphigus
• Pregnancy
• Proteinuria
• Thrombocytopenic disorder

• Aphthous stomatitis
• Iron deficiency anemia

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More Frequent

• Allergic dermatitis
• Aphthous stomatitis
• Pruritus of skin
• Skin rash
• Stomatitis
• Urticaria

Less Frequent

• Agranulocytosis
• Aplastic anemia
• Glomerulonephritis
• Hemolytic anemia
• Leukopenia
• Thrombocytopenic disorder

Rare or Very Rare

• Acute pancreatitis
• Angioedema
• Bronchiolitis obliterans
• Eosinophilia
• Exacerbation of peptic ulcer
• Exfoliative dermatitis
• Goodpasture's syndrome
• Jaundice
• Lupus-like syndrome
• Myasthenia gravis
• Optic neuritis
• Pemphigus
• Tinnitus
• Toxic epidermal necrolysis

More Frequent

• Abdominal pain with cramps
• Anorexia
• Diarrhea
• Dysgeusia
• Nausea
• Vomiting

Rare or Very Rare

• Hematuria
• Maculopapular rash
• Proteinuria
• Urinary incontinence

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One cystinuric patient treated with penicillamine throughout pregnancy delivered a child with a generalized connective tissue defect which may have been caused by penicillamine. The manufacturers state that, if possible, the drug should not be administered during pregnancy to women with cystinuria. If stones continue to form in cystinuric women, the potential benefits of penicillamine therapy must be weighed against the possible risks.

One woman with rheumatoid arthritis treated with less than 900 mg of penicillamine daily during pregnancy delivered (by cesarean section) 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. The manufacturers state that penicillamine is contraindicated in women with rheumatoid arthritis who are pregnant. The drug should not be used in women with rheumatoid arthritis who may become pregnant unless the possible benefits outweigh the risks; if pregnancy is suspected or occurs in these women during penicillamine therapy, the drug should be discontinued. Women with rheumatoid arthritis receiving penicillamine should be informed about the possible hazards of the drug to the fetus and should be advised to promptly report to their physician any missed menstrual periods or other indication of possible pregnancy.

To date, there have been no reports of serious adverse fetal effects when penicillamine was used for the treatment of Wilson disease in pregnant women. One woman with Wilson disease who received 1.5 g of penicillamine daily during pregnancy delivered an infant with loose body skin; at 9 weeks of age the infant's skin was normal. It appears that continued penicillamine therapy in these patients prevents relapse of Wilson disease and that discontinuance of the drug may be deleterious to the mother; however, dosage should be limited to 750 mg daily. In patients with Wilson disease in whom a cesarean section is planned, dosage of penicillamine should be limited to 250 mg daily during the 6 weeks before delivery and postoperatively until wound healing is complete in order to preclude impairment of wound healing.

Although there are no studies to date using penicillamine in nursing women, the manufacturers state that nursing should not be undertaken by women receiving the drug.

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