Ridaura (auranofin)

Dosage of auranofin must be adjusted according to the clinical response and tolerance of the patient. Therapeutic effects occur slowly and generally are not evident until at least 3-4 months after beginning therapy with the drug. To encourage patient compliance with visits to the physician for appropriate clinical and laboratory monitoring, it is recommended that treatment with auranofin be initiated with a prescription for 2 weeks of therapy and only one authorized refill, and that subsequent prescriptions for the drug be limited to a quantity sufficient for 1 month of therapy.

For the management of active rheumatoid arthritis in adults, the recommended initial dosage of auranofin is 6 mg daily, administered as a single dose or in 2 divided doses. Because of potential adverse GI effects, some clinicians initiate therapy with 3 mg once daily and increase dosage to 6 mg daily after several weeks if the initial dosage is well tolerated. Initiating therapy with dosages greater than 6 mg daily is not recommended, since these dosages are associated with an increased incidence of diarrhea.

If diarrhea or loose stools occur and are not self-limiting or are intolerable, these adverse GI effects can generally be managed by dosage reduction (e.g., from 6 to 3 mg daily) or temporary discontinuance of auranofin (e.g., for 3-7 days). Because an adequate response is more likely to be attained, subsequent attempts should be made to increase dosage back to 6 mg daily in patients who require a reduction to 3 mg daily. About one-third of patients in whom dosage is reduced from 6 to 3 mg daily will have a deterioration in clinical status during the period of dosage reduction. In patients who do not tolerate a dosage of 6 mg daily, a dosage of 3 mg daily may be continued for 6 months or longer; however, because the likelihood of attaining an adequate response with this dosage may be reduced, many clinicians would discontinue auranofin and institute therapy with another antirheumatic agent.

If a patient's response to auranofin is inadequate after 6 months of therapy at a dosage of 6 mg daily, dosage may be increased to 9 mg daily (3 mg 3 times daily), if tolerated. Some clinicians would increase dosage from 6 to 9 mg daily as early as 4 months after initiating therapy if the patient's response is inadequate. If a patient's response remains inadequate after 3 months at a dosage of 9 mg daily, auranofin therapy should be discontinued. Alternatively, if a patient's response is inadequate after 6 months of therapy at a dosage of 6 mg daily, some clinicians would continue this dosage for an additional 3-6 months to assess response, while others would discontinue auranofin and institute therapy with another antirheumatic agent. The safety of auranofin dosages exceeding 9 mg daily has not been assessed.

When transferring patients from therapy with another second-line antirheumatic agent to auranofin, patients should be informed of the adverse effect profile of auranofin, particularly its adverse GI effects. (See Cautions: Precautions and Contraindications.) When transferring patients from therapy with a parenteral gold compound to auranofin, a transition period is not necessary; therapy with the parenteral gold compound may be discontinued and auranofin therapy initiated at a dosage of 6 mg daily. When transferring patients from therapy with penicillamine to auranofin, it is recommended that penicillamine therapy be discontinued 1 month before auranofin therapy is initiated.

The optimum duration of treatment in patients who benefit from chrysotherapy has not been established, but chrysotherapy is generally continued as long as clinical improvement is evident and adverse effects do not require discontinuance of treatment. Various maintenance dosage regimens of auranofin and the value of continuing therapy in patients who respond to the drug are currently being evaluated.

Auranofin is administered orally.

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

Gold Salts/Penicillamine

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)

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)

There are no moderate interactions for this drug.

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• Exfoliative dermatitis
• Necrotizing enterocolitis
• Pregnancy
• Pulmonary fibrosis

• Blood dyscrasias
• Disease of liver
• Eczema
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Leukopenia
• Neutropenic disorder
• Severe debilitation
• Sjogren's syndrome
• Systemic lupus erythematosus
• Thrombocytopenic disorder

• Colitis
• Ultraviolet light therapy

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More Frequent

• Conjunctivitis
• Proteinuria
• Pruritus of skin
• Skin rash
• Stomatitis

Less Frequent

• Alopecia
• Eosinophilia
• Glossitis
• Hematuria
• Leukopenia
• Purpura
• Thrombocytopenic disorder
• Urticaria

Rare or Very Rare

• Agranulocytosis
• Anemia
• Angioedema
• Aplastic anemia
• Dysphagia
• Gastrointestinal hemorrhage
• Gingivitis
• Hepatitis
• Hypoplastic anemia
• Interstitial pneumonitis
• Jaundice
• Pancytopenia
• Peripheral neuropathy
• Pure red cell aplasia
• Ulcerative enterocolitis

More Frequent

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

Less Frequent

• Constipation
• Dysgeusia

No enhanced messaging available.

No enhanced messaging available.

Reproduction studies in rats and rabbits have shown auranofin to have maternotoxic and/or teratogenic effects. In pregnant rabbits receiving oral auranofin dosages of 0.5, 3, or 6 mg/kg daily (4.2, 25, or 50 times the human dosage, respectively), impaired maternal food intake, decreased maternal weight, decreased fetal weight, and an increased incidence of fetal resorptions, abortions, and congenital abnormalities (mainly abdominal defects such as gastroschisis and umbilical hernia, but also anomalies of the brain, heart, lung, and skeleton) were observed. In rats, an increased incidence of fetal resorptions and decreases in litter size and weight related to maternal toxicity were observed with an oral auranofin dosage of 5 mg/kg daily (42 times the human dosage), but these effects were not observed with a dosage of 2.5 mg/kg daily (21 times the human dosage). In mice, auranofin was not found to be maternotoxic or embryotoxic at dosages up to 5 mg/kg daily or teratogenic at dosages up to 40 mg/kg daily.

There are no adequate and controlled studies to date using auranofin in pregnant women. The drug has reportedly been used in a small number of pregnant women and these women subsequently delivered healthy infants, but the manufacturer recommends that auranofin not be used during pregnancy. In addition, the manufacturer recommends that women of childbearing potential be warned of the potential risks of auranofin therapy during pregnancy. Women of childbearing potential in whom auranofin therapy is considered should be counseled about methods of birth control and advised not to become pregnant while receiving the drug; these women should be advised to inform their physician if pregnancy occurs or is suspected during auranofin therapy. The prolonged elimination of gold from the body after discontinuance of chrysotherapy should be considered when a woman of childbearing potential receiving chrysotherapy plans to become pregnant. Chrysotherapy is usually not administered to pregnant women and is usually discontinued if pregnancy occurs; however, chrysotherapy may be used with caution during pregnancy when the potential benefits to the mother justify the possible risks to the fetus. There are no adequate and controlled studies to date using parenteral gold compounds in pregnant women, but clinical experience to date has not revealed substantial evidence of adverse effects on the fetus.

It is not known if gold from auranofin is distributed into human milk. Gold from auranofin is distributed into milk in rats and mice, but has not been detected in their nursing pups. Small amounts of gold have been shown to be distributed into milk in women receiving currently available parenteral gold compounds and to have been absorbed in their nursing infants. The manufacturer recommends that nursing not be undertaken by women receiving auranofin. The prolonged elimination of gold from the body after discontinuance of chrysotherapy should also be considered.

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