Auranofin (Monograph)

Drug class: Gold Compounds
- Disease-modifying Antirheumatic Drugs
- DMARDs

Medically reviewed by Drugs.com on Jun 10, 2024. Written by ASHP.

Introduction

Auranofin, a disease-modifying antirheumatic drug, is an orally active gold compound that exhibits anti-inflammatory, antiarthritic, and immunomodulating effects.

Uses for Auranofin

Rheumatoid Arthritis

Auranofin is used in the management of rheumatoid arthritis in adults whose symptoms progress despite an adequate regimen of nonsteroidal anti-inflammatory agents (NSAIAs). Auranofin is one of several disease-modifying antirheumatic drugs (DMARDs) that can be used when DMARD therapy is appropriate.

Administration of auranofin alone is not a complete treatment for rheumatoid arthritis, and the drug should only be used as one part of a comprehensive treatment program, including non-drug therapies such as rest and physical therapy. Most patients with active rheumatoid arthritis will show some benefit from therapy with gold compounds, including auranofin, and favorable results may be most likely when chrysotherapy is administered in patients with active synovitis, particularly in the early stage. There is no substantial evidence that gold compounds, including auranofin, permanently arrest or reverse the underlying disease process, although the drugs may slow its progression. Auranofin appears to be less effective and less toxic than currently available parenteral gold compounds. There currently are only a limited number of studies comparing auranofin with other DMARDs, and their relative efficacy and safety remain to be more fully determined.

Results of uncontrolled clinical studies in patients with active rheumatoid arthritis receiving auranofin suggest that the drug is generally effective in decreasing the number of painful and/or tender and swollen joints, the duration of morning stiffness, articular index, and rheumatoid activity index, and in increasing grip strength. The effects of the drug on erythrocyte sedimentation rate and rheumatoid factor titers are variable, with decreases observed in some studies but not in others. In placebo-controlled studies, auranofin has generally been more effective than placebo in decreasing the number of painful and/or tender and swollen joints and erythrocyte sedimentation rate and in global assessment by the physician; in some of the studies, auranofin was also more effective than placebo in decreasing the duration of morning stiffness and in increasing grip strength. Auranofin does not possess direct analgesic activity, but as a result of anti-inflammatory and antiarthritic effects, therapy with the drug generally results in a reduction of disease-associated pain. As with parenteral gold compounds, there is some limited evidence from radiographic studies suggesting that auranofin may slow or arrest the progression of joint space narrowing and/or bone erosion associated with rheumatoid arthritis; however, conflicting results have been reported, and many of the studies were subject to design and methodologic difficulties. Further well-designed studies are needed to conclusively determine whether the drug can reduce the severity or rate of progression of joint space narrowing and bone erosion associated with the disease. Limited data suggest that auranofin does not affect the progression of osteoporosis associated with rheumatoid arthritis. When damage to cartilage and bone has already occurred, therapy with gold compounds, including auranofin, cannot reverse structural damage to joints caused by previous disease.

Results of numerous comparative clinical studies suggest that auranofin is about as effective as or slightly less effective and less toxic than gold sodium thiomalate or aurothioglucose in the management of active rheumatoid arthritis. While some comparative studies have not shown a substantial difference in efficacy between auranofin and these parenteral gold compounds, the therapeutic effects generally tended to be slightly more pronounced and, in some studies, occurred sooner with the parenteral gold compounds. Patients receiving auranofin generally discontinue therapy more frequently because of an inadequate or poor therapeutic response (about 10% of patients), but substantially less often because of adverse effects (about 15–20% of patients), than patients receiving parenteral gold compounds. Because it offers the convenience of oral administration, auranofin may be preferred to a parenteral gold compound in some patients (e.g., those who dislike injections or for whom weekly injections and/or visits to the physician are inconvenient); however, in other patients, including those in whom compliance with a daily dosing regimen may be a problem, therapy with a parenteral gold compound may be preferred. Because auranofin may be slightly less effective, some clinicians prefer a parenteral gold compound in patients with severe or rapidly progressive disease. Auranofin appears to be capable of sustaining a therapeutic response for at least 6–12 months in many patients transferred from effective therapy with a parenteral gold compound; however, no additional therapeutic benefit from auranofin has been demonstrated following the transfer, and some patients effectively treated with a parenteral gold compound may experience worsening of disease (particularly those whose disease was more active at the initiation of chrysotherapy) or may not respond to auranofin following the transfer. Additional studies are needed to further evaluate the efficacy of auranofin in patients who have an adequate therapeutic response to a parenteral gold compound and vice versa. Data currently are limited, but some patients who have an inadequate therapeutic response or an adverse reaction to a parenteral gold compound and/or penicillamine may respond to and tolerate auranofin, and some patients who have an inadequate response to or do not tolerate auranofin may respond to and tolerate a parenteral gold compound; further studies are needed. The safety and efficacy of auranofin in patients who have adverse reactions to a parenteral gold compound and vice versa remain to be more clearly established. Many clinicians, however, would consider cautious administration of auranofin to patients who have had mild to moderate adverse reactions (e.g., adverse mucocutaneous reactions) to a parenteral gold compound, but not to those who have had adverse hematologic reactions or potentially fatal adverse reactions.

There currently are only a limited number of clinical studies comparing auranofin and other DMARDs in the management of progressive rheumatoid arthritis; most of the studies have been of short duration and involved small numbers of patients. Based on the results to date, auranofin appears to be as effective as hydroxychloroquine but possibly less well tolerated and about as effective as or slightly less effective than penicillamine and better tolerated. Further studies are needed to more clearly determine the relative efficacy and safety of auranofin and non-gold-containing DMARDs.

Auranofin has been used with good results and without unusual toxicity in several preliminary, uncontrolled clinical studies for the management of juvenile rheumatoid arthritis^{† [off-label]} in children with an inadequate response to therapy with nonsteroidal anti-inflammatory agents. Results of the studies suggest that the drug is generally effective in decreasing the number of painful and swollen joints, duration of morning stiffness, and erythrocyte sedimentation rate; in some of the children, functional class improved. Controlled studies are needed to further evaluate the efficacy and safety of auranofin in the management of juvenile rheumatoid arthritis. (See Precautions and Contraindications: Pediatric Precautions.)

Other Uses

Like parenteral gold compounds, auranofin may be beneficial in the management of psoriatic arthritis^{† [off-label]}. In some patients with this condition, therapy with the drug appeared to be generally effective in decreasing the number of swollen and tender joints, duration of morning stiffness, and erythrocyte sedimentation rate. Further studies to determine the efficacy and safety of auranofin in the management of psoriatic arthritis are needed.

An uncontrolled clinical study of auranofin in the management of active systemic lupus erythematosus^{† [off-label]} has been reported. In a small number of patients with this condition (without renal insufficiency), auranofin therapy was associated with a minimal decrease in disease activity as judged by physician assessment and a reduction in maintenance corticosteroid dosage; however, objective clinical and laboratory assessment of disease activity did not reveal any evidence of therapeutic benefit. Gold compounds are generally considered to be contraindicated in patients with systemic lupus erythematosus. Limited data suggest that auranofin may be useful in the management of refractory discoid lupus erythematosus^{† [off-label]}.

Auranofin therapy was reportedly associated with improvement of arthritic symptoms and reversal of leukopenia and splenomegaly in two patients with Felty’s syndrome^{† [off-label]}.

Auranofin Dosage and Administration

Administration

Auranofin is administered orally.

Dosage

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.

Cautions for Auranofin

Auranofin appears to be less toxic and better tolerated than currently available parenteral gold compounds, generally resulting in substantially fewer withdrawals from therapy because of adverse reactions (about 15–20% of patients); however, additional experience is needed to more fully characterize the adverse effect profile of auranofin, particularly with long-term therapy. Auranofin produces more adverse GI effects, including those severe enough to require discontinuance of therapy, than parenteral gold compounds, but fewer and substantially less severe adverse mucocutaneous (and possibly renal) effects than parenteral gold compounds. The overall difference in toxicity-related rates of withdrawal from therapy between auranofin and parenteral gold compounds results principally from the decreased frequency and severity of adverse mucocutaneous effects associated with auranofin. The incidence and severity of other auranofin-induced adverse effects appear to be generally comparable to those of parenteral gold compounds.

Most auranofin-induced adverse effects, including GI and mucocutaneous effects, occur with the greatest frequency during the first 6 months of therapy; however, adverse effects may occur at any time during therapy with the drug. Although gold-induced adverse effects may occur very rarely following discontinuance of parenteral chrysotherapy, most clinicians believe that the possibility of such reactions occurring after discontinuance of auranofin is remote. The incidence of adverse effects with gold compounds, including auranofin, is high, but many auranofin-induced adverse effects are mild in severity, of short duration, and are self-limiting or tolerated with continued administration of the drug or may be obviated by temporary dosage reduction or discontinuance of the drug; most adverse effects respond favorably to discontinuance of the drug, but severe reactions may require specific treatment. The incidence of severe reactions to gold compounds, and particularly to auranofin, is low, with such reactions usually occurring when therapy is continued despite the occurrence of less serious signs and symptoms of gold toxicity. Geriatric patients do not appear to have an increased risk of auranofin-induced toxicity compared with younger adults. Patients with HLA-DR locus histocompatibility antigen DR3 appear to have a genetic predisposition to develop adverse effects, including specific adverse reactions (e.g., proteinuria), during chrysotherapy. Although not clearly established, there is also some evidence that gold-induced adverse effects, including specific adverse reactions (e.g., mucocutaneous effects, thrombocytopenia), may be immunologically mediated.

GI Effects

The most common adverse effects of auranofin are changes in bowel habits, ranging from more frequent or loose stools to diarrhea, which occur in about 45–50% of patients. Auranofin-induced changes in bowel habits are most likely to occur within the first 3 months of therapy, appear to be dose related, and may be accompanied by abdominal cramping, with the effects often occurring principally within the first several hours after ingestion of a dose. The mechanism of GI toxicity has not been established, but may involve a direct effect of the drug on intestinal water and electrolyte absorption. Auranofin-induced changes in bowel habits may be self-limiting and subside with continued therapy or can generally be managed by dosage reduction or temporary discontinuance of the drug (e.g., for 3–7 days). Changes in bowel habits have also been controlled in some patients by temporary concomitant administration of an antidiarrhea agent (e.g., diphenoxylate hydrochloride), by concomitant administration of an oral iron preparation (in patients with iron deficiency anemia), or by increasing the amount of dietary fiber. Auranofin-induced changes in bowel habits have been severe enough to require discontinuance of the drug in about 4–6% of patients. Some patients, particularly geriatric patients, may consider the changes in bowel habits beneficial.

Abdominal cramping or pain has occurred in about 14% of patients receiving auranofin and required discontinuance in about 1% of patients. Nausea, with or without vomiting, has occurred in about 10% of patients and required discontinuance in about 1% of patients. Other adverse GI effects have occurred in about 13% of patients and required discontinuance in about 1% of patients. Adverse GI effects occurring in 3–9% of patients include anorexia, dyspepsia, and flatulence; those occurring in 1–3% of patients include constipation and dysgeusia; those occurring in less than 1% of patients include GI bleeding, melena, and positive stool for occult blood; and those occurring in less than 0.1% of patients include dysphagia and ulcerative enterocolitis. Enterocolitis accompanied by eosinophilia has been reported. Limited data suggest that orally administered cromolyn sodium may be beneficial in the management of gold-induced eosinophilic enterocolitis. Epigastric pain and erosive gastritis have been reported rarely in patients receiving auranofin.

Mucocutaneous Effects

Adverse effects involving the skin and mucous membranes are the second most common adverse reactions of auranofin. Rash has occurred in about 24% of patients receiving the drug and required discontinuance in about 3% of patients, and pruritus has occurred in about 17% of patients and required discontinuance in about 1% of patients. Pruritus often occurs before rash becomes apparent and should be considered a warning signal of an impending cutaneous reaction. Although not reported to date with auranofin, the most severe form of cutaneous reaction reported with parenteral gold compounds is generalized exfoliative dermatitis. Gold-induced dermatitis may be aggravated by exposure to sunlight or an actinic rash may develop. Urticaria has occurred in about 1–3% of patients receiving auranofin, hair loss or alopecia in about 2.5% of patients, and angioedema in less than 0.1% of patients.

Stomatitis has occurred in about 13% of patients receiving auranofin and required discontinuance in about 1% of patients. Stomatitis may be manifested as shallow ulcers on the buccal membranes, palate, pharynx, or borders of the tongue and may sometimes occur concurrently with dermatitis. Glossitis has occurred in about 1–3% of patients and gingivitis in less than 1% of patients receiving auranofin. A metallic taste may precede oral mucous membrane reactions and should be considered a warning signal of impending gold toxicity.

Minor auranofin-induced skin and mucous membrane reactions seldom require interruption of therapy or specific treatment. Localized skin conditions may respond to topical corticosteroids. The manufacturer suggests that rinsing the mouth with a hypotonic sodium chloride solution may be helpful for the symptomatic treatment of mild mouth ulcers. When skin and mucous membrane reactions are more severe, it is recommended that auranofin therapy be discontinued. (See Cautions: Precautions and Contraindications.) Moderately severe skin and mucous membrane reactions may benefit from therapy with topical corticosteroids, oral antihistamines, and/or soothing or anesthetic topical preparations. Severe or generalized gold-induced dermatitis or stomatitis may require systemic corticosteroid therapy (e.g., oral prednisone 10–40 mg daily in divided doses).

Renal Effects

Like other gold compounds, auranofin may cause proteinuria (and rarely nephrotic syndrome) or membranous glomerulonephritis with proteinuria and hematuria. Proteinuria has occurred in about 5% of patients receiving auranofin and required discontinuance in about 1% of patients, and hematuria has occurred in about 1.5% of patients and required discontinuance in less than 0.1% of patients. Patients receiving auranofin appear to be at greatest risk of developing proteinuria during the first 9 months of therapy. Other adverse renal effects (e.g., increased BUN and serum creatinine concentrations) have occurred in about 1.5% of patients receiving auranofin and required discontinuance in less than 0.1% of patients.

Gold-induced adverse renal effects are usually relatively mild and completely reversible if recognized early and chrysotherapy is discontinued; however, adverse renal effects may become severe and chronic if chrysotherapy is continued. If clinically important proteinuria (greater than 500 mg daily) or microscopic hematuria occurs during auranofin therapy, auranofin and other therapies with the potential for causing these adverse renal effects should be promptly discontinued. (See Cautions: Precautions and Contraindications.) Auranofin-induced proteinuria resolves spontaneously and completely in most patients following discontinuance of the drug, usually within 1 year (range: 1 week to 2 years). High-Dose systemic corticosteroids may be of benefit for some cases of severe or progressive gold-induced adverse renal effects, but are usually not necessary.

Hematologic Effects

Like parenteral gold compounds, auranofin may cause leukopenia, thrombocytopenia, and/or anemia. These adverse hematologic effects have occurred in about 1–3% of patients receiving the drug and collectively required discontinuance in less than 1% of patients. At least 5 deaths have reportedly been attributed to auranofin-induced thrombocytopenia, several of which occurred within the first 2 months of therapy with the drug. Eosinophilia has occurred in about 1–3% of patients, neutropenia in less than 1% of patients, and agranulocytosis, pure red cell aplasia, pancytopenia, and aplastic anemia in less than 0.1% of patients receiving auranofin. Eosinophilia appears to be most likely to occur concurrently with mucocutaneous toxicity, but does not appear to be a reliable indicator of auranofin-induced gold toxicity. Because gold-induced blood dyscrasias may be potentially serious, the hematologic status of patients receiving auranofin must be regularly and carefully monitored. (See Cautions: Precautions and Contraindications.)

Auranofin-induced thrombocytopenia may occur at any time during therapy with the drug and its course may be rapid. The exact mechanism is not known, but the thrombocytopenia usually appears to be peripheral in origin. If a precipitous decline in platelet count, a platelet count less than 100,000/mm³, or signs and/or symptoms suggestive of thrombocytopenia occur during auranofin therapy, auranofin and other therapies with the potential for causing thrombocytopenia should be immediately discontinued. (See Cautions: Precautions and Contraindications.) Thrombocytopenia is usually spontaneously reversible, generally within several weeks, following discontinuance of auranofin; however, corticosteroids and/or platelet transfusions should be considered for the management of severe thrombocytopenia.

Ocular Effects

Conjunctivitis has occurred in about 4% of patients receiving auranofin. Gold occasionally is deposited in the cornea or lens in patients receiving auranofin but is not associated with visual impairment or ocular disorders.

Other Adverse Effects

Elevations in serum concentrations of hepatic enzymes (i.e., aminotranferases and alkaline phosphatase) have occurred in about 1% of patients and jaundice in less than 0.1% of patients receiving auranofin. Headache, dizziness, peripheral neuropathy, and interstitial pneumonitis have been reported rarely in patients receiving the drug. Several patients have developed herpes zoster during auranofin therapy, but the disease cleared spontaneously despite continued administration in most patients. Vasomotor (nitritoid), anaphylactoid, or anaphylactic reactions have not been reported to date in patients receiving auranofin.

The possibility that auranofin may cause other adverse effects reported with parenteral gold compounds should be considered.

Precautions and Contraindications

Auranofin should be administered only to carefully selected patients who are under constant supervision of a physician experienced with chrysotherapy and thoroughly familiar with the toxicity and benefits of the drug. The fact that gold compounds can produce severe toxic reactions should always be kept in mind. To minimize the toxicity associated with chrysotherapy, emphasis should be placed on careful clinical and laboratory monitoring and early detection of adverse reactions. Medical conditions that might affect the signs or symptoms used to detect auranofin toxicity should be adequately controlled before therapy with the drug is initiated. When deciding whether to use auranofin in candidates for chrysotherapy, physicians should consider the relative benefits and risks of auranofin and parenteral gold compounds. (See Uses: Rheumatoid Arthritis.)

Before initiation of auranofin therapy, the possibility of adverse reactions should be explained to patients. Patients may be given a copy of the patient information provided by the manufacturer. Patients should be advised to promptly report any sign or symptom of possible gold toxicity, particularly pruritus, rash, stomatitis, or metallic taste, to their physician. Patients should also be advised to contact their physician promptly if unusual bruising, unusual or prolonged bleeding, or diarrhea that persists longer than 3 or 4 days or interferes with their normal daily routine occurs. In addition, patients should be questioned regarding these signs and symptoms. Since photosensitivity reactions may develop or gold-induced dermatitis may be aggravated with exposure to sunlight or artificial ultraviolet light, patients should also be cautioned to minimize such exposure. Because the therapeutic effects of auranofin occur slowly and are generally not evident until at least 3–4 months after beginning therapy with the drug, patients should be encouraged to comply with the prescribed regimen so that optimum benefits may be achieved.

Before auranofin therapy is initiated, a complete blood cell count with differential, platelet count, urinalysis, and renal and liver function tests should be performed to establish a baseline and identify any preexisting conditions. During therapy with the drug, it is recommended that a complete blood cell count with differential, platelet count, and urinalysis be performed at least monthly and that other parameters be monitored as appropriate. Patients with GI symptoms should also be monitored for the appearance of GI bleeding. Physicians should carefully review the results of laboratory tests to determine if an interruption of auranofin therapy is necessary. Signs of possible gold toxicity include a decrease in hemoglobin concentration, leukocyte count less than 4000/mm³, granulocyte count less than 1500/mm³, a decrease in platelet count to less than 150,000/mm³, proteinuria, hematuria, pruritus, rash, stomatitis, and persistent diarrhea. If a precipitous decline in platelet count, a platelet count less than 100,000/mm³, or signs and/or symptoms suggestive of thrombocytopenia (e.g., purpura, ecchymoses, petechiae, bleeding gums) occur during auranofin therapy, auranofin and other therapies with the potential for causing thrombocytopenia should be immediately discontinued and additional platelet counts should be subsequently obtained. Auranofin therapy should not be resumed unless the thrombocytopenia resolves and further studies confirm that it was not caused by chrysotherapy. If clinically important proteinuria (greater than 500 mg daily) or microscopic hematuria occurs during auranofin therapy, auranofin and other therapies with the potential for causing these adverse renal effects should be promptly discontinued. When proteinuria decreases to less than 500 mg daily, auranofin therapy may be reinstituted at a lower dosage; if proteinuria increases to greater than 500 mg daily on rechallenge, the drug should be permanently discontinued. Any skin eruption, especially if pruritic, that develops during auranofin therapy should be considered a reaction to gold until proven otherwise. When rash and/or pruritus, or stomatitis occurs in patients receiving auranofin and is moderate to severe in nature, therapy with the drug should be discontinued. After these adverse mucocutaneous effects are resolved, cautious reinstitution of auranofin at a lower dosage may be considered; if the reaction recurs on rechallenge, the drug should be permanently discontinued. If other signs of possible gold toxicity (e.g., leukocyte count less than 4000/mm³) occur during auranofin therapy, auranofin should generally be discontinued until further studies confirm that the adverse effect was not gold induced.

The potential benefits of auranofin in patients with progressive renal disease, substantial hepatocellular disease, inflammatory bowel disease, rash, or a history of bone marrow depression must be weighed against the potential risks of gold toxicity on organ systems that were previously compromised or have decreased reserve and against the difficulty in rapidly detecting a toxic effect and determining it to be gold induced.

In clinical studies of auranofin, most patients received a nonsteroidal anti-inflammatory agent concomitantly and some patients received low-dose corticosteroid therapy concomitantly without unusual toxicity. The safety of concomitant administration of auranofin and parenteral gold compounds, antimalarials (e.g., hydroxychloroquine), penicillamine, immunosuppressive agents (e.g., azathioprine, cyclophosphamide, methotrexate), or high-dose corticosteroids has not been established. Concomitant administration of gold compounds with antimalarials, immunosuppressive agents, penicillamine, or phenylbutazone is generally contraindicated because of the drugs’ potential to cause blood dyscrasias or other mutual, potentially severe adverse effects (e.g., proteinuria, dermatitis).

The manufacturer states that auranofin is contraindicated in patients with a history of severe gold toxicity, including gold-induced anaphylactic reactions, necrotizing enterocolitis, exfoliative dermatitis, pulmonary fibrosis, or bone marrow aplasia or other severe hematologic disorders. Gold compounds are also generally contraindicated in patients with a history of severe toxicity resulting from previous exposure to other heavy metals. The drugs are also generally contraindicated in patients with urticaria, eczema, colitis, severe debilitation, hemorrhagic conditions, or systemic lupus erythematosus and in patients who have recently received radiation therapy.

Pediatric Precautions

Auranofin has been used with good results and without unusual toxicity in several preliminary, uncontrolled clinical studies for the management of juvenile rheumatoid arthritis^† in children 4–16 years of age; however, controlled studies are needed and are currently ongoing. Since the safety and efficacy of auranofin in children have not been established, the manufacturer recommends that the drug not be used in this age group.

Mutagenicity and Carcinogenicity

At high concentrations (313–700 ng/mL), auranofin induced increases in the mutation frequencies in the mouse lymphoma forward mutation assay with metabolic activation; however, no evidence of auranofin-induced mutagenesis was seen in the Ames microbial mutagen test, the Saccharomyces microbial mutagen test with metabolic activation, the mouse cell transformation assay, or the dominant lethal assay.

Following oral administration of auranofin 0.4, 1, or 2.5 mg/kg daily (3, 8, or 21 times the human dosage, respectively) for 2 years in rats, malignant renal epithelial tumors and a substantial increase in the frequency of renal tubular cell karyomegaly and cytomegaly and renal adenoma were observed in the animals receiving 1 or 2.5 mg/kg daily. Following oral administration of auranofin in rats for 1 year, tumors of the renal tubular epithelium were observed in animals receiving 23 mg/kg daily (192 times the human dosage) but not in those receiving 3.6 mg/kg daily (30 times the human dosage). No evidence of an increased incidence of tumors was observed in mice receiving oral auranofin dosages of 1, 3, or 9 mg/kg daily (8, 24, or 72 times the human dosage, respectively) for 18 months.

Pregnancy, Fertility, and Lactation

Pregnancy

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.

Fertility

Reproduction studies using oral auranofin dosages of 3 mg/kg daily (25 times the human dosage) in female rats or 4 mg/kg daily (33 times the human dosage) in male rats did not reveal evidence of impaired fertility.

Lactation

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.

Drug Interactions

Phenytoin

Data from one patient suggested that concomitant administration of auranofin and phenytoin may have resulted in increased blood phenytoin concentrations. Further documentation of this potential interaction is needed.

Laboratory Test Interferences

Tuberculin Skin Test

Limited data suggest that auranofin may enhance the response to a tuberculin skin test, apparently as a result of its effects on cell-mediated immune responses. Further documentation of this potential interaction is needed. When the tuberculin skin test is used for diagnostic purposes related to tuberculosis in patients receiving auranofin, the possible effect of the drug on the response to tuberculin and its interpretation should be considered.

Acute Toxicity

Pathogenesis

The oral LD₅₀ of auranofin is 310 and 265 mg/kg in adult mice and adult rats, respectively. The minimum lethal dose in rats is 30 mg/kg.

Manifestations

There is limited experience to date with acute auranofin overdosage. A 50-year-old female with rheumatoid arthritis who had been receiving 6 mg of auranofin daily for about 6 months took 27 mg of the drug daily for 10 days and developed severe neurotoxicity manifested as encephalopathy and peripheral neuropathy. The patient exhibited diffuse multifocal myoclonus, mental derangement with impaired consciousness, restlessness, choreoathetoid movements, bilateral foot drop, facial dyskinesias, dysarthria, and fecal and urinary incontinence. Auranofin was discontinued and penicillamine therapy initiated; progressive clinical improvement was observed, and the patient recovered completely from the neurologic symptoms after about 3 months.

Treatment

In acute auranofin overdosage, the stomach should be emptied immediately by inducing emesis or by gastric lavage. If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents. Appropriate supportive therapy should be instituted as necessary. Although their use in the management of severe gold toxicity is controversial, chelating agents (e.g., dimercaprol, penicillamine) have been used in the management of severe toxicity induced by parenteral gold compounds and may be considered for auranofin overdosage. Gold from auranofin does not appear to be appreciably removed by hemodialysis. It is not known if gold from auranofin is removed by peritoneal dialysis.

Pharmacology

Anti-inflammatory, Antiarthritic, and Immunomodulating Effects

Like other gold compounds, auranofin exhibits anti-inflammatory, antiarthritic, and immunomodulating effects. The exact mechanism(s) of action of gold compounds, including auranofin, in the treatment of rheumatoid arthritis has not been clearly established, in part because the pharmacologic effects of the drugs and the etiology of the disease are complex; however, auranofin is generally believed to act principally via immunomodulating effects and by decreasing lysosomal enzyme release. Gold is apparently essential for the antiarthritic activity of auranofin, since the non-gold-containing ligands of the drug are inactive against experimentally induced arthritis in animals; however, it is not definitely known whether nonprotein-bound gold, protein-bound gold, or the gold associated with cells is the pharmacologically active moiety of gold compounds, including auranofin. Some data suggest that the active moiety is nonprotein-bound gold. The pharmacologic effects of auranofin and other gold compounds (e.g., gold sodium thiomalate) are generally qualitatively similar, but some effects of the drugs differ quantitatively and/or qualitatively; however, it remains to be determined whether such differences are clinically important. Similarly, much of the information on the potential mechanism(s) of action of auranofin and other gold compounds is based on in vitro studies, and the relevance of the results to in vivo activity of the drugs and any potential clinical importance remain to be more clearly defined.

Auranofin has been shown to have anti-inflammatory activity in vivo in animals and in patients with rheumatoid arthritis. The drug affects numerous cellular processes involved with inflammation. Auranofin inhibits monocyte chemotaxis in vitro and has variable effects on neutrophil chemotaxis in vitro, but is associated with enhanced neutrophil chemotaxis in vitro with neutrophils obtained from patients with rheumatoid arthritis treated with the drug. Auranofin also has variable effects on neutrophil aggregation in vitro; inhibits neutrophil, monocyte, and macrophage phagocytosis in vitro; inhibits neutrophil and monocyte superoxide radical production in vitro; and inhibits neutrophil lysosomal enzyme release in vitro. In vitro inhibition of neutrophil lysosomal enzyme release observed with neutrophils obtained from auranofin-treated patients with rheumatoid arthritis has been associated with a clinical response to the drug in some patients.

Auranofin has also been shown to modulate various humoral and cell-mediated immune responses in vitro and in vivo. In rats, the drug suppresses hemagglutinin responses to sheep erythrocytes and decreases the levels and/or activity of antibodies involved in antibody-dependent cellular cytotoxicity and antibody-dependent complement lysis. The effects of auranofin on serum immunoglobulin concentrations and rheumatoid factor titers in patients with rheumatoid arthritis are variable, with decreases in serum IgG, IgA, and/or IgM concentrations, or IgM-rheumatoid factor titers observed in some studies but not in others. Comparative studies suggest that decreases in serum immunoglobulin concentrations and rheumatoid factor titers induced by auranofin may be smaller than those induced by gold sodium thiomalate. Auranofin has variable effects on cell-mediated immune responses. In animals, the drug enhances the delayed hypersensitivity response to oxazolone or sheep erythrocytes and inhibits the onset of experimental allergic encephalomyelitis. In patients with rheumatoid arthritis, auranofin suppresses the response to skin testing with dinitrochlorobenzene and appears to have variable effects on (but may principally enhance) the response to other skin test antigens (e.g., mumps, tuberculin). In vitro, auranofin appears to have concentration-dependent effects on cells involved with antibody-dependent cellular cytotoxicity, generally inhibiting the effects of the cells on this activity at gold concentrations of 1–2 mcg/mL; however, in vivo in patients with rheumatoid arthritis, auranofin therapy has been associated with normalization of lymphocyte antibody-dependent cellular cytotoxicity that was initially suppressed. Auranofin also appears to have concentration-dependent effects on natural killer cells in vitro, stimulating the activity of the cells at gold concentrations of 0.5 mcg/mL or less and suppressing the activity at concentrations of 1 mcg/mL and greater. The drug has been shown to suppress mitogen-induced lymphocyte proliferation (i.e., DNA synthesis) in vitro and in vivo in patients with rheumatoid arthritis.

Other Effects

In vitro, auranofin inhibits DNA, RNA, and protein synthesis in HeLa cells, RAJI lymphoma cells, and Epstein-Barr virus-transformed lymphocytes. In vitro, the drug also exhibits substantial cytotoxic effects against a variety of animal and human tumor cell lines, but its in vivo activity against numerous murine tumors is extremely limited. While auranofin inhibits DNA, RNA, and protein synthesis in tumor cells in vitro, the cytotoxic action of the drug appears to result from its effects on other cellular processes.

In vitro, auranofin inhibits platelet aggregation induced by adenosine diphosphate (ADP), epinephrine, and collagen. The mechanism is not known.

Like other gold compounds, auranofin has decreased plasma copper concentrations in animals with experimentally induced arthritis and in patients with rheumatoid arthritis; the reductions were associated with a clinical response to the drug. In patients with rheumatoid arthritis who had low initial plasma zinc concentrations and responded to auranofin, increases in plasma zinc concentration were inversely correlated with decreases in plasma copper concentration. The clinical relevance and importance of these effects are not known.

In vitro, auranofin inhibits histamine release from basophils induced by various stimulating factors (e.g., IgE).

Auranofin Pharmacokinetics

Absorption

Unlike other currently available gold compounds, auranofin is appreciably absorbed from the GI tract. Studies in animals and in humans indicate that approximately 20–25% of the gold contained in a dose of auranofin is absorbed from the GI tract following oral administration of the drug. The absorption process has not been fully characterized. Studies in animals suggest that gold from auranofin is poorly absorbed from the stomach and is absorbed principally from the small intestine and to a small extent from the large intestine. The actual forms in which gold from auranofin is absorbed and the mechanisms involved have not been clearly determined. Results of animal studies indicate that the ligands of auranofin are almost completely absorbed; since a much smaller fraction of the gold is absorbed, the drug is believed to undergo extensive disruption at its coordination bonds within the GI tract. Some experimental data suggest that auranofin is loosely and reversibly adsorbed onto GI mucosa. Other experimental data suggest that gold-containing forms of auranofin may undergo transmucosal absorption, possibly with the initial metabolic process being deacetylation within the GI mucosa. Unchanged auranofin has not been detected in blood to date following oral administration of the drug. The effect of food on absorption of the drug has not been evaluated.

Following oral administration of a single 6-mg dose of auranofin in healthy adults, mean peak blood gold concentrations of 0.025 mcg/mL (range: 0.014–0.046 mcg/mL) occurred at 2 hours. Following oral administration of multiple doses of the drug in patients with rheumatoid arthritis, steady-state blood gold concentrations are usually attained after 8–12 weeks, although periods of 13–16 weeks may be necessary in some patients. While there appears to be considerable interindividual variation, once steady-state blood gold concentrations are attained during auranofin therapy, there appears to be minimal intraindividual variation in blood gold concentration with continued dosing. Mean steady-state blood gold concentrations attained with auranofin are substantially lower than those attained with parenteral gold compounds and are generally proportional to dose, increasing by approximately 0.1 mcg/mL for each 1-mg increment in the daily dose of the drug. Mean steady-state blood gold concentrations with auranofin therapy are approximately 0.3 mcg/mL in patients receiving 3 mg of the drug daily, 0.5–0.7 mcg/mL in patients receiving 6 mg daily, and 0.9–1 mcg/mL in patients receiving 9 mg daily. Correlations between blood gold concentrations and urinary gold excretion or the daily dose of auranofin expressed on a mg/kg basis have been found in some studies. Therapeutic response to auranofin may begin within 1–2 months but generally is not evident until at least 3–4 months after beginning therapy with the drug; a response may not occur in some patients for 6 months or longer.

Because a substantial portion of the gold in blood during auranofin therapy is associated with circulating cells, blood gold concentrations determined during therapy with the drug are generally higher than plasma or serum gold concentrations, although gold concentrations in blood may actually be higher or lower than those in plasma or serum, depending on the patient’s hematocrit. Plasma and serum concentrations of gold during auranofin therapy are approximatey equivalent. As with other gold compounds, most studies have shown that blood or serum gold concentrations attained with auranofin do not correlate well with therapeutic effects or toxicity. It is not clear whether the concentration of gold associated with blood cells during chrysotherapy is correlated with therapeutic efficacy or toxicity.

Distribution

There currently is little information on the distribution of gold into human body tissues and fluids during auranofin therapy. Since relatively small amounts of gold are retained in the body during long-term therapy with auranofin, tissue gold concentrations achieved with auranofin therapy are likely to be substantially lower than those attained with parenteral gold therapy, and this is supported by the results of distribution studies in animals and limited human data to date. The apparently lower tissue concentrations of gold may account in part for the tendency for some adverse effects of auranofin to occur less frequently and be less severe than those of parenteral gold compounds.

Following oral administration of multiple doses of auranofin in animals, gold is distributed in highest concentrations into the kidneys; gold is also distributed into the spleen, lungs, adrenals, and liver, with lower concentrations being distributed into the heart, testes, GI tract, muscle, eyes, fat, and brain. In animals (and possibly in humans), small amounts of gold from auranofin are distributed into bile. Synovial fluid gold concentrations in rheumatoid arthritis patients receiving auranofin are much lower than those in patients receiving therapy with parenteral gold compounds, but the ratio of blood-to-synovial fluid gold concentrations during auranofin therapy is similar to that during parenteral gold therapy (approximately 1.7:1). Preliminary data suggest that little or no gold cumulates in skin during auranofin therapy, in contrast to the accumulation that occurs during therapy with parenteral gold compounds. Little or no gold accumulation occurs in hair or nails during auranofin therapy, and accumulation of gold in the cornea or lens during therapy with the drug has not been detected to date with total cumulative doses as high as 6.1 g. Following a single oral dose of auranofin in animals, gold appears to be distributed intracellularly principally within the cytosol rather than within organelles (e.g., lysosomes, mitochondria), as occurs following a single dose of a parenteral gold compound; however, as the intracellular gold concentration increases, it appears that binding of gold within the cytosol may become saturated, with a resultant increase in gold distribution within organelles. Within the cytosol, gold is bound in part to metallothionein(s).

In contrast to the distribution of gold in blood during therapy with parenteral gold compounds, a substantial portion of the gold in blood during auranofin therapy is associated with circulating cells. The importance of this association, if any, is not known. Although variable, the fraction of blood gold associated with circulating cells during auranofin therapy is generally about 40%. The extent of association appears to be dose dependent, but changes in the extent of association may not be reflected by changes in serum gold concentration. The gold from auranofin that is associated with blood cells is associated almost exclusively with erythrocytes; only small amounts are associated with leukocytes (principally lymphocytes) and platelets. The gold from auranofin that is associated with erythrocytes is about 90% distributed intracellularly and about 10% membrane bound. Whether distribution of gold from auranofin into erythrocytes is increased in individuals who smoke cigarettes, as apparently occurs with gold sodium thiomalate therapy in patients with rheumatoid arthritis who smoke, has not been clearly determined.

In vivo, gold from auranofin is approximately 60% bound to serum proteins. Of the gold bound to serum proteins, 82% is bound to albumin and the remainder to α₁-, α₂-, and β-globulins and possibly to IgG. Less than 1–2% of gold from auranofin in serum is present as free gold; serum concentrations of free gold attained with auranofin appear to be similar to those attained with gold sodium thiomalate.

It is not known if gold from auranofin crosses the placenta in pregnant women, but it does cross the placenta in animals. Gold has been shown to cross the placenta in pregnant women receiving gold sodium thiomalate. It is also not known if gold from auranofin is distributed into human milk, but it is distributed into milk in animals. Small amounts of gold have been shown to be distributed into milk in women receiving currently available parenteral gold compounds.

Elimination

In patients with rheumatoid arthritis receiving an auranofin dosage of 6 mg daily, the terminal plasma and biologic half-lives of gold following the initial dose of the drug averaged 17 days (range: 11–23 days) and 58 days (range: 30–78 days), respectively; after 6 months of therapy with the same dosage, the terminal plasma and biologic gold half-lives averaged 26 days (range: 21–31 days) and 81 days (range: 42–128 days), respectively. During continuous administration of auranofin in these patients, about 15% of the gold contained in a single dose of the drug was retained in the body 10 days after administration and about 1% or less was retained 6 months after administration. It has been estimated that after 6 months of auranofin therapy at a dosage of 6 mg daily, an average of 24 mg (range: 5–89 mg) of the gold contained in the total cumulative dose of the drug may be retained in the body. The true potential of gold compounds, including auranofin, to cumulate has not been clearly defined, but it is clear that substantially smaller amounts of gold are retained in the body during auranofin therapy than during therapy with currently available parenteral gold compounds.

The metabolic fate of auranofin has not been fully elucidated. Although gold from auranofin is only partially absorbed from the GI tract, results of animal studies indicate that the ligands of the drug are almost completely absorbed, suggesting that auranofin undergoes extensive disruption at its coordination bonds within the GI tract. In vitro studies also indicate that auranofin rapidly undergoes disruption at its coordination bonds in blood. Supporting evidence for bond disruption includes identification of the major product of the gold-phosphorus bond cleavage, triethylphosphine oxide, in the urine of animals and humans receiving the drug. Further studies are needed to identify other metabolic products, but they may include tetraacetylthioglucopyranose and a gold-protein complex(es). Some experimental data suggest that gold-containing forms of auranofin may undergo transmucosal absorption, possibly with the initial metabolic process being deacetylation within the GI mucosa.

The elimination of gold from auranofin has been fairly well characterized. About 4–5% of the gold contained in a single dose of auranofin is excreted in urine within 10 days and about 15% over 6 months; about 70–75% of the gold is excreted in feces within 10 days and about 85% over 6 months. It is estimated that about 60% of the absorbed gold from auranofin is excreted in urine and the remainder in feces. Urinary and fecal clearances of gold are similar in patients receiving the drug. The gold excreted in feces during auranofin therapy is principally unabsorbed drug; however, since fecal gold excretion continues over a prolonged period after a single dose of auranofin, other mechanisms of fecal elimination, which have yet to be clearly determined, may exist. In animals (and possibly in humans), small amounts of auranofin-gold are excreted in feces via biliary elimination. Other mechanisms of fecal gold excretion may include secretion via the intestinal mucosa and/or mucosal adsorption with subsequent release. Enterohepatic circulation of gold from auranofin has not been demonstrated in humans and is negligible in animals.

Gold from auranofin does not appear to be appreciably removed by hemodialysis. It is not known if gold from auranofin is removed by peritoneal dialysis.

Chemistry and Stability

Chemistry

Auranofin is an orally active gold compound. The drug is an organic coordination compound in which gold(I) is complexed with a triethylphosphine group via the phosphorus atom and with tetraacetylthioglucopyranose via the sulfur atom. Auranofin occurs as a white, odorless, crystalline powder and contains 29% gold. The drug is very slightly soluble in water and soluble in alcohol, having solubilities of 0.17 and 83.8 mg/mL, respectively, at 25°C.

Like the gold in the parenteral gold compounds, aurothioglucose and gold sodium thiomalate, the gold in auranofin is attached to sulfur; however, unlike the gold in these compounds, the gold in auranofin is also attached to a triethylphosphine group. In addition, unlike these parenteral gold compounds, auranofin occurs as a monomer, is very lipophilic, has only a slight net ionic charge in solution, and possibly may not react as strongly with sulfhydryl groups; these properties may facilitate transport of auranofin across cellular membranes and account in part for absorption of the drug from the GI tract and its tissue and cellular distribution characteristics.

Stability

Auranofin powder darkens slightly when exposed to strong light and also to some extent when stored at a temperature of 60°C or warmer; the darkening indicates a small degree of chemical degradation, but the effect on biologic activity is not known. Commercially available auranofin capsules should be stored in tight, light-resistant containers at 15–30°C. Auranofin capsules have an expiration date of 4 years after the date of manufacture.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Reload page with references included

Medical Disclaimer