Auranofin

678.48

679.140511

251-801-9

321521

DTXSID4020115

White crystalline powder

M - Musculo-skeletal system

112-115 °C

425.5°C at 760 mmHg

298ºC

DMSO: ≥5mg/mL

room temp

Oral-rat LD50:265 mg/kg; Oral-Mouse LD50; 310 mg/kg

Combustible; burning produces toxic nitrogen oxides and sulfur oxide fumes; patient side effects are: stomach bleeding and stomach ulcers

Odorless

Unstable to light and heat

Ⅲ

UN 2811 6.1 / PGIII

3

63-22

36/37

MD6500000

Xn

Ventilated, low temperature and dry; store with food materials in warehouse

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.

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl auranofin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Danger|H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]|P201, P202, P264, P270, P281, P301+P310, P308+P313, P321, P330, P405, and P501|Aggregated GHS information provided by 44 companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

highly toxic

...there may be a higher incidence of penicillamine toxicity in patients who have previously shown toxic reactions. The interval between stopping the gold and starting the penicillamine did not influence incidence of toxicity. The development of a rash during gold treatment does not seem to influence the development of a rash during penicillamine treatment, but patients who have had proteinuria or bone-marrow depression during gold treatment may have an increased likelihood of developing a similar side effect with penicillamine.|In a single-patient report, there is the suggestion that concurrent administration of Ridaura /auranofin/ and phenytoin may have increased phenytoin blood levels.

LD50 Rat oral 265 mg/kg|LD50 Mouse oral 310 mg/kg

In patients with rheumatoid arthritis receiving an auranofin dosage of 6 mg daily, ... 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.

Auranofin is indicated in the treatment of adult rheumatoid arthritis and is used in the treatment of (juvenile arthritis /NOT included in US product labeling/). ... Gold compounds may induce remission or suppression of rheumatoid arthritis. In chronic advanced rheumatoid arthritis, they may prevent further damage to affected joints; however, they do not reverse existing damage. /Included in US product labeling/

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.|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. ... Epigastric pain and erosive gastritis have been reported rarely in patients receiving auranofin.|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.|For more Drug Warnings (Complete) data for AURANOFIN (13 total), please visit the HSDB record page.

Drugs that are used to treat RHEUMATOID ARTHRITIS. (See all compounds classified as Antirheumatic Agents.)

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 alpha1-, alpha2-, and beta-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.|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 oral administration of a single 6-mg dose of auranofin in healthy adults, mean peak blood gold concentrations of 0.025 ug/mL (range: 0.014-0.046 ug/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.|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.|For more Absorption, Distribution and Excretion (Complete) data for AURANOFIN (9 total), please visit the HSDB record page.

Metabolized so rapidly that the intact molecule has not been detected in blood.|For a patient receiving gold sodium thiomalate the principal gold species in the urine is [Au(CN)2]-, which is also seen in a low molecular weight infiltrate of the blood. The same compound is also identified in the urine and blood of a patient taking auranofin|Auranofin, 2,3,4,6-tetra-O-acetyl-1-thio-beta-D-glucopyranosato-S-(triethylphosphine)- gold(I), ...metabolized in contact with hamster or rat gut wall to yield the deacetylated form of the drug. This product, 1-thio-beta-D-glucopyranosato-S-(triethylphosphine)-gold(I), passed through hamster or rat intestinal wall in an everted gut experiment...|The efflux of gold from red blood cells (RBCs) exposed to 10-100 microM auranofin, triethylphosphine(2,3,4,6-tetra-O-acetyl- 1-beta-D-gludopyranosato-S-)gold(I) was studied. RBCs in whole blood were allowed to accumulate gold, and then were place in fresh plasma or buffered saline solution. ...[14C]Glutathione, generated by in situ labeling, also effluxed and associated with the albumin and gold, providing the first direct evidence that the albumin-gold-glutathione complex (AlbSAuSG) may be a circulating metabolite of auranofin formed after both of the original ligands of auranofin are displaced.

The mean terminal plasma half-life of auranofin gold at steady state was 26 days (range 21 to 31 days; n = 5). The mean terminal body half-life was 80 days (range 42 to 128; n= 5)|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. ...

The mechanism of action of anti-rheumatic gold compounds on 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced prostaglandin E(2) (PGE(2)) production in rat peritoneal macrophages were examined. Auranofin (AF) at 3-10 muM inhibited TPA-induced PGE(2) production in concentration-dependent manner. In the pharmacological experiments, prostaglandin G/H synthase (PGHS)-2-dependent PGE(2) production was inhibited by 10 muM of AF. The enzyme activities of both PGHS-1 and PGHS-2 were not affectecd by the 10 muM AF. ...AF decreased the PGHS-2 protein content, but had no effect on the PGHS-1 protein content. AF at 3-10 muM decrease the PGHS-2 messenger RNA (mRNA) level by RT-PCR determination. Then the effect of AF on nuclear factor kappa B (NF-kappaB), one of the transcription factors known to regulate transcription of a group of proinflammatory proteins, was determined. AF at 1-10 muM inhibited nuclear translocation of NF-kappaB in a concentration-dependent manner. AF ...did not affect the binding of NF-kappaB to its specific DNA. These observations may suggest that the effects of gold compounds on the inhibition of NF-kappaB nuclear translocation plays one of the major role in its anti-inflammatory effects in rat peritoneal macrophages.|...The effect of AF /auranofin/ on PMN activated by two stimulates (PMA, ConA) added sequentially. AF (0.1-10 microM) caused a dose-dependent inhibition of lucigenin-dependent chemiluminescence regardless of the activator (FMLP, ConA, A23 187, PMA) when AF was added before the activator. In contrast, when AF was added to PMN after stimulation, it inhibited only the chemiluminescence of PMN stimulated by PMA. Furthermore, the chemiluminescence was largely unaffected by AF in sequentially activated PMN. The relative sensitivity to AF of the various processes studied indicate that blockade of the activation signal appears to be responsible for inhibition of the respiratory burst of PMN.

There has been no experience with treating Ridaura overdosage with modalities such as chelating agents. However, they have been used with injectable gold and may be considered for Ridaura /(auranofin)/ overdosage.|In case of acute overdosage, immediate induction of emesis or gastric lavage and appropriate supportive therapy is recommended.|Pulmonary toxicity associated with gold salt treatment of rheumatoid arthritis...has a good prognosis if treated properly with the simple interruption of gold salts or with corticosteroids, with complete cure in the majority of cases. A case with good response to corticosteroid therapy is reported and the differential diagnosis with pulmonary fibrosis associated with rheumatoid arthritis is analyzed. /Gold salt/|BAL (British anti-Lewisite, Dimercaprol) is a dithiol-chelating agent used in the treatment of poisoning by the heavy metal ... gold. Adequate doses of BAL must be given to ensure an excess of free BAL. An insufficient concentration of BAL may allow dissociation of the BAL-metal complex. This chelate dissociates more rapidly in an acidic urine; adequate renal function must exist to allow elimination of the mercaptide complex. /Gold compounds/|For treatment of adverse effects: Recommended treatment may include: Discontinuing the medication promptly. Administering appropriate therapy, such as topical adrenocorticoids, soothing lotions, or local anesthetics, for relief of mild to moderately severe skin or mucous membrane reactions. Administering systemic glucocorticoids ... for severe or generalized dermatitis or stomatitis. Administering high doses of glucocorticoids ... if required for severe pulmonary or other complications. If symptoms do not improve with high-dose glucocorticoid treatment, or if significant glucocorticoid-induced adverse effects develop, use of a chelating agent such as dimercaprol (BAL) to enhance gold excretion may be considered. However, the efficacy of BAL has not been established. Also, caution in use of BAL is recommended because of its toxicity. Administering other supportive treatment as required for specific complications. /Gold medication/

/SIGNS AND SYMPTOMS/ Danger signs of possible gold toxicity include fall in hemoglobin, leucopenia below 4,000 WBC/cu mm, granulocytes below 1,500 /cu mm, decrease in platelets below 150,000 cu mm, proteinuria, hematuria, pruritus, rash, stomatitis or persistent diarrhea.|/CASE REPORTS/ 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.|/OTHER TOXICITY INFORMATION/ Auranofin (AF) when administered orally, frequently causes diarrhea with abnormal stool electrolyte content. Studies were designed to determine the mechanism of the diarrhea caused by AF. In perfused canine Thiry-Vella loops, AF caused significant elevations in effluent volume, osmolarity, and sodium concentration and a significant decrease in potassium concentration. In mucosal homogenates of rat small bowel, AF inhibited sodium, potassium ATPase in a concentration dependent manner. AF did not alter canine colonic smooth muscle activity in vitro. AF /may/ induce diarrhea from interruption of normal water and electrolyte absorption by inhibition of enterocyte sodium, potassium ATPase activity.|/OTHER TOXICITY INFORMATION/ The effects of auranofin, on basal and forskolin-activated adenylyl cyclase activity in human total lymphocyte membranes and in membranes of T and B lymphocyte subsets /was studied/. The gold compounds inhibited adenylyl cyclase activity. This inhibitory effect required the presence of both the sulfhydryl ligands and aurous cation. Regulation of lymphocyte adenylyl cyclase by gold compounds represents a potential mode of action of these drugs in rheumatic disease.|For more Human Toxicity Excerpts (Complete) data for AURANOFIN (7 total), please visit the HSDB record page.

Auranofin

Oral: capsules 3 mg; Ridaura (with benzyl alcohol and povidone), Prometheus

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients