Auranofin: Package Insert / Prescribing Info

The mechanism of action of auranofin is not understood. In patients with adult rheumatoid arthritis, Auranofin Capsules may modify disease activity as manifested by synovitis and associated symptoms, and reflected by laboratory parameters such as ESR. There is no substantial evidence, however, that gold-containing compounds induce remission of rheumatoid arthritis.

Pharmacokinetics

Pharmacokinetic studies were performed in rheumatoid arthritis patients, not in normal volunteers. Auranofin is rapidly metabolized and intact auranofin has never been detected in the blood. Thus, studies of the pharmacokinetics of auranofin have involved measurement of gold concentrations. Approximately 25% of the gold in auranofin is absorbed.

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). Approximately 60% of the absorbed gold (15% of the administered dose) from a single dose of auranofin is excreted in urine; the remainder is excreted in the feces.

In clinical studies, steady state blood-gold concentrations are achieved in about three months. In patients on 6 mg auranofin/day, mean steady state blood-gold concentrations were 0.68 ±0.45 mcg/mL (n=63 patients). In blood, approximately 40% of auranofin gold is associated with red cells, and 60% associated with serum proteins. In contrast, 99% of injectable gold is associated with serum proteins.

Mean blood-gold concentrations are proportional to dose; however, no correlation between blood-gold concentrations and safety or efficacy has been established.

General

The safety of concomitant use of Auranofin Capsules (auranofin) with injectable gold, hydroxychloroquine, penicillamine, immunosuppressive agents (e.g., cyclophosphamide, azathioprine, or methotrexate) or high doses of corticosteroids has not been established.

Medical problems that might affect the signs or symptoms used to detect Auranofin Capsules toxicity should be under control before starting Auranofin Capsules (auranofin).

The potential benefits of using Auranofin Capsules in patients with progressive renal disease, significant hepatocellular disease, inflammatory bowel disease, skin rash or history of bone marrow depression should be weighed against 1) the potential risks of gold toxicity on organ systems previously compromised or with decreased reserve, and 2) the difficulty in quickly detecting and correctly attributing the toxic effect.

The following adverse reactions have been reported with the use of gold preparations and require modification of Auranofin Capsules treatment or additional monitoring. See ADVERSE REACTIONS for the approximate incidence of those reactions specifically reported with Auranofin Capsules.

Gastrointestinal Reactions

Gastrointestinal reactions reported with gold therapy include diarrhea/loose stools, nausea, vomiting, anorexia and abdominal cramps. The most common reaction to Auranofin Capsules is diarrhea/ loose stools reported in approximately 50% of the patients. This is generally manageable by reducing the dosage (e.g., from 6 mg daily to 3 mg) and in only 6% of the patients is it necessary to discontinue Auranofin Capsules (auranofin) permanently. Ulcerative enterocolitis is a rare serious gold reaction. Therefore, patients with gastrointestinal symptoms should be monitored for the appearance of gastrointestinal bleeding.

Cutaneous Reactions

Dermatitis is the most common reaction to injectable gold therapy and the second most common reaction to Auranofin Capsules. Any eruption, especially if pruritic, that develops during treatment should be considered a gold reaction until proven otherwise. Pruritus often exists before dermatitis becomes apparent, and therefore should be considered to be a warning signal of a cutaneous reaction. Gold dermatitis may be aggravated by exposure to sunlight or an actinic rash may develop. The most serious form of cutaneous reaction reported with injectable gold is generalized exfoliative dermatitis.

Mucous Membrane Reactions

Stomatitis, another common gold reaction, may be manifested by shallow ulcers on the buccal membranes, on the borders of the tongue, and on the palate or in the pharynx. Stomatitis may occur as the only adverse reaction or with a dermatitis. Sometimes diffuse glossitis or gingivitis develops. A metallic taste may precede these oral mucous membrane reactions and should be considered a warning signal.

Renal Reactions

Gold can produce a nephrotic syndrome or glomerulitis with proteinuria and hematuria. These renal reactions are usually relatively mild and subside completely if recognized early and treatment is discontinued. They may become severe and chronic if treatment is continued after the onset of the reaction. Therefore it is important to perform urinalyses regularly and to discontinue treatment promptly if proteinuria or hematuria develops.

Hematologic Reactions

Blood dyscrasias including leukopenia, granulocytopenia, thrombocytopenia and aplastic anemia have all been reported as reactions to injectable gold and Auranofin Capsules. These reactions may occur separately or in combination at anytime during treatment. Because they have potentially serious consequences, blood dyscrasias should be constantly watched for through regular monitoring (at least monthly) of the formed elements of the blood throughout treatment.

Miscellaneous Reactions

Rare reactions attributed to gold include cholestatic jaundice; gold bronchitis and interstitial pneumonitis and fibrosis; peripheral neuropathy; partial or complete hair loss; fever.

Information for Patients

Patients should be advised of the possibility of toxicity from Auranofin Capsules and of the signs and symptoms that they should report promptly. (Patient information sheets are available.) Women of childbearing potential should be warned of the potential risks of Auranofin Capsules therapy during pregnancy (See PRECAUTIONS— Pregnancy).

Laboratory Tests

CBC with differential, platelet count, urinalysis, and renal and liver function tests should be performed prior to Auranofin Capsules (auranofin) therapy to establish a baseline and to identify any preexisting conditions.

CBC with differential, platelet count and urinalysis should then be monitored at least monthly; other parameters should be monitored as appropriate.

Drug Interactions

In a single patient-report, there is the suggestion that concurrent administration of Auranofin Capsules and phenytoin may have increased phenytoin blood levels.

Carcinogenesis/Mutagenesis

In a 24-month study in rats, animals treated with auranofin at 0.4, 1.0 or 2.5 mg/kg/day orally (3, 8 or 21 times the human dose) or gold sodium thiomalate at 2 or 6 mg/kg injected twice weekly (4 or 12 times the human dose) were compared to untreated control animals.

There was a significant increase in the frequency of renal tubular cell karyomegaly and cytomegaly and renal adenoma in the animals treated with 1.0 or 2.5 mg/kg/day of auranofin and 2 or 6 mg/kg twice weekly of gold sodium thiomalate. Malignant renal epithelial tumors were seen in the 1.0 mg/kg/day and the 2.5 mg/kg/day auranofin and in the 6 mg/kg twice weekly gold sodium thiomalate–treated animals.

In a 12-month study, rats treated with auranofin at 23 mg/kg/day (192 times the human dose) developed tumors of the renal tubular epithelium, whereas those treated with 3.6 mg/ kg/day (30 times the human dose) did not.

In an 18-month study in mice given oral auranofin at doses of 1, 3 and 9 mg/kg/day (8, 24 and 72 times the human dose), there was no statistically significant increase above controls in the instances of tumors.

In the mouse lymphoma forward mutation assay, auranofin at high concentrations (313 to 700 ng/mL) induced increases in the mutation frequencies in the presence of a rat liver microsomal preparation. Auranofin produced no mutation effects in the Ames test (Salmonella), in the in vitro assay (Forward and Reverse Mutation Inducement Assay with Saccharomyces), in the in vitro transformation of BALB/T3 cell mouse assay or in the Dominant Lethal Assay.

Pregnancy

Nursing Mothers

Nursing during Auranofin Capsules therapy is not recommended.

Following auranofin administration to rats and mice, gold is excreted in milk. Following the administration of injectable gold, gold appears in the milk of nursing women; human data on auranofin are not available.

Pediatric Use

Auranofin Capsules (auranofin) is not recommended for use in pediatric patients because its safety and effectiveness have not been established.

Usual Adult Dosage

The usual adult dosage of Auranofin Capsules (auranofin) is 6 mg daily, given either as 3 mg twice daily or 6 mg once daily. Initiation of therapy at dosages exceeding 6 mg daily is not recommended because it is associated with an increased incidence of diarrhea. If response is inadequate after six months, an increase to 9 mg (3 mg three times daily) may be tolerated. If response remains inadequate after a three-month trial of 9 mg daily, Auranofin Capsules therapy should be discontinued. Safety at dosages exceeding 9 mg daily has not been studied.

Transferring from Injectable Gold

In controlled clinical studies, patients on injectable gold have been transferred to Auranofin Capsules (auranofin) by discontinuing the injectable agent and starting oral therapy with Auranofin Capsules, 6 mg daily. When patients are transferred to Auranofin Capsules, they should be informed of its adverse reaction profile, in particular the gastrointestinal reactions. (See PRECAUTIONS— Information for Patients.) At six months, control of disease activity of patients transferred to Auranofin Capsules and those maintained on the injectable agent was not different. Data beyond six months are not available.

STORAGE AND HANDLING

Store between 15° and 30°C (59° and 86°F). Dispense in a tight, light-resistant container.