Ridaura (Auranofin)

RIDAURA®

Pharmascience

Auranofin

Antirheumatic Agent

Action And Clinical Pharmacology: Auranofin is a gold preparation and therefore has the potential for serious gold toxicity. The mechanism by which auranofin exerts its therapeutic effect has not been established.

In patients with adult rheumatoid arthritis or psoriatic arthritis, auranofin may modify disease activity as manifested by synovitis and associated symptoms, and reflected by laboratory parameters such as elevated ESR. There is no substantial evidence, however, that gold-containing compounds induce remission of rheumatoid arthritis.

Clinically the usual time of onset of therapeutic response to auranofin is 3 to 4 months. Continuing therapy beyond this time depends upon patient responsiveness, which includes improvement in parameters such as joint swelling, tenderness, pain, morning stiffness and grip strength. Continuing therapy beyond 6 months is unwarranted in patients showing insufficient improvement in the above parameters, and auranofin should be discontinued because of potential serious adverse reactions.

Pharmacokinetics: In 5 rheumatoid arthritic patients, the oral administration of a single 6 mg (equivalent to 1.74 mg of gold) dose of a solution of radiolabeled auranofin demonstrated that approximately 25% of the oral dose was absorbed. Peak plasma radioactive gold concentrations of 0.039 to 0.11 g 95u/mL were reached in 1.5 to 2.5 hours. The mean plasma terminal half-life was 17 days, while the mean total body terminal half-life was 58 days. By day 10 post-administration, 77% of the initially administered labeled gold had been excreted, 73% in the feces and 4% in the urine. Six months after this single dose, approximately 99.6% of the initially administered labeled gold had been excreted, with 0.4% retained in the body.

Following 6 months of therapy with unlabeled auranofin 3 mg twice daily, a single 6 mg dose of radiolabeled auranofin was administered. Peak plasma radioactive gold concentrations of 0.027 to 0.138 g 95u/mL were reached in 1.0 to 1.5 hours. The mean plasma half-life was 25.5 days, while the mean total body terminal half-life was 80.8 days. By day 10 post-administration, 75% of the labeled gold had been excreted, 70% in the feces and 5% in the urine.

In clinical studies, steady state blood gold levels were achieved in about 3 months. With auranofin at 6 mg/day, mean blood gold levels of 0.62±0.195 g/mL (91 patients) have been observed after 3 months of treatment and 0.68±0.452 g/mL (63 patients) after 6 months. 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.

Indications And Clinical Uses: In the management of adults with active (classical or definite) rheumatoid arthritis who have not responded to adequate trials of conventional anti-inflammatory therapy. Auranofin might also be of benefit in patients with psoriatic arthritis.

It should be considered only when salicylates or other nonsteroidal anti-inflammatory drugs, and, when appropriate, steroids, have proven to be inadequate for controlling the symptoms of rheumatoid arthritis.

Physicians planning to use auranofin should be experienced with chrysotherapy and should thoroughly familiarize themselves with the toxicity and benefits of auranofin.

In controlled clinical trials, comparing auranofin with injectable gold, auranofin was associated with fewer drop-outs due to adverse reactions, while injectable gold was associated with fewer drop-outs for inadequate or poor therapeutic effects. Physicians should consider these findings when deciding on the use of auranofin in patients who are candidates for chrysotherapy.

Auranofin should be added to an ongoing comprehensive treatment program which includes physical as well as other drug therapy. The usual time of onset of therapeutic response is 3 to 4 months; some patients require as long as 6 months to show a full clinical response.

Auranofin is not indicated in other arthropathies, such as osteoarthritis.

Contra-Indications: In patients with a history of serious gold-induced toxicity such as necrotizing enterocolitis, pulmonary fibrosis, exfoliative dermatitis or hypersensitivity. Auranofin should not be prescribed for patients with progressive renal disease, severe hepatocellular disease, bone marrow aplasia or other severe hematological disorders.

Pregnancy: Auranofin has been shown to be embryotoxic in rats at dose levels of 5 mg/kg/day or higher and both embryotoxic and teratogenic in rabbits at doses of 0.5 mg/kg/day or higher. Therefore, it should not be given to pregnant women. Furthermore, women of childbearing potential should be made aware of the necessity to avoid pregnancy during treatment and for at least 6 months after because of the slow excretion of gold and its persistence in the body tissues after discontinuation of treatment.

Lactation: Gold is excreted in rodent milk following the administration of auranofin. It is not known whether Ridaura is excreted in human milk; however, injectable gold appears in the milk of nursing mothers following administration. Therefore, it is recommended that Ridaura should not be given during nursing.

Manufacturers’ Warnings In Clinical States: Auranofin contains gold and, like other gold-containing drugs, can cause gold toxicity. Danger signs of possible gold toxicity include the following: fall in hemoglobin, leukopenia below 4 000 WBC/mm granulocytes below 1 500/mm decrease in platelets below 150 000/mm proteinuria, hematuria, pruritus, rash, stomatitis or persistent diarrhea. Therefore, it is recommended that white blood cells with differential platelet count, hemoglobin, urinary protein and renal and liver function be measured prior to therapy to establish a baseline and to identify pre-existing conditions (see Contraindications).

The possibility of adverse reactions should be explained to patients before starting therapy (see Information for the Patient).

Patients should be advised to report promptly any unusual signs and symptoms occurring during treatment such as sore throat or tongue, mouth ulceration, skin rash, easy bruising, purpura, epistaxis, bleeding gums or menorrhagia.

When the following adverse reactions occur, therapy may require modification or additional monitoring as outlined below:

Thrombocytopenia: Thrombocytopenia has occurred in approximately 1 to 3% of patients (see Adverse Effects) treated with auranofin, some of whom developed bleeding. The thrombocytopenia appears to be peripheral in origin in most cases and is usually reversible upon withdrawal of auranofin. Its onset bears no relationship to the duration of therapy and its course may be rapid. While patients’ platelet counts require monitoring every 2 weeks for the first 3 months and at least monthly thereafter, the occurrence of a precipitous decline in platelets or a platelet count less than 100 000/mmor signs and symptoms (e.g., purpura, ecchymoses or petechiae) suggestive of thrombocytopenia indicates a need to immediately withdraw auranofin and all other therapies with the potential to cause thrombocytopenia, and to obtain additional platelet counts. No additional auranofin should be given unless the thrombocytopenia resolves and further studies show it was not due to gold therapy.

Proteinuria: Proteinuria has developed in approximately 3 to 9% of patients (see Adverse Effects) treated with auranofin. Urinalysis should be performed every 2 weeks for the first 3 months and at least monthly thereafter. If clinically significant proteinuria or microscopic hematuria is found, auranofin and all other therapies with the potential to cause proteinuria or microscopic hematuria should be stopped immediately.

There has been little experience with the concomitant use of auranofin and penicillamine, chloroquine/hydroxychloroquine, immunosuppressive agents (e.g., cyclophosphamide, azathioprine, or methotrexate) or high doses of corticosteroids and therefore, such use cannot be recommended.

Precautions: General: The potential benefits of using auranofin in patients with 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 effects have been reported with the use of gold preparations and require modification of auranofin treatment or additional monitoring. See Adverse Effects for the approximate incidence of those reactions specifically reported with auranofin.

Gastrointestinal: Gastrointestinal reactions reported with gold therapy include diarrhea/loose stools, nausea, vomiting, anorexia and abdominal cramps. The most common reaction is diarrhea/loose stools reported in approximately 47% of patients. This is generally manageable by reducing the dosage (e.g., from 6 mg daily to 3 mg). In 4% of the patients it has been necessary to discontinue 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: Dermatitis is the most common reaction to parenteral gold therapy and the second most common reaction to auranofin. 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; an actinic rash may develop. The most serious form of cutaneous reaction reported with parenteral gold is generalized exfoliative dermatitis.

In patients with psoriatic arthritis who were involved in all clinical trials with Ridaura, 5/438 (1.1%) Ridaura-treated patients and 2/183 (1.1%) placebo-treated patients had an exacerbation of their psoriasis requiring withdrawal.

Mucous Membrane: 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: Auranofin, like other gold preparations, 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 urinalysis regularly and to discontinue treatment promptly if proteinuria or hematuria develops.

Hematologic: Blood dyscrasias including leukopenia, granulocytopenia and thrombocytopenia have all been reported as reactions to injectable gold and auranofin. These reactions may occur separately or in combination at any time during treatment. In addition, a case of pure red cell aplasia has been reported as a reaction to auranofin. Because these reactions have potentially serious consequences, blood dyscrasias should be constantly watched for, through monitoring of the formed elements of the blood, every 2 weeks for the first 3 months and at least monthly thereafter.

Ocular: There have been some reports of gold deposits in the lens or corneas of patients treated with auranofin. These deposits have not led to any eye disorders or any degree of visual impairment, and have cleared within 3 to 6 months of cessation of therapy. Initial and periodic ophthalmic examinations are recommended in patients being treated with auranofin.

Miscellaneous: Rare reactions attributed to gold include cholestatic jaundice; gold bronchitis and interstitial pneumonitis and fibrosis; peripheral neuropathy; partial or complete hair loss; fever. The physician should be constantly on guard for any of the above changes, and as a precaution, suitable laboratory monitoring should be done at appropriate intervals.

Children: The safety and effectiveness of auranofin in children under age 16 have not yet been established. Consequently, use in this age group cannot be recommended.

Carcinogenesis: 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 instances 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 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 adenomas of the renal tubular epithelium, whereas those treated with 3.6 mg/kg/day (30 times the human dose) did not.

Drug Interactions: One report suggests that, in a single patient, concurrent administration of auranofin and phenytoin was associated with increased phenytoin blood levels.

Adverse Reactions: The adverse reactions listed below are based on observations on 4 784 rheumatoid arthritis patients treated with auranofin, of whom 2 729 were treated for more than 1 year and 573 for more than 3 years. The overall incidence of adverse reactions was 62%, of whom 18.6% discontinued therapy. The most common adverse reactions were diarrhea (47%), rash (24%), pruritus (17%), abdominal pain (14%) and stomatitis (13%). More serious adverse reactions were anemia (1.6%), leukopenia (1.9%), thrombocytopenia (0.9%) and proteinuria (5.0%). The highest incidence was during the first 6 months of treatment. However, reactions can occur at any time throughout the course of therapy.

Clinical trials were conducted assessing Ridaura in the treatment of 438 psoriatic arthritis patients. The nature and incidence of adverse reactions were similar to those observed in rheumatoid arthritis patients.

Reactions occurring in more than 1% of auranofin-treated patients: Gastrointestinal: loose stools or diarrhea (47%); abdominal pain (14%); nausea with or without vomiting (10%); anorexia; flatulence; constipation and dysgeusia.

Dermatological: rash (24%); pruritus (17%); hair loss; urticaria.

Mucous membrane: stomatitis (13%); conjunctivitis; glossitis.

Hematological: anemia; leukopenia; thrombocytopenia; eosinophilia.

Renal: proteinuria; hematuria.

Hepatic: elevated liver enzymes.

Miscellaneous: weight loss.

Reactions marked with an asterisk occurred in 3 to 9% of the patients. The other reactions listed occurred in 1 to 3%.

Reactions occurring in less than 1% of auranofin-treated patients: Gastrointestinal: gastrointestinal bleeding; melena; stool positive for occult blood; dysphagia
Dermatological: angioedema
Mucous membrane: gingivitis.

Hematological: neutropenia; agranulocytosis
Renal: membranous glomerulonephritis
Hepatic: jaundice
Respiratory: interstitial pneumonitis
Neurological: peripheral neuropathy

Symptoms And Treatment Of Overdose: Symptoms and Treatment: In case of acute overdosage, immediate induction of emesis or gastric lavage and appropriate supportive therapy are recommended.

Auranofin overdosage experience is limited. A 50-year-old female, previously on 6 mg daily, took 27 mg (9 capsules) daily for 10 days and developed an encephalopathy and peripheral neuropathy. Auranofin was discontinued and she eventually recovered.

There has been no experience with treating auranofin overdosage with modalities such as chelating agents; however, they have been used with injectable gold and may be considered when treating auranofin overdosage.

Dosage And Administration: Adults: Usual starting dosage is 6 mg/day. This dose may be given: twice a day – one 3 mg capsule with breakfast and one with the evening meal; or once a day – two 3 mg capsules with breakfast or two 3 mg capsules with the evening meal.

Auranofin should be discontinued in those patients in whom no response is observed after 4 months administration. In those patients in whom a partial response is observed after 4 months, it may be continued at 6 mg/day, or the dose may be increased to 9 mg/day (one 3 mg capsule 3 times a day), for an additional 2 months. Auranofin should be discontinued in patients in whom a satisfactory clinical response has not occurred after 6 months treatment. Daily dosages above 9 mg are not recommended.

Because of possible serious adverse reactions, some rheumatologists suggest reducing the dosage or discontinuing gold altogether when patients are in clinical remission (ARA criteria) lasting for at least 6 months, keeping in mind that cessation of therapy may allow the disease to progress further. Each patient must be evaluated individually.

Transferring from Injectable Gold: In a controlled clinical trial, patients on injectable gold were transferred to auranofin by discontinuing the injectable agent and starting oral therapy with 6 mg daily. At 6 months, control of disease activity of patients transferred to auranofin and those maintained on the injectable agent was not different. Data beyond 6 months are not available. When patients are transferred to auranofin, they should be informed of its adverse reaction profile, in particular the gastrointestinal reactions (see Precautions).

Availability And Storage: Each tan and brown opaque capsule contains: auranofin 3 mg. Also contains lactose 115.8 mg. Energy: 2.80 kJ (0.67 kcal). Sodium:

RIDAURA® Pharmascience Auranofin Antirheumatic Agent

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