Summary for UKPID GOLD SALTS (AURANOFIN; AUROTHIOMALATE) Kathryn Pughe, BSc (Hons) MRPharmS National Poisons Information Service (Newcastle Centre) Regional Drug & Therapeutics Centre Wolfson Building Claremont Place Newcastle upon Tyne NE1 4LP UK This monograph has been produced by staff of a National Poisons Information Service Centre in the United Kingdom. The work was commissioned and funded by the UK Departments of Health, and was designed as a source of detailed information for use by poisons information centres. Peer review group: Directors of the UK National Poisons Information Service. Summary Name Generic Auranofin Proprietary Ridaura Generic Sodium aurothiomalate Proprietary Myocrisin Synonyms Gold sodium thiomalate, Sodium aurothiosuccinate Chemical Group/Family Drugs suppressing rheumatic disease BNF 10.1.3 Reference Number Na aurothiomalate CAS 12244-57-4 (xNa, anhydrous) CAS 39377-38-3 (2Na monohydrate) Auranofin CAS 34031-32-8 Product licence numbers: Myocrisin: 10 mg inj 0012/5114 20 mg inj 0012/5113 50 mg inj 0012/5006 Ridaura: 0002/0082 Manufacturer/Supplier Myocrisin: Rhone-Poulenc Rorer Ltd RPR House 52 St Leonards Road Eastbourne East Sussex BN21 3YG Tel: 01323 417125 Fax: 01323 534086 Ridaura: Bencard Welwyn Garden City Hertfordshire AL7 1EY Tel: 0800 616482 Fax: 0181 913 4560 Presentation Myocrisin Pale yellow solution 0.5ml amps in boxes of 10 x 10 mg 0.5ml amps in boxes of 10 x 20 mg 0.5ml amps in boxes of 10 x 50 mg Ridaura Pale yellow, film coated square tablets 3 mg tabs in containers of 60 Physico-Chemical Properties Chemical structure Myocrisin C4H3AuNa2O4S Disodium salt of (aurothio)succinic acid Auranofin C20H34AuO9PS 2,3,4,6-Tetra-O-acetyl-1-thio-ß-D-glucopyranosato- S-tri-ethylphosphine gold Physical state at room temperature Aurothiomalate Fine, pale yellow powder with a slight odour Auranofin Fine white powder Molecular weight Aurothiomalate (Hexomer) 2500 in 0.5M NaCl (Monomer) 390.1 Auranofin 678.5 pKa thiomalate 3.2 carboxyl 4.2 Auranofin - Solubility Aurothiomalate in alcohol insoluble in water very soluble Auranofin in alcohol 1 in 27 in water 1 in 5900 USES Indications Sodium aurothiomalate - active progressive rheumatoid arthritis, and progressive juvenile chronic arthritis. Auranofin - active progressive rheumatoid arthritis when NSAIDs inadequate alone. Therapeutic Dosage Sodium aurothiomalate By deep im injection only. Adults: Initial test dose of 10 mg in first week followed by weekly doses of 50 mg until signs of remission occur. With full remission, the interval between injections should be progressively increased to 3, 4 and then, after 18-24 months, to 6 weeks. If after reaching a total dose of 1g, excluding the test dose, no major improvement has occurred and the patient has not shown any signs of gold toxicity, six 100 mg injections may be administered at weekly intervals. If no signs of remission occur after this time, consider alternative treatments. Children: Weekly doses of 1mg/kg up to maximum weekly dose of 50 mg. This dose may be preceded by a smaller test dose of 1/10th or 1/5th of the full dose for 2-3 weeks. Continue weekly doses until signs of remission appear then increase intervals to 2 weeks. With full remission increase interval to 3 then 4 weeks. I f no signs of remission after 20 weeks, consider alternative treatments. Treatment should be continued for 6 months. Expect response at 300-500 mg level. If patients respond, maintenance therapy should be continued with the dosage administered over the previous 2-4 weeks for 1-5 years. Auranofin Adults: Starting dose 3 mg twice daily, then 6 mg as single daily dose if well tolerated. Continue for minimum of 3-6 months to assess response. Increase to 3 mg three times a day if response inadequate after 6 months, if still inadequate after a further 3 months, then discontinue Child: Not recommended Contraindications Sodium aurothiomalate Severe renal and hepatic disease; history of blood disorders or bone marrow aplasia; exfoliative dermatitis; systemic lupus erythematosus; necrotising enterocolitis; pulmonary fibrosis; pregnancy and breastfeeding; porphyria. Auranofin Not for use in patients with a history of gold-induced disorders as for sodium aurothiomalate. Abuses NIF HAZARD / RISK CLASSIFICATION NIF PHARMACOKINETICS Absorption Aurothiomalate Intramuscular absorption 100%, not orally absorbed Auranofin Oral absorption 13-33% Distribution Aurothiomalate Volume of distribution - 0.1Lkg-1 Auranofin Volume of distribution - NIF Metabolism Aurothiomalate No presystemic metabolism, 95% plasma protein bound Auranofin No presystemic metabolism, 60% plasma protein bound Elimination Aurothiomalate 70% excreted in urine, 30% in faeces Auranofin 85% excreted in faeces, 15% in urine Half-life Aurothiomalate Initial 5.5 days; terminal 250 days Auranofin 17-25 days (plasma); total body 70 days Special Populations Pregnancy The safety of gold salts in pregnancy has not been established. Gold salts should not be used in women of child-bearing potential, unless the benefits outweigh the possible risks, as clinical experience is limited. Gold is teratogenic in rats and rabbits at high doses which produce maternal toxicity, increased frequencies of skeletal, CNS and other malformations were seen. There are no controlled studies of gold administration during human pregnancy. Placental passage of gold salts has been documented in clinical reports. The frequency of malformations was not increased in a study of 119 children born to women who had been treated with gold compounds during the first trimester of pregnancy. 26 patients in this series received gold treatment throughout pregnancy, 2 minor anomalies were seen but a causal association with gold has not been established. Hepatic disease Use with caution in patients with any degree of hepatic dysfunction. Intrahepatic cholestasis with eosinophilia may be seen after gold injections. The condition is self-limiting, and liver function tests return to normal within about 3 months. Renal disease Use with caution in patients with any degree of renal impairment. Elderly Monitor with extra caution due to decreased renal function Lactation Avoid if breastfeeding as significant amounts of gold excreted. TOXICOKINETICS EPIDEMIOLOGY OF POISONING Acute overdose is usually the result of administration errors with IM injections, and until 1984 therapeutic gold drugs were only available parenterally. Most toxic data are based on therapeutic toxicity. ADVERSE EFFECTS There is a high incidence of adverse reactions when gold salts are used for rheumatoid arthritis, incidence is between 5-50% (Eyring & Engleman, 1963; Davis & Hughes, 1974). The rate of serious reactions is approximately 3-5%. Anaphylactoid effects may occur after any course of therapy, usually within the first 10 minutes of administration. Problems with therapeutic use include mouth ulcers, skin reactions,, proteinuria, blood disorders (sometimes sudden onset and fatal). Rarely colitis, peripheral neuritis, pulmonary fibrosis, hepatotoxicity with cholestatic jaundice and alopecia can also occur. Diarrhoea and other gastrointestinal symptoms are associated with auranofin use. Proteinuria occurs in 2-20% of patients treated with injected gold and may be sufficiently severe to cause nephrotic syndrome in 10-30% of those affected. Proteinuria usually resolves on stopping treatment. Gold lung is a rare toxic side effect of gold therapy that may begin after administration of 300-1000 mg total gold dose. Dyspnoea appears suddenly over a period of 2-10 days. Chest x-rays show diffuse bilateral pulmonary shading (Gortenuti et al 1985), and a moderate eosinophilia may be present. The prognosis is good after withdrawal of treatment (McFadden et al 1989), although impairment of lung function may be permanent (Cohen 1988). Patients treated with gold salts should be asked to report immediately the appearance of pruritis, metallic taste, sore throat or tongue, buccal ulceration or easy bruising, purpura, epistaxis, bleeding gums, menorrhagia or diarrhoea. INTERACTIONS Increased risk of toxicity with other nephrotoxic and myelosuppressive drugs. MECHANISM OF ACTION / TOXICITY Acute: No deaths have been recorded. Adults have been given up to 500 mg (10 times the therapeutic dose ) in a single dose with variable consequences. One patient took 27 mg auranofin daily for 10 days and developed an encephalopathy and peripheral neuropathy. The patient made a gradual recovery after auranofin was discontinued (manufacturer). Chronic: Effects would be expected to be extensions of toxic therapeutic effects. Features: Most of the reported cases of overdose have not developed features. Early features of acute overdose have included a generalized skin rash, which settled within a few hours, and oedema of the eyelids in one case, and ventricular tachycardia in another. Acute renal failure is a potential problem but has not been reported. Abnormal LFTs with elevation of ALT and alkaline phosphatase were reported 3 weeks post- overdose in one case. MANAGEMENT Observation and supportive measures are probably all that are required. There is some doubt as to whether toxic reactions seen are due to direct effects of gold, or an indirect effect through the immune system. Decontamination Overdose with oral gold salts is not commonly seen and it is not known if activated charcoal is effective in minimizing drug absorption in such cases. Metallic gold is poorly adsorbed by activated charcoal. Supportive care D-Penicillamine has been used to treat skin reactions (Davis 1969) and thrombocytopenia (Bluhm et al 1962) in cases where BAL and corticosteroids showed initial but not sustained results. It should be avoided in penicillin-allergic patients. Monitoring for proteinuria should be performed. Adults: 15-40mg/kg/day orally; max 250-500 mg four times a day before meals. Children: 20-30mg/kg/day orally once or twice daily before meals. Immunosuppressives such as cyclophosphamide have also been used to control toxic reactions. A dose of 100 mg daily for 6 months was used until platelets stabilised at 100,000 per cubic mm, and then the dose was reduced to 75mg daily (Kozloff et al 1979). Monitoring Haematology, liver and renal functions should be monitored. Gold urine levels during treatment vary considerably. There seems to be no correlation between blood gold levels and toxicity or therapeutic effect. In a summary of 20 cases of toxicity, the cumulative toxic dose was from 230 mg to 10g of gold salt. Antidotes Some patients have been given dimercaprol (BAL) to chelate the gold but there is no evidence that it is of value. The dose of BAL is individualized. A common dosage schedule is 3-5 mg/kg/dose every 4 hours by deep IM injection for the first 2 days, then 2.5-3/mg/kg/dose IM every 6 hours for 2 days, then 2.5-3 mg/kg IM every 12 hours for 7 days. Elimination techniques N-acetylcysteine (NAC) has been used to remove / redistribute gold and reduce haematological reactions (Godfrey et al 1982). Lorber et al (1973) demonstrated in vitro and in vivo chelation of gold by NAC, with up to a 54% increase over normal excretion in subjects tested. Dose: 2-9g in 100ml dextrose 5% or 0.45% sodium chloride iv over 2-6 hours. Total dose per therapy ranged from 13 to 153g. D-Penicillamine was shown to enhance the urinary excretion of gold when tested in 9 patients (Erying & Engleman 1963). Investigations Haematology, liver and renal functions should be monitored. Management controversies Use of dimercaprol: Patients with high gold levels not given dimercaprol do not appear to have had an adverse outcome, but there is insufficient data to make categoric statements. Chelation reduces the amount of circulating gold, but it is nearly impossible to remove all the gold from the system. CASE DATA A. AURANOFIN 1. Auranofin overdose (27 mg/day for 10 days) has resulted in peripheral neuropathy and encephalopathy, which resolved upon drug withdrawal (Ridaura Prod Info, 1985). B. AUROTHIOMALATE 1. Pik et al (1985) reported two acute overdose cases in which patients received 1000 mg and 500 mg of intramuscular aurothioglucose, respectively. Both patients were asymptomatic and recovered uneventfully without treatment. One patient, however, developed microhaematuria and granular casts without proteinuria which resolved spontaneously within four weeks. 2. A 53 year old male was accidentally injected with an im dose of 450 mg sodium aurothiomalate. Palpebral oedema and a cutaneous generalized rash were observed within 30 minutes. The gold blood levels reached 29.7mg/L without significant toxicity. The patient was treated with BAL and recovered (Barelli et al 1987). 3. A 32 year old patient developed ventricular tachycardia 3 hours after im injection of 500 mg of aurothiomalate (Sharf et al 1976). Author Kathryn Pughe, BSc (Hons) MRPharmS National Poisons Information Service (Newcastle Centre) Regional Drug & Therapeutics Centre Wolfson Building Claremont Place Newcastle upon Tyne NE1 4LP UK This monograph was produced by the staff of the Newcastle Centre of the National Poisons Information Service in the United Kingdom. The work was commissioned and funded by the UK Departments of Health, and was designed as a source of detailed information for use by poisons information centres. Peer review was undertaken by the Directors of the UK National Poisons Information Service. Last updated March 1997 REFERENCES: Books: 1. ABPI Compendium of Data Sheets and Summaries of Product Characteristics. Datapharm Publications Ltd. 1996-97. 2. AHFS Drug Information. McEvoy GK (Ed.) 1997. 3. British National Formulary. Number 32 (September 1996). British Medical Association and Royal Pharmaceutical Society. 4. Dollery C. Therapeutic Drugs. Churchill Livingstone. 1991. 5. Ellenhorn MJ. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd Edition. Williams & Wilkins. 1997. 6. Martindale : The Extra Pharmacopoeia. 31st Edition. Reynolds JEF (Ed.) Pharmaceutical Press. 1996. Papers: 1. Barrelli A, Calimici A, Pala F. Gold salts acute poisoning: a case report. Vet Hum Toxicol 1987; 29(suppl 2): 108-110. 2. Bluhm GB, Sigler JW, Ensign DC et al. D-penicillamine therapy of thrombocytopenia secondary to chrysotherapy: a case report. 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