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.
Arthritis Rheum 1962; 5: 638.
3. Cohen MAH. Adverse reactions to gold compounds. Adverse Drug
React Acute Poison Rev 1988; 4: 163-178.
4. Davis CM. D-penicillamine for the treatment for the treatment of
gold dermatitis. Am J Med 1969; 46: 472-477.
5. Davis P & Hughes GRV. Significance of eosinophilia during gold
therapy. Arthritis Rheum 1974; 17: 964-967.
6. Erying EJ & Engleman EP. Interaction of gold and penicillamine.
Arthritis Rheum 1963; 6: 216-223.
7. Godfrey NF, Peter A, Simon TM et al. IV N-acetylcysteine
treatment of hematologic reactions to chrysotherpay. J Rheum
1982; 9: 519-526.
8. Gortenuti G, Parrinello A, Vicentini D. Diffuse pulmonary changes
caused by gold salt therapy. Report of a case. Diagn Imag Clin
Med 1985; 54: 298-303.
9. Kozloff M, Votaw M & Penner JA. Gold-induced thrombocytopenia
responsive to cyclophosphamide. South Med J 1979; 72: 1490-1491.
10. Lorber A, Baumgartner WA, Bovy RA et al. Clinical application for
heavy metal complexing potential of N-acetylcysteine. J Clin
Pharmacol 1973; 13: 332-336.
11. McFadden RG, Traher LJ, Thompson JM. Gold-naproxen pneumonitis. A
toxic drug reaction? Chest 1989; 96: 216-218.
12. Pik A, Cohen N, Yona E et al. Should gold overdose be invariably
treated? J Rheumatol 1985; 12: 1174-1175.
13. Rubinstein I et al. Aurothioglucose overdosage in five patients
with rheumatoid arthritis. Clin Rheumatol 1987; 6: 583-587.
14. Sharf J, Nahir M, Nirenberg L. Ventricular tachycardia caused by
gold overdose. Arthritis Rheum 1976; 19: 137-138.
Computer databases:
1. Poisindex System(R), Micromedex inc., Denver Colorado, Edition
Expires 31/3/97.
2. Reprotox System(R), Micromedex inc., Denver Colorado, Edition
Expires 31/3/97.
3. TOXBASE, National Poisons Information Service, 1997.
See Also:
Toxicological Abbreviations