CONTRAINDICATIONS
Auranofin is contraindicated in patients with a history of any of the following gold-induced
disorders: anaphylactic reactions, necrotizing enterocolitis, pulmonary fibrosis, exfoliative
dermatitis, bone marrow aplasia or other severe hematologic disorders.
WARNINGS
Danger signs of possible gold toxicity include fail in hemoglobin, leukopenia below 4000
WBC/cu mm, granulocytes below 1500/cu mm, decrease in platelets below 150,000/cu
mm, proteinuria, hematuria, pruritus, rash, stomatitis or persistent diarrhea.
Thrombocytopenia has occurred in 1-3% of patients (See ADVERSE REACTIONS)
treated with auranofin, some of whom developed bleeding. The thrombocytopenia usually
appears to be peripheral in origin and is usually reversible upon withdrawal of auranofin.
Its onset bears no relationship to the duration of auranofin therapy and its course may be
rapid. While patients' platelet counts should normally be monitored at least monthly (See
PRECAUTIONS, Laboratory Tests), the occurrence of a precipitous decline in platelets
or a platelet count less than 100,000/cu mm or signs and symptoms (e.g., purpura,
ecchymoses or petechiae) suggestive of thrombocytopenia indicates a need to
immediately withdraw auranofin and 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 has developed in 3-9% of patients (See ADVERSE REACTIONS) treated
with auranofin. If clinically significant proteinuria or microscopic hematuria is found (See
PRECAUTIONS, Laboratory Tests), auranofin and other therapies with the potential to
cause proteinuria or microscopic hematuria should be stopped immediately.
PRECAUTIONS
General
The safety of concomitant use of 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
toxicity should be under control before starting auranofin.
The potential benefits of using auranofin 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 treatment or additional monitoring. See ADVERSE
REACTIONS for the approximate incidence of those reactions specifically reported with
auranofin.
Gastrointestinal Reactions: Gastrointestinal reactions reported with gold therapy include
diarrhea/loose stools, nausea, vomiting, anorexia and abdominal cramps. The most
common reaction to auranofin 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
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.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 urinalysis 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. 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 the Patient
Patients should be advised of the possibility of toxicity from auranofin 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
therapy during pregnancy (see PRECAUTIONS, Pregnancy, Teratogenic Effects,
Pregnancy Category C.)
Laboratory Tests
CBC with differential, platelet count, urinalysis, and renal and liver function tests should
be performed prior to 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.
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 auranofin and 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 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, Teratogenic Effects, Pregnancy Category C
Use of auranofin by pregnant women is not recommended. Furthermore, women of
childbearing potential should be warned of the potential risks of auranofin therapy during
pregnancy (see below).
Pregnant rabbits given auranofin at doses of 0.5, 3 or 6 mg/kg/day (4.2 to 50 times the
human dose) had impaired food intake, decreased maternal weights, decreased fetal
weights and an increase above controls in the incidence of resorptions, abortions and
congenital abnormalities, mainly abdominal defects such as gastroschisis and umbilical
hernia.
Pregnant rats given auranofin at a dose of 5 mg/kg/day (42 times the human dose) had an
increase above controls in the incidence of resorptions and a decrease in litter size and
weight linked to maternal toxicity. No such effects were found in rats given 2.5
mg/kg/day (21 times the human dose).
Pregnant mice given auranofin at a dose of 5 mg/kg/day (42 times the human dose) had
no teratogenic effects).
There are no adequate and well-controlled auranofin studies in pregnant women.
Nursing Mothers
Nursing during auranofin 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 is not recommended for use in pediatric patients because its safety and
effectiveness have not been established.