AURANOFIN
DESCRIPTION:
Ridaura (auranofin) contains gold and, like
other gold-containing drugs, can cause gold
toxicity, signs of which include: fall in
hemoglobin, leukopenia below 4,000 WBC/cu
mm, granulocytes below 1,500/cu mm,
decrease in platelets below 150,000/cu mm,
proteinuria, hematuria, pruritus, rash,
stomatitis or persistent diarrhea.
Therefore, the results of recommended
laboratory work (See PRECAUTIONS) should be
reviewed before writing each Ridaura
prescription. Like other gold preparations,
Ridaura is only indicated for use in
selected patients with active rheumatoid
arthritis. Physicians planning to use
Ridaura should be experienced with
chrysotherapy and should thoroughly
familiarize themselves with the toxicity
and benefits of Ridaura.
In addition, the following precautions
should be routinely employed:
1. The possibility of adverse reactions
should be explained to patients before
starting therapy.
2. Patients should be advised to report
promptly any symptoms suggesting toxicity.
(See PRECAUTIONS--Information for
Patients.)
Ridaura (auranofin) is available in oral form as TAB containing 3 mg
auranofin.
Auranofin is (2,3,4,6-tetra-O-acetyl-1-thio-beta- D-glucopyranosato-S-)
(triethylphosphine) gold.
.
ACTIONS/CLINICAL PHARMACOLOGY:
The mechanism of action of Ridaura (auranofin) is not understood. In patients
with adult rheumatoid arthritis, Ridaura 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.
INDICATIONS AND USAGE:
Ridaura (auranofin) is indicated in the management of adults with active
classical or definite rheumatoid arthritis (ARA criteria) who have had an
insufficient therapeutic response to, or are intolerant of, an adequate trial of
full doses of one or more nonsteroidal anti- inflammatory drugs. Ridaura should
be added to a comprehensive baseline program, including non- drug therapies.
Unlike anti-inflammatory drugs, Ridaura does not produce an immediate response.
Therapeutic effects may be seen after three to four months of treatment,
although improvement has not been seen in some patients before six months.
When cartilage and bone damage has already occurred, gold cannot reverse
structural damage to joints caused by previous disease. The greatest potential
benefit occurs in patients with active synovitis, particularly in its early
stage.
In controlled clinical trials comparing Ridaura with injectable gold, Ridaura
was associated with fewer dropouts due to adverse reactions, while injectable
gold was associated with fewer dropouts for inadequate or poor therapeutic
effect. Physicians should consider these findings when deciding on the use of
Ridaura in patients who are candidates for chrysotherapy.
CONTRAINDICATIONS:
Ridaura (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:
Ridaura (auranofin) contains gold and, like
other gold-containing drugs, can cause gold
toxicity, signs of which include: fall in
hemoglobin, leukopenia below 4,000 WBC/cu
mm, granulocytes below 1,500/cu mm,
decrease in platelets below 150,000/cu mm,
proteinuria, hematuria, pruritus, rash,
stomatitis or persistent diarrhea.
Therefore, the results of recommended
laboratory work (See PRECAUTIONS) should be
reviewed before writing each Ridaura
prescription. Like other gold preparations,
Ridaura is only indicated for use in
selected patients with active rheumatoid
arthritis. Physicians planning to use
Ridaura should be experienced with
chrysotherapy and should thoroughly
familiarize themselves with the toxicity
and benefits of Ridaura.
In addition, the following precautions
should be routinely employed:
1. The possibility of adverse reactions
should be explained to patients before
starting therapy.
2. Patients should be advised to report
promptly any symptoms suggesting toxicity.
(See PRECAUTIONS--Information for
Patients.)
Danger signs of possible gold toxicity include fall in hemoglobin, leukopenia
below 4,000 WBC/cu mm, granulocytes below 1,500/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 Ridaura (auranofin), some of whom developed bleeding. The
thrombocytopenia usually appears to be peripheral in origin and is usually
reversible upon withdrawal of Ridaura. Its onset bears no relationship to the
duration of Ridaura 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 Ridaura and other therapies with the potential to cause
thrombocytopenia, and to obtain additional platelet counts. No additional
Ridaura 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 Ridaura. If clinically significant proteinuria or microscopic hematuria is
found (See PRECAUTIONS--Laboratory Tests), Ridaura and other therapies with the
potential to cause proteinuria or microscopic hematuria should be stopped
immediately.
PRECAUTIONS:
GENERAL: The safety of concomitant use of Ridaura (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 Ridaura
toxicity should be under control before starting Ridaura (auranofin).
The potential benefits of using Ridaura 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 Ridaura treatment or additional
monitoring. See ADVERSE REACTIONS for the approximate incidence of those
reactions specifically reported with Ridaura.
GASTROINTESTINAL REACTIONS: Gastrointestinal reactions reported with gold
therapy include diarrhea/loose stools, nausea, vomiting, anorexia and abdominal
cramps. The most common reaction to Ridaura 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 Ridaura (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 Ridaura. 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 Ridaura. 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 Ridaura 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
Ridaura 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 Ridaura (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 Ridaura 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: Teratogenic Effects--Pregnancy Category C. Use of Ridaura (auranofin)
by pregnant women is not recommended. Furthermore, women of childbearing
potential should be warned of the potential risks of Ridaura 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 Ridaura studies in pregnant women.
NURSING MOTHERS: Nursing during Ridaura 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: Ridaura (auranofin) is not recommended for use in pediatric
patients because its safety and effectiveness have not been established.
DRUG INTERACTIONS:
In a single patient-report, there is the suggestion that concurrent
administration of Ridaura and phenytoin may have increased phenytoin blood
levels.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
The adverse reactions incidences listed below are based on observations of 1)
4,784 Ridaura-treated patients in clinical trials (2,474 U.S., 2,310 foreign),
of whom 2,729 were treated more than one year and 573 for more than three years;
and 2) postmarketing experience. The highest incidence is during the first six
months of treatment; however, reactions can occur after many months of therapy.
With rare exceptions, all patients were on concomitant nonsteroidal anti-
inflammatory therapy; some of them were also taking low dosages of
corticosteroids.
REACTIONS OCCURRING IN MORE THAN 1% OF RIDAURA- TREATED PATIENTS
GASTROINTESTINAL: loose stools or diarrhea (47%); abdominal pain (14%); nausea
with or without vomiting (10%); constipation; anorexia*; flatulence*;
dyspepsia*; 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.
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* Reactions marked with an asterisk occurred in 3-9% of the patients. The other
reactions listed occurred in 1-3%.
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REACTIONS OCCURRING IN LESS THAN 1% OF RIDAURA- TREATED PATIENTS
GASTROINTESTINAL: dysphagia; gastrointestinal bleeding**; melena**; positive
stool for occult blood**; ulcerative enterocolitis.
DERMATOLOGICAL: angioedema.
MUCOUS MEMBRANE: gingivitis**.
HEMATOLOGICAL: aplastic anemia; neutropenia**; agranulocytosis; pure red cell
aplasia; pancytopenia.
HEPATIC: jaundice.
RESPIRATORY: interstitial pneumonitis.
NEUROLOGICAL: peripheral neuropathy.
OCULAR: gold deposits in the lens or cornea unassociated clinically with eye
disorders or visual impairment.
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**Reactions marked with a double asterisk occurred in 0.1-1% of the patients.
The other reactions listed occurred in less than 0.1%.
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REACTIONS REPORTED WITH INJECTABLE GOLD PREPARATIONS, BUT NOT WITH RIDAURA
(AURANOFIN) (BASED ON CLINICAL TRIALS AND ON POSTMARKETING EXPERIENCE)
CUTANEOUS REACTIONS: generalized exfoliative dermatitis.
INCIDENCE OF ADVERSE REACTIONS FOR SPECIFIC CATEGORIES--18 COMPARATIVE TRIALS
Ridaura Injectable Gold
(445 patients) (445 patients)
Proteinuria 0.9% 5.4%
Rash 26.0% 39.0%
Diarrhea 42.5% 13.0%
Stomatitis 13.0% 18.0%
Anemia 3.1% 2.7%
Leukopenia 1.3% 2.2%
Thrombocytopenia 0.9% 2.2%
Elevated liver
function tests 1.9% 1.7%
Pulmonary 0.2% 0.2%
OVERDOSAGE:
The acute oral LD50 for auranofin is 310 mg/kg in adult mice and 265 mg/kg in
adult rats. The minimum lethal dose in rats is 30 mg/kg.
In case of acute overdosage, immediate induction of emesis or gastric lavage and
appropriate supportive therapy are recommended.
Ridaura overdosage experience is limited. A 50-year-old female, previously on 6
mg Ridaura daily, took 27 mg (9 capsules) daily for 10 days and developed an
encephalopathy and peripheral neuropathy. Ridaura was discontinued and she
eventually recovered.
There has been no experience with treating Ridaura overdosage with modalities
such as chelating agents. However, they have been used with injectable gold and
may be considered for Ridaura overdosage.
DOSAGE AND ADMINISTRATION:
USUAL ADULT DOSAGE: The usual adult dosage of Ridaura (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, Ridaura 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 Ridaura (auranofin) by discontinuing
the injectable agent and starting oral therapy with Ridaura, 6 mg daily. When
patients are transferred to Ridaura, 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 Ridaura and those maintained on the
injectable agent was not different. Data beyond six months are not available.
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