Action and Clinical
Although the mechanism of action is not well understood, gold compounds have been reported to decrease synovial inflammation and retard cartilage and bone destruction.:
Gold is absorbed from injection sites, reaching peak concentration in blood in 4 to 6 hours. Following a single i.m. injection of 50 mg aurothioglucose suspension in each of 2 patients, peak serum levels were about 235 g/dL in one patient and 450 g/dL in the other. In plasma, 95% is bound to the albumin fraction. Approximately 70% of the gold is eliminated in the urine and approximately 30% in the feces. When the standard weekly treatment schedule is followed, approximately 40% of the administered dose is excreted each week, and the remainder is excreted over a longer period. The biological half-life of gold salts following a single 50 mg dose has been reported to range from 3 to 27 days. Following successive weekly doses, the half-life increases and may be 14 to 40Â days after the third dose and up to 168 days after the eleventh weekly dose.
After the initial injection, the serum level of gold rises sharply and declines over the next week. Peak levels with aqueous preparations are higher and decline faster than those with oily preparations. Weekly administration produces a continuous rise in the basal value for several months, after which the serum level becomes relatively stable. After a standard weekly dose, considerable individual variation in the levels of gold has been found. A steady decline in gold levels occurs when the interval between injections is lengthened, and small amounts may be found in the serum for months after discontinuance of therapy. The incidence of toxic reactions is apparently unrelated to the plasma level of gold, but it may be related to the cumulative body content of gold.
Storage of gold in human tissues is dependent upon organ mass as well as upon the concentration of gold. Therefore, tissues having the highest gold levels (w/w) do not necessarily contain the greatest total amounts of gold. The major depots, in decreasing order of total gold content are the bone marrow, liver, skin and bone, accounting for approximately 85% of body gold. The highest concentrations of gold are found in the lymph nodes, adrenal glands, liver, kidneys, bone marrow, and spleen. Relatively small concentrations are found in articular structures.
Gold passes the blood-brain barrier in hamsters.
Transfer of gold across the human placenta at the 20th week of pregnancy has been documented. The placenta showed numerous gold deposits and smaller amounts were detected in the fetal liver and kidneys; other tissues provided no evidence of gold deposition.
Gold is excreted into human milk in significant amounts and trace amounts can be demonstrated in the blood of nursing infants (see Precautions, Lactation).
Indications And Clinical Uses:
For the adjunctive treatment of early active rheumatoid arthritis (both of the adult and juvenile types) not adequately controlled by other anti-inflammatory agents and conservative measures. In chronic, advanced cases of rheumatoid arthritis, gold therapy is less valuable.
Antirheumatic measures such as salicylates and other anti-inflammatory drugs (both steroidal and nonsteroidal) may be continued after initiation of gold therapy. After improvement commences, these measures may be discontinued slowly as symptoms permit.
See Precautions, Laboratory Tests and Dosage.
A history of known hypersensitivity to any component of aurothioglucose contraindicates its use. Gold therapy is contraindicated in patients with uncontrolled diabetes mellitus, severe debilitation, systemic lupus erythematosus, renal disease, hepatic dysfunction, uncontrolled congestive heart failure, marked hypertension, agranulocytosis, other blood dyscrasias or hemorrhagic diathesis; or if there is a history of infectious hepatitis. Patients who recently have had radiation, and those who have developed severe toxicity from previous exposure to gold or other heavy metals should not receive aurothioglucose.
Urticaria, eczema, and colitis are also contraindications.
Gold therapy is usually contraindicated in pregnancy (see Precautions, Pregnancy).
Gold salts should not be used with penicillamine (see Adverse Effects, Management of Adverse Effects), or antimalarials. The safety of coadministration with immunosuppressive agents other than corticosteroids has not been established.
Warnings in Clinical States:
The following signs should be considered danger signals of gold toxicity, and no additional injection should be given unless further studies reveal some other cause for their presence: rapid reduction of hemoglobin, leukopenia (WBC below 4 000/mm)
Effects that may occur immediately following an injection, or at any time during gold therapy, include: anaphylactic shock, syncope, bradycardia, thickening of the tongue, difficulty in swallowing and breathing, and angioneurotic edema. If such effects are observed, treatment with aurothioglucose should be discontinued.
Tolerance to gold usually decreases with advancing age. Diabetes mellitus or congestive heart failure should be under control before gold therapy is instituted.
Aurothioglucose should be used with extreme caution in patients with: skin rash, hypersensitivity to other medications, or a history of renal or liver disease.
General: Before each injection, the physician should personally check the patient for adverse reactions and inquiry should be made regarding pruritus, rash, sore mouth, indigestion and metallic taste. The patient should be observed for at least 15 minutes following each injection (see Laboratory Tests).
Patients with HLA-D locus histocompatibility antigens DRw2 and DRw3 may have a genetic predisposition to develop certain toxic reactions, such as proteinuria, during treatment with gold or D-penicillamine.
Aurothioglucose should be used with caution in patients with compromised cardiovascular or cerebral circulation.
Information for the Patient: 1. Promptly report to the physician any unusual symptoms such as pruritus (itching), rash, sore mouth, indigestion, or metallic taste.
2. Increased joint pain may occur for 1 or 2 days after an injection and usually subsides after the first few injections.
3. Exposure to sunlight or artificial ultraviolet light should be minimized.
4. Careful oral hygiene is recommended in conjunction with therapy.
5. Patients should be aware of potential hazards if they become pregnant while receiving gold therapy (see Pregnancy).
Laboratory Tests: Before treatment is started, a complete blood count, platelet count and urinalysis should be done to serve as reference points. Since gold therapy is usually contraindicated in pregnant patients, pregnancy should be ruled out before treatment is started. Throughout the treatment period, urinalysis should be repeated prior to each injection, and complete blood cell and platelet counts should be performed every 2 weeks. A platelet count is indicated any time that purpura or ecchymosis occurs.
Drug interactions have not been reported (see Contraindications).
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Renal adenomas developed in rats receiving an injectable gold product similar to aurothioglucose at doses of 2 mg/kg weekly for 46 weeks, followed by 6 mg/kg daily for 47 weeks. These doses were higher and administered more frequently than the recommended human doses. The adenomas were similar histologically to those produced by chronic administration of other gold compounds and heavy metals, such as lead or nickel.
Renal tubular cell neoplasia consisting of renal adenoma and adenocarcinoma were noted in a dose-response relationship in another study in rats using daily i.m. doses of 3 mg/kg and 6 mg/kg for up to 2 years. These doses were higher and were administered more frequently than the recommended human doses. In this same study, sarcomas at the injection site occurred in some rats but their numbers were not sufficient to demonstrate a dose-response relationship.
No report of renal adenoma or sarcoma at the injection site in man in association with the use of aurothioglucose has been received.
Gold compounds have not been studied for evaluation of mutagenesis.
Gold sodium thiomalate given s.c. did not adversely affect fertility or reproductive performance.
Pregnancy: Gold therapy is usually contraindicated in pregnant patients. The patient should be warned about the hazards of becoming pregnant while on gold therapy. Rheumatoid arthritis frequently improves when the patient becomes pregnant, thereby eliminating the need for gold therapy. The potential nephrotoxicity of gold should not be superimposed on the increased renal burden which normally occurs in pregnancy and hence, gold therapy should be discontinued upon recognition of pregnancy unless continued use is required in an individual case. The slow excretion of gold and its persistence in body tissue after discontinuation of treatment should be kept in mind when a woman of child-bearing potential being treated with gold plans to become pregnant.
Pregnancy Category C: Gold sodium thiomalate administered s.c., a route not used clinically, has been shown to be teratogenic during the organogenic period in rats and rabbits when given in doses 140 and 175 times, respectively, the usual human dose. Hydrocephalus and microphthalmia were the malformations observed in rats when gold sodium thiomalate was administered at a dose of 25 mg/kg/day from day 6 through day 15 of gestation. In rabbits, limb defects and gastroschisis were the malformations observed when gold sodium thiomalate was administered at doses of 20 to 45 mg/kg/day from day 6 through day 18 of gestation.
Gold compounds administered orally to rabbits from days 6 through 18 of pregnancy resulted in the occurrence of abdominal defects such as gastroschisis and umbilical hernia; anomalies of the brain, heart, lung, and skeleton; and microphthalmia.
The administration of excessive doses of gold-containing compounds during pregnancy in the above studies was toxic to the mothers and their embryos; the embryotoxic effects probably were secondary to maternal toxicity. Therefore, the significance of these findings in relation to human use is unknown.
There are no adequate and well-controlled studies with aurothioglucose in pregnant women. Extensive clinical experience with aurothioglucose has not demonstrated human teratogenicity.
Lactation: Gold has been demonstrated in the milk of lactating mothers. In one patient, a total dose of 135 mg of gold thioglucose was given during the postpartum period. Samples of the maternal milk and urine, and samples of red blood cells and serum of the mother and child were evaluated by atomic absorption spectrophotometry. Trace amounts of gold appeared in the serum and red blood cells of the nursing offspring. It has been postulated that this may be the cause of unexplained rashes, nephritis, hepatitis, and hematologic aberrations in the nursing infants of mothers treated with gold. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the gold therapy, taking into account the importance of the drug to the mother. The slow excretion of gold and its persistence in the mother after discontinuation of treatment should be kept in mind.
Children: Safety and effectiveness in children below the age of 6 years have not been established.
Adverse reactions to gold therapy may occur at any time during treatment or many months after therapy has been discontinued. The incidence of toxic reactions is apparently unrelated to the plasma level of gold, but it may be related to the cumulative body content of gold. Higher than conventional dosage schedules may increase the occurrence and severity of toxicity. Severe effects are most common after 300 to 500 mg have been administered.
Cutaneous: Dermatitis is the most common reaction. Pruritus should be considered a warning signal of an impending cutaneous reaction. Erythema and occasionally the more severe reactions such as papular, vesicular, and exfoliative dermatitis leading to alopecia and shedding of the nails may occur. Chrysiasis (gray-to-blue pigmentation) has been reported, especially on photoexposed areas. Gold dermatitis may be aggravated by exposure to sunlight, or an actinic rash may develop.
Mucous Membrane: Stomatitis is the second most common adverse reaction. Shallow ulcers on the buccal membranes, on the borders of the tongue and on the palate, diffuse glossitis or gingivitis may be preceded by the sensation of metallic taste. Careful oral hygiene is recommended. Inflammation of the upper respiratory tract, pharyngitis, gastritis, colitis, tracheitis, and vaginitis have also been reported. Conjunctivitis is rare.
Renal: Nephrotic syndrome or glomerulitis with hematuria, which is usually relatively mild, subsides completely if recognized early and treatment is discontinued. These reactions become severe and chronic if gold therapy is continued after their onset. Therefore, it is important to perform a urinalysis before each injection and to discontinue treatment promptly if proteinuria or hematuria develops.
Hematologic: Although rare, blood dyscrasias, including granulocytopenia, agranulocytosis, thrombocytopenia with or without purpura, leukopenia, eosinophilia, panmyelopathy, hemorrhagic diathesis, and hypoplastic and aplastic anemia, have been reported. These reactions may occur separately or in combination.
Nitritoid and Allergic: These reactions, which may rarely occur with aurothioglucose and which resemble anaphylactoid effects, include flushing, fainting, dizziness, sweating, malaise, weakness, nausea, and vomiting.
Miscellaneous: On rare occasions, gastrointestinal symptoms, i.e., nausea, vomiting, colic, anorexia, abdominal cramps, diarrhea, ulcerative enterocolitis, and headache have been reported.
There have been rare reports of iritis and corneal ulcers. Transient asymptomatic gold deposits in the cornea or conjunctiva may occur.
Other reported reactions include encephalitis, immunological destruction of the synovia, EEG abnormalities, intrahepatic cholestasis, hepatitis with jaundice, toxic hepatitis, acute yellow atrophy, peripheral neuritis, gold bronchitis, pulmonary injury manifested by interstitial pneumonitis or fibrosis, fever, and partial or complete hair loss.
Less common but more severe effects that may occur shortly after an injection or at any time during gold therapy include; anaphylactic shock, syncope, bradycardia, thickening of the tongue, difficulty in swallowing and breathing, and angioneurotic edema. If they are observed, treatment with aurothioglucose should be discontinued.
Arthralgia may occur for 1Â or 2Â days after an injection and usually subsides after the first few injections. The mechanism of the transient increase in rheumatic symptoms after injection of gold (the so-called nonvasomotor postinjection reaction) is unknown. These reactions are usually mild but occasionally may be so severe that treatment is stopped prematurely.
Management of Adverse Effects: In the event of toxic reactions, gold therapy should be discontinued immediately.
In the presence of mild reactions, it may be sufficient to discontinue the administration of aurothioglucose for a short period and then to resume treatment with smaller doses.
Dermatitis and pruritus may respond to soothing lotions, other appropriate antipruritic treatment, or topical glucocorticoids.
If dermatitis or stomatitis becomes severe or spreads, systemic glucocorticoid treatment may be indicated. For renal, hematologic, and most other adverse reactions, glucocorticoids may be required in larger doses and for a longer time than for dermatologic reactions. Often this treatment may be required for many months because of the slow elimination of gold from the body.
If severe adverse reactions do not improve with steroid treatment in patients who receive large doses of gold, a chelating agent, such as dimercaprol (BAL), may be used. In one case, it was reported that penicillamine was beneficial in the treatment of gold-induced thrombocytopenia. Adjunctive use of an anabolic steroid with other drugs (i.e.,Â BAL, penicillamine, and corticosteroids) may contribute to recovery of bone marrow deficiency.
In the presence of severe or idiosyncratic reactions, treatment with aurothioglucose should not be reinstituted.
Symptoms And Treatment Of Overdose:
OverdoseSymptoms: Overdose resulting from too rapid increases in dosing with aurothioglucose will be manifested by rapid appearance of toxic reactions, particularly those relating to renal damage, such as hematuria, proteinuria, and to hematologic effects, such as thrombocytopenia and granulocytopenia. Other toxic effects, including fever, nausea, vomiting, diarrhea, and various skin disorders such as papulovesicular lesions, urticaria, and exfoliative dermatitis, all attended with severe pruritus, may develop.Treatment
Treatment: Treatment consists of prompt discontinuation of the medication and early administration of dimercaprol. Specific supportive therapy should be given for the renal and hematologic complications (see also Adverse Effects, Management of Adverse Effects).
Dosage & Administration:
Adults: The usual dosage schedule for the i.m. administration of aurothioglucose is as follows: first dose, 10Â mg; second and third doses, 25 mg; fourth and subsequent doses, 50 mg. The interval between doses is 1 week. The 50 mg dose is continued at weekly intervals until 0.8 to 1 g has been given. If the patient has improved and has exhibited no sign of toxicity, the 50 mg dose may be continued many months longer at 3 to 4 week intervals. A weekly dose above 50 mg is usually unnecessary and contraindicated; the tendency in gold therapy is toward lower dosage. With this in mind, it may eventually be established that a 25 mg dose is the one of choice. If no improvement has been demonstrated after a total administration of 1 g of aurothioglucose, the necessity for gold therapy should be reevaluated.
Children 6 to 12 years: one-fourth of the adult dose, governed chiefly by body weight, not to exceed 25 mg/dose.
Aurothioglucose should be injected i.m. (preferably intragluteally), never i.v. The patient should be lying down and should remain recumbent for approximately 10 minutes after the injection. The vial should be thoroughly shaken in order to suspend all of the active material. Heating the vial to body temperature (by immersion in warm water) will facilitate drawing the suspension into the syringe. An 18-gauge, 1 1/2 inch needle is recommended for depositing the preparation deep into the muscular tissue. For obese patients, an 18-gauge, 2 inch needle may be used. The site usually selected for injection is the upper outer quadrant of the gluteal region.
Note: Shake the vial in horizontal position before the dose is withdrawn. Needle and syringe must be dry. The patient should be observed for at least 15Â minutes following each injection.
Availability And Storage:
Each mL of sterile suspension contains: aurothioglucose USP 50 mg (5%) in sesame oil. Nonmedicinal ingredients: aluminum monostearate 2% and propylparaben. Multiple-dose vials of 10 mL, boxes of 1. Shake well before using. Store between 0 and 30°C. Protect from light. Store in carton until contents are used.
SOLGANAL® Schering Aurothioglucose Antirheumatic Agent