Auranofin

Name: Auranofin

What brand names are available for auranofin?

Ridaura

Description

RIDAURA (auranofin) is available in oral form as capsules containing 3 mg auranofin.

Auranofin is (2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranosato-S-) (triethylphosphine) gold. Auranofin contains 29% gold and has the following chemical structure:

Each RIDAURA capsule, with opaque brown cap and opaque tan body, contains auranofin, 3 mg, and is imprinted with the product name RIDAURA. Inactive ingredients consist of benzyl alcohol, cellulose, cetylpyridinium chloride, D&C Red No. 33, FD&C Blue No. 1, FD&C Red No. 40, FD&C Yellow No. 6, gelatin, lactose, magnesium stearate, povidone, sodium lauryl sulfate, sodium starch glycolate, starch, titanium dioxide and trace amounts of other inactive ingredients.

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. RIDAURA® (auranofin) Capsules 2

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.

Auranofin Precautions

Serious side effects have been reported with auranofin including:

  • Gastrointestinal reactions.
    • Diarrhea or loose stools
    • Nausea or vomiting
    • Decreased appetite or anorexia
    • Abdominal cramps
    • Bloody or tar-like stools
  • Dermatitis. An itchy rash may appear after exposure to auranofin; it may be worsened by exposure to sunlight.
  • Ulcers in the mouth, on the touch, on the palate, or in the throat. These sores may appear with or without dermatitis. A metallic taste may precede the appearance of the ulcers.
  • Blood or protein in the urine.
  • Changes in the composition of blood, including decreased white blood cells and decreased thrombocytes, and aplastic anemia.

Do not take auranofin if you:

  • are allergic to auranofin or to any of its ingredients
  • have a history of anaphylactic reactions to gold
  • have or have had necrotizing enterocolitis
  • have or have had pulmonary fibrosis
  • have or have had exfoliative dermatitis
  • have or have had bone marrow aplasia
  • have or had had a severe blood disorder

What is the most important information I should know about auranofin?

You should not use this medication if you have ever had a severe reaction to gold therapy that affected your skin, lungs, bone marrow, blood cells, or your stomach or intestines.

Before taking auranofin, tell your doctor if you have a weak immune system, bone marrow disorder, kidney or liver disease, or inflammatory bowel disease.

Auranofin can lower blood cells that help your body fight infections. This can make it easier for you to bleed from an injury or get sick from being around others who are ill. To be sure your blood cells do not get too low, your blood will need to be tested on a regular basis.

Keep using auranofin as directed. Talk with your doctor if your symptoms do not improve after 3 or 4 months of treatment.

Stop taking auranofin and call your doctor at once if you have a skin rash or itching, mouth sores, severe diarrhea, easy bruising or bleeding, blood in your urine or stools, coughing up blood, or unusual weakness, or any signs of infection (fever, chills, flu symptoms).

Auranofin side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop taking this medication and call your doctor at once if you have a serious side effect such as:

  • itching or skin rash;

  • white patches or sores inside your mouth or on your lips;

  • pain or swelling in your gums or tongue, metallic taste in your mouth;

  • severe or ongoing diarrhea;

  • severe nausea, vomiting, stomach cramps;

  • pale skin, easy bruising or bleeding;

  • blood in your urine;

  • weakness or fainting;

  • black, bloody, or tarry stools; or

  • coughing up blood or vomit that looks like coffee grounds.

Less serious side effects may include:

  • mild stomach pain or upset;

  • gas, bloating; or

  • loss of appetite.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
  • Black, tarry, or bloody stools.
  • Throwing up blood or throw up that looks like coffee grounds.
  • Very bad belly pain.
  • Skin irritation.
  • Change in eyesight, eye pain, or very bad eye irritation.

If OVERDOSE is suspected

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Use Labeled Indications

Rheumatoid arthritis: Management of adult patients with active stage classic or definite rheumatoid arthritis in patients who do not respond to or tolerate an adequate trial of full doses of one or more nonsteroidal anti-inflammatory drugs (NSAIDs)

Dosing Adult

Rheumatoid arthritis: Oral: Initial: 6 mg/day in 1-2 divided doses; after 6 months may be increased to 9 mg/day in 3 divided doses; discontinue therapy if no response after 3 months at 9 mg/day

Note: Signs of clinical improvement may not be evident until after 3 months of therapy.

Adverse Reactions

>10%:

Dermatologic: Skin rash (24%), pruritus (17%)

Gastrointestinal: Diarrhea (≤47%), loose stools (≤47%), abdominal pain (14%), stomatitis (13%)

1% to 10%:

Dermatologic: Alopecia (1% to 3%), urticaria (1% to 3%)

Gastrointestinal: Nausea (10%), vomiting (10%), anorexia (3% to 9%), dyspepsia (3% to 9%), flatulence (3% to 9%), constipation (1% to 3%), dysgeusia (1% to 3%), glossitis (1% to 3%)

Genitourinary: Proteinuria (3% to 9%), hematuria (1% to 3%)

Hematologic and Oncologic: Anemia (1% to 3%), eosinophilia (1% to 3%), leukopenia (1% to 3%), thrombocytopenia (1% to 3%)

Hepatic: Increased serum transaminases (1% to 3%)

Ophthalmic: Conjunctivitis (3% to 9%)

<1% (Limited to important or life-threatening): Agranulocytosis, aplastic anemia, angioedema, bronchitis (gold), corneal deposits, dysphagia, exfoliative dermatitis (other gold compounds), fever, gastrointestinal hemorrhage, gingivitis, hepatotoxicity, interstitial pneumonitis, jaundice, metallic taste, melena, neutropenia, pancytopenia, peripheral neuropathy, pure red cell aplasia, ulcerative enterocolitis

Monitoring Parameters

Patients should have baseline CBC with differential, platelet count, renal function tests, liver function tests, and urinalysis; CBC with differential, platelet count and urinalysis should also be monitored monthly during therapy. Skin and oral mucosa should be inspected for skin rash, bruising or oral ulceration/stomatitis. Specific questioning for symptoms such as pruritus, rash, stomatitis or metallic taste should be included.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience lack of appetite, nausea, vomiting, abdominal cramps, flatulence, or mouth irritation. Have patient report immediately to prescriber signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), severe abdominal pain, skin irritation, severe loss of strength and energy; bruising; bleeding; hematuria; itching; rash; severe diarrhea; signs of infection; black, tarry, or bloody stools; vomiting blood; vision changes; eye pain; or severe eye irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

For Healthcare Professionals

Applies to auranofin: oral capsule

Gastrointestinal

In one study evaluating the incidence of diarrhea during auranofin therapy, diarrhea occurred in 74% of patients during the first month of treatment. The diarrhea was categorized as mild in 64% of cases, moderate in 28% of cases, and severe in 8% of cases. These symptoms may be reduced by the use of antidiarrheals or bulk-forming agents. Approximately 11% of patients required discontinuation of therapy.

Diarrhea is often dose-related as it increases in incidence with higher doses (for example, 9 mg per day). Initiating therapy at lower doses, or reducing the dose if diarrhea develops, may help to prevent or alleviate symptoms.

While diarrhea is generally mild and self-limiting, the possibility of more serious gastrointestinal pathology should be kept in mind. Enterocolitis and toxic megacolon have been reported. Diarrhea may be accompanied by nausea and/or vomiting, abdominal pain, and fever as well as bloody stools in cases of auranofin-induced enterocolitis.[Ref]

Gastrointestinal side effects are among the most common complaints in patients treated with auranofin. Diarrhea or loose stools may occur in 50% to 74% of patients. Abdominal pain (14%), nausea/vomiting (10%), anorexia (3% to 9%), flatulence (3% to 9%), dyspepsia (3% to 9%), stomatitis, constipation, and dysgeusia have also been reported. More serious gastrointestinal effects include gastrointestinal bleeding (0.1% to 1%), enterocolitis and toxic megacolon, as well as aphthous ulcerations of the gastric and intestinal mucosa.[Ref]

Dermatologic

Pruritus and rash may be early warning signs of gold toxicity. Any eruption during auranofin therapy should be considered a drug-related side effect until proven otherwise. Serious dermatologic toxicity, including exfoliative dermatitis, has been associated with parenteral gold.

Skin pigmentation--known as chrysiasis--characterized by a gray or blue discoloration of sun-exposed skin, has been reported following the use of parenteral gold salts.[Ref]

Dermatologic reactions are relatively common and include rash (24%) and pruritus (17%). Pityriasis rosea and discoid eczema as well as skin pigmentation, known as chrysiasis, have also been reported. While not associated with auranofin, per se, exfoliative dermatitis has been associated with parenteral gold therapy. Topical use of 0.1% to 0.6% products may produce contact dermatitis.[Ref]

Ocular

Ocular side effects include gold deposits in the cornea and, occasionally, the lens. Vision is not usually affected. Conjunctivitis is also reported.[Ref]

Gold deposits in either the lens or cornea are not usually associated with visual disturbances. Deposits typically disappear within months following discontinuation of gold therapy.[Ref]

Hematologic

Hematologic abnormalities associated with auranofin include thrombocytopenia (>1%), eosinophilia (>1%), leukopenia (>1%), neutropenia (0.1% to 1%), agranulocytosis, aplastic anemia, pure red cell aplasia, and pancytopenia.[Ref]

Decreases in hemoglobin as well as leukopenia, granulocytopenia, and thrombocytopenia may be warning signs of gold toxicity. Any rapid decline in platelet counts or a platelet count of less than 100,000/mm3 necessitates discontinuation of auranofin. Gold therapy should not be reinstituted unless the thrombocytopenia is shown to be unrelated to gold.

Auranofin-induced thrombocytopenia appears to be due to an immune-mediated peripheral destruction of platelets. Bone marrow aspirates in cases of auranofin thrombocytopenia revealed an increased number of megakaryocytes. In addition, platelet reactive antibodies were detectable only in the presence of gold. In one case report, increased uptake of platelets by the spleen with subsequent platelet destruction was demonstrated.[Ref]

Renal

Renal side effects include hematuria, proteinuria, and nephropathy. Parenteral gold salts are associated with glomerulonephritis as well as nephrotic syndrome.[Ref]

Proteinuria occurs in 3% to 9% of patients treated with auranofin. Clinically significant proteinuria and/or hematuria may require cessation of auranofin therapy. Renal toxicity is usually reversible if recognized early and auranofin is discontinued.[Ref]

Hepatic

Hepatic side effects include elevations in liver function tests (>1%) and jaundice. These effects are usually reversible and may be more common in patients with preexisting liver disease. Cholestatic jaundice has been associated with the use of parenteral gold salts.[Ref]

Cardiovascular

Cardiovascular side effects are limited to a case report of a vasomotor or nitritoid reaction. While not usually seen with auranofin or aurothioglucose therapy, this reaction is not uncommon in patients treated with gold sodium thiomalate.[Ref]

Vasomotor, or nitritoid, symptoms typically include faintness, palpitations, and flushing and occur most often following injection of gold sodium thiomalate. In the elderly, this may result in myocardial infarction or central nervous system injury.

A 37-year-old female with a history of a nitritoid reaction to gold sodium thiomalate, developed similar symptoms during oral therapy with auranofin. Onset of symptoms (i.e. nausea, palpitations, and presyncope) occurred after 18 months of auranofin (6 mg/day) therapy.

Several case reports suggest that concomitant therapy with angiotensin converting enzyme inhibitors may increase the risk of nitritoid reactions in some patients.[Ref]

Respiratory

Irreversible bronchiolitis developed in a 44-year-old female with seropositive rheumatoid arthritis treated with auranofin (6 mg/day) for five months. A lung biopsy revealed a dense, cellular infiltrate around the bronchioles, with mucous plugging and macrophage infiltration of the bronchiole lumens. The extent to which auranofin versus rheumatoid arthritis contributed to the pathology is uncertain.[Ref]

Respiratory side effects are uncommon although rare cases of bronchiolitis and interstitial pneumonitis have been reported.[Ref]

Nervous system

Nervous system side effects are rare. Peripheral neuropathy after long-term use has been reported. Serious nervous system toxicity, including Guillain Barre-type syndrome and acute disseminated encephalomyelitis, has been associated with parenteral gold salts.[Ref]

Endocrine

Endocrine side effects are limited to a single case report of gynecomastia.[Ref]

Some side effects of auranofin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Renal Dose Adjustments

CrCl < 50 mL/min: auranofin is contraindicated for use in these patients.

CrCl 50 to 80 mL/min: the dose should be reduced by 50%.

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