Generic Name: Sulfasalazine
VA Class: AM650
CAS Number: 599-79-1
Prodrug converted in vivo to sulfapyridine (a sulfonamide anti-infective) and 5-aminosalicylic acid (mesalamine; anti-inflammatory agent).116
Uses for Azulfidine
May be useful in patients with mild to moderately active disease, especially those with ileocolonic or colonic involvement.107 108 157 May not be effective in patients with small bowel disease.157 Many clinicians recommend that the drug be used in patients with left-sided disease, restricted to the colon.159
Patients who have previously received corticosteroid therapy or have undergone surgical resection may fail to respond to sulfasalazine therapy.159 Those who have not received corticosteroids or have not undergone surgery may respond substantially better to sulfasalazine than to placebo.159
There is some evidence that concomitant therapy with sulfasalazine and corticosteroids may not be more effective than either drug alone,105 106 157 but some subgroups of patients may have a better response to combined therapy (e.g., those with disease localized in the colon).105
Rheumatoid Arthritis in Adults
Management of rheumatoid arthritis in adults whose symptoms progress despite an adequate regimen of NSAIAs.119 121 146 147 148 149 150 151 152 153 154 155 One of several disease-modifying antirheumatic drugs (DMARDs) that can be used when DMARD therapy is appropriate.154 155
Usually used in conjunction with analgesic and/or NSAIA therapy, at least until the beneficial effects of sulfasalazine are apparent.146 Administration of sulfasalazine alone is not a complete treatment for rheumatoid arthritis.146
Management of the signs and symptoms of polyarticular course juvenile rheumatoid arthritis in children who have not responded adequately to NSAIAs.115 146 Not recommended for management of systemic course juvenile rheumatoid arthritis because of the high frequency of adverse effects reported in children.146
Azulfidine Dosage and Administration
Delayed-release tablets should be swallowed whole.146
Conventional tablets in children ≥6 years of age: Initial dosage is 40–60 mg/kg daily in 3–6 divided doses and usual maintenance dosage is 30 mg/kg daily in 4 divided doses.145
Delayed-release tablets in children ≥6 years of age: Initial dosage is 40–60 mg/kg daily in 3–6 divided doses and usual maintenance dosage is 30 mg/kg daily in 4 divided doses.146
Delayed-release tablets in children ≥6 years of age: 30–50 mg/kg daily in 2 equally divided doses; the maximum dosage usually is 2 g daily.146
To reduce GI intolerance, the manufacturers recommend that therapy be initiated with ¼ to (1/3) of the planned maintenance dosage, and that dosage be increased at weekly intervals until the planned maintenance dosage is achieved (usually at week 4).146
Conventional or delayed-release tablets: Initial dosage is 3–4 g daily given in equally divided doses; interval between doses should not exceed 8 hours.145 146 In some patients, it may be advantageous to initiate therapy with a dosage of 1–2 g daily to lessen adverse GI effects.a Usual maintenance dosage is 2 g daily145 146 in 4 divided doses, although some clinicians advocate a lower maintenance dosage of 1–1.5 g daily if necessary to prevent adverse effects.a
Dosage as high as 12 g daily has been used for initial therapy, but dosage >4 g daily is accompanied by increased incidence of adverse effects.a Generally avoid dosage >4 g daily unless serum concentrations of total sulfapyridine and the phenotype of the patient are known.
Efficacy of maintenance therapy appears to be dose related, but potential benefits of dosages >2 g daily must be weighed against the risks of increased adverse effects and the necessity for more careful patient monitoring.114
Maintenance: 1.5–3 g daily (as conventional or delayed-release tablets) has been used, although such dosages do not appear to be more effective than placebo when used in patients with medically induced remission.160 168
It may be advantageous to initiate therapy with a dosage of 0.5–1 g daily to lessen adverse GI effects.146 The manufacturers recommend that patients receive 0.5 g every evening the first week of therapy, 0.5 g twice daily (morning and evening) the second week, 0.5 g every morning and 1 g every evening the third week, and 1 g twice daily (morning and evening) thereafter.146
A response to sulfasalazine (manifested by improvement in the number and extent of actively inflamed joints) may not occur until after 4–12 weeks of therapy.146
Patients receiving sulfasalazine dosages >2 g daily should be carefully monitored.146
Maximum 2 g daily.146
Maximum 4 g daily.164
Cautions for Azulfidine
Perform CBC and differential prior to initiation of sulfasalazine therapy and every 2 weeks during the first 3 months of therapy.145 146 Monitor CBC and differential once monthly during the second 3 months, then once every 3 months and as clinically indicated.145 146 The drug can be discontinued while awaiting results of blood tests.145 146
Erythema multiforme (Stevens-Johnson syndrome), exfoliative dermatitis, epidermal necrolysis (Lyell’s syndrome) with corneal damage, rash with eosinophilia and systemic symptoms (DRESS), anaphylaxis, serum sickness syndrome, interstitial lung disease, pneumonitis with or without eosinophilia, vasculitis, fibrosing alveolitis, pleuritis, pericarditis with or without tamponade, allergic myocarditis, polyarteritis nodosa, lupus erythematosus-like syndrome, hepatitis and hepatic necrosis with or without immune complexes, fulminant hepatitis sometimes leading to liver transplantation, parapsoriasis varioliformis aculta (Mucha-Haberman syndrome), rhabdomyolysis, photosensitization, arthralgia, periorbital edema, conjunctival and scleral injection, and alopecia reported with sulfasalazine or other sulfonamides.145 146
Desensitization should not be attempted in patients with a history of agranulocytosis, toxic epidermal necrolysis, fibrosing alveolitis, or anaphylactoid reaction while receiving sulfasalazine.117 145 146
Specialized references should be consulted for specific information on desensitization procedures and dosage.117 118 Although various desensitization procedures have been reported to be effective, many regimens use an initial sulfasalazine dosage of 50–250 mg daily which is then doubled every 4–7 days until the desired therapeutic dosage is attained.145 146
Although cross-sensitization has been reported to occur between the various anti-infective sulfonamides, some diuretics such as acetazolamide and the thiazides, some goitrogens, and sulfonylurea antidiabetic agents, the association between hypersensitivity to sulfonamide anti-infectives and subsequent sensitivity reactions to non-anti-infective sulfonamides (e.g., thiazides, sulfonylurea antidiabetic agents, furosemide, dapsone, probenecid) appears to result from a predisposition to allergic reactions in general rather than to cross-sensitivity to the sulfa moiety per se.c
Sulfonamides have been associated with renal toxicity manifested by renal colic, nephritis, urolithiasis, toxic nephrosis with anuria and oliguria, hematuria, proteinuria, crystalluria, kidney stone formation, and elevation of BUN and serum creatinine concentrations.146 b Nephrotic syndrome and hemolytic-uremic syndrome have been reported.146
Adverse renal effects usually are the result of crystalluria.b Risk of crystalluria may be decreased by maintaining an adequate urinary output and by increasing urinary pH.b Unless the urine is highly acidic and/or the drug is relatively insoluble, alkalinization of the urine usually is not necessary if the urinary output is maintained at a minimum of 1500 mL daily.b
Maintain adequate fluid intake to minimize risk of crystalluria and stone formation.145 146 If persistent, heavy crystalluria, hematuria, or oliguria occurs, sulfonamide therapy should be discontinued and alkali therapy maintained.b
Hepatotoxicity, including increased liver enzyme concentration, jaundice, cholestatic jaundice, cirrhosis and possible hepatocellular damage including liver necrosis and liver failure, have been reported rarely.145 146 Fatalities associated with hepatic damage have occurred.145 146
Perform liver function tests prior to initiation of sulfasalazine therapy and every 2 weeks during the first 3 months of therapy.145 146 Monitor hepatic function once monthly during the second 3 months, then once every 3 months and as clinically indicated.145 146
Because sulfasalazine and sulfapyridine cross the placenta, the potential for kernicterus in neonates should be considered despite the fact that sulfapyridine has been shown to have poor bilirubin-displacing capacity.145 146
Safety and efficacy for management of polyarticular course juvenile rheumatoid arthritis in children 6–16 years of age is supported by evidence from adequate and well-controlled studies in adults.146
Adverse effects observed in children receiving sulfasalazine for management of juvenile rheumatoid arthritis generally are similar to those observed in adults with rheumatoid arthritis.146
Not recommended for treatment of systemic course juvenile rheumatoid arthritis in children because a high incidence of serum sickness-like syndrome has been reported in these children.146 The serum sickness-like syndrome may be severe and presents as fever, nausea, vomiting, headache, rash, and abnormalities in liver function tests.146
Sulfasalazine (initially 25–40 mg/kg daily and increased to 50–75 mg/kg daily [maximum 4 g daily]) has been used for the management of Crohn’s disease† (i.e., mild ileal, ileocecal, ileocolonic, or colonic disease) in a limited number of pediatric patients.164 165 166 Efficacy in maintaining remission in children is similar to that observed with oral mesalamine delayed-release tablets,166 although some preferred mesalamine because of ease and frequency of administration and better tolerance.166
Common Adverse Effects
GI effects (anorexia, nausea, dyspepsia, vomiting, abdominal pain, gastric distress); headache; fever; rash; abnormal liver function test results; leukopenia; thrombocytopenia; reversible oligospermia.145 146 a Rash occurs more frequently in patients with rheumatoid arthritis than in those with ulcerative colitis.a
Interactions for Azulfidine
Anticoagulants, oral (warfarin)
Possibility that sulfonamides may potentiate the effects of coumarin anticoagulants by displacing them from their protein-binding sites or by impairing anticoagulant metabolisma
If used concomitantly, monitor closelya
Antidiabetic agents, sulfonylureas
Sulfonamides may potentiate the hypoglycemic effects of tolbutamide and chlorpropamide by displacing the antidiabetic agents from their protein-binding sitesa
Use concomitantly with cautiona
Possibility that concomitant anti-infectives may alter the action of sulfasalazine by altering intestinal flora and consequently sulfasalazine metabolisma
If used concomitantly, monitor to ensure adequate digoxin concentrationsb
Sulfasalazine inhibits folic acid absorption,111 112 113 145 146 interferes with folic acid metabolism, and may result in decreased serum folic acid concentrations and possibly folic acid deficiency in some patients111 112 113
Folic acid deficiency may be prevented in patients receiving sulfasalazine by increased dietary intake of folic acid, taking the drug between meals, and/or by administration of folic acid supplements113
Sulfasalazine chelates iron, altering distribution of sulfasalazine in the intestinal lumen, interfering with its absorption and resulting in lower blood concentrations of sulfasalazinea
Part of an oral dose of sulfasalazine passes intact into the colon where the azo-linkage is cleaved by intestinal flora to form sulfapyridine and 5-aminosalicylic acid (mesalamine).a Sulfapyridine is rapidly absorbed from the colon; only a small portion of the 5-aminosalicylic acid present in the colon is absorbed.a
Following administration of a single oral dose of sulfasalazine to healthy adults, peak serum sulfasalazine concentrations occur within 1.5–6 hours and peak serum sulfapyridine concentrations occur within 6–24 hours.a When delayed-release tablets are used, peak serum sulfasalazine concentrations occur within 3–12 hours and peak sulfapyridine concentrations occur within 12–24 hours.a
Mean serum concentration of total sulfapyridine (sulfapyridine and its metabolites) tends to be greater in patients who are slow acetylator phenotypes than in fast acetylator phenotypes.a
Plasma Protein Binding
Sulfasalazine is >99.3% bound to albumin; sulfapyridine is 70% bound to albumin; acetylsulfapyridine (principal metabolite of sulfapyridine) is approximately 90% bound to plasma proteins.a
Sulfasalazine is cleaved by intestinal flora in the colon to form sulfapyridine and 5-aminosalicylic acid.145
Following absorption, sulfapyridine undergoes hepatic N 4-acetylation and ring hydroxylation followed by conjugation with glucuronic acid.a A small portion of 5-aminosalicylic acid is absorbed and undergoes N 4-acetylation; the major portion is excreted in the feces.a The rate of metabolism of sulfapyridine and acetylsulfapyridine depends on the acetylator phenotype of the patient.145 146 d
Most of a sulfasalazine dose is excreted in the urine.a Unchanged sulfasalazine accounts for up to 15%, sulfapyridine and its metabolites account for about 60%, and 5-aminosalicylic acid and its metabolites account for 20–33% of a dose.a
Although total fecal excretion of sulfasalazine and its metabolites depends on GI transit time and the activity of the intestinal bacteria; fecal excretion may account for about 5% of a daily dose (primarily as sulfapyridine metabolites).a
Mean serum half-life of sulfasalazine is 5.7 hours following a single dose and 7.6 hours following multiple doses.a
Half-life of sulfapyridine is 8.4 hours following a single sulfasalazine dose and 10.4 hours following multiple sulfasalazine doses.a
Tablets, Conventional and Delayed-release
Mechanism of action in management of ulcerative colitis has not been fully determined. Sulfasalazine may serve as a vehicle to deliver sulfapyridine and 5-aminosalicylic acid (mesalamine) to the colon in higher concentrations than can be achieved by oral administration of these metabolites alone.a Therapeutic effect may result from antibacterial action of sulfapyridine and/or topical anti-inflammatory action of 5-aminosalicylic acid.a
Relative contribution of sulfasalazine and its major metabolites to the management of rheumatoid arthritis is not known.146
Advice to Patients
Advise patients that sulfasalazine may cause orange-yellow discoloration of the urine or skin.145 146 If tablets pass into feces undisintegrated, importance of notifying clinician since the drug should be discontinued immediately.146
Advise patients of the possibility of adverse effects and need for careful medical supervision.145 146 Importance of reporting the occurrence of sore throat, fever, pallor, purpura, or jaundice to a clinician since this may indicate a serious blood disorder.145 146
Advise patients that photosensitivity has been reported with sulfonamides and they should avoid exposure to UV light or prolonged exposure to sunlight.b
Advise patients with ulcerative colitis that symptoms rarely remit completely and that the risk of relapse can be substantially reduced by continued administration of sulfasalazine using a maintenance dosage.145 146
Advise patients with rheumatoid arthritis that symptoms rarely remit completely and that it is important to consult with their clinician to determine the need for continued administration of sulfasalazine.146
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.
Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.
Importance of advising patients of other important precautionary information. (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Tablets, delayed-release (enteric-coated), film-coated
AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
Last reviewed: August 01, 2009
Date modified: February 08, 2016
Date published: May 01, 2004
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