⬇ ⬇Sulfasalazine, a sulfonamide, generally is considered a prodrug since the diazo bond is cleaved in vivo to provide sulfapyridine and 5-aminosalicyclic acid (mesalamine); the drug exhibits antibacterial and anti-inflammatory activity.116
⬆ ⬇Sulfasalazine is used for the management of mild to moderate ulcerative colitis in adults and children 2 years of age or older145,146 and also has been used in the management of Crohn's disease† in adult and pediatric patients.101,102,103,104,105,106,107,164,165,166,167,168,169 In addition, sulfasalazine administered as delayed-release tablets is used for the management of rheumatoid arthritis in adults146 and for the management of polyarticular course juvenile rheumatoid arthritis in children 6-16 years of age.146
Sulfasalazine is used for the management of mild to moderate ulcerative colitis in conjunction with usual supportive and dietary measures. Corticosteroids are more effective than sulfasalazine in treating acute attacks and concomitant administration of corticosteroid retention enemas may be required. Patients who do not respond to concomitant sulfasalazine and topical corticosteroid therapy or who have extensive intestinal involvement may require systemic corticosteroids. Sulfasalazine is more effective than corticosteroids in reducing the frequency and severity of relapses, and usually is used for maintenance therapy. The manufacturers state that sulfasalazine also may be used as an adjunct in the treatment of severe ulcerative colitis. Controlled studies supporting this indication are lacking, and other treatment such as parenteral corticosteroids or surgery generally is required.
Sulfasalazine has been used for the management of mildly to moderately active Crohn's disease†, but its role in the management of this condition is not as well defined as in the symptomatic treatment of ulcerative colitis.101,102,103,105,107,108,158,161,168,169,170
Sulfasalazine may be used as initial drug therapy in patients with mildly to moderately active disease, especially in those with ileocolonic or colonic involvement;102,105,107,108,157,158,159,162,168,170 the drug does not seem be effective in patients with small bowel disease.101,102,103,157,158 Many clinicians recommend that sulfasalazine be used in patients with left-sided disease, restricted to the colon.159 Limited data indicate that patients who have been previously treated with corticosteroids or have undergone surgical resection may fail to respond to sulfasalazine therapy, while those who have not received corticosteroids at initiation of sulfasalazine therapy or did not undergo surgery may respond substantially better to sulfasalazine than those receiving placebo.159 There also is some evidence that concomitant therapy with sulfasalazine and corticosteroids may not be more effective than either drug alone,105,106,157,168 but some subgroups of patients may have a better response to combined therapy (e.g., those with disease localized in the colon).105
Sulfasalazine does not appear to be useful for maintenance therapy in Crohn's disease once a remission has been attained by drug therapy or following surgical resection.102,104,105,107,108,157,158,163,167 However, limited data indicate that sulfasalazine may be superior to placebo in delaying clinical flare-ups in patients with Crohn's disease involving the colon and/or rectum, although results have been conflicting.160
For additional information on the management of Crohn's disease, see Uses: Crohn's Disease in Mesalamine 56:36.
Rheumatoid Arthritis in Adults 
Sulfasalazine is used for the management of rheumatoid arthritis in adults whose symptoms progress despite an adequate regimen of nonsteroidal anti-inflammatory agents (NSAIAs) or those intolerant to an adequate trial of recommended dosages of one or more NSAIAs.119,121,146,147,148,149,150,151,152,153,154,155 Sulfasalazine is one of several disease-modifying antirheumatic drugs (DMARDs) that can be used when DMARD therapy is appropriate.154,155 (For further information on the treatment of rheumatoid arthritis, see Uses: Rheumatoid Arthritis, in Methotrexate 10:00.) 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, and the drug only should be used as one part of a comprehensive treatment program, including non-drug therapies such as rest and physical therapy.146 Unlike anti-inflammatory agents, sulfasalazine does not produce immediate response in patients with this condition.146
Sulfasalazine has been used in combination with other DMARDs (e.g., azathioprine, gold compounds, hydroxychloroquine, methotrexate, penicillamine) and/or systemic corticosteroids.148,149,150 In patients with rheumatoid arthritis, sulfasalazine improves grip strength, decreases erythrocyte sedimentation rate, reduces joint tenderness, and decreases duration of early morning stiffness.147,148,150 Limited data indicate that sulfasalazine appears to be as effective as gold compounds, hydroxychloroquine, or penicillamine in the management of rheumatoid arthritis.150
Sulfasalazine is used for the management of the signs and symptoms of polyarticular course juvenile rheumatoid arthritis in children who have not responded adequately to NSAIAs.115,146 Safety and efficacy of sulfasalazine for the 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 Extrapolation of data from adults with rheumatoid arthritis to children with polyarticular course juvenile rheumatoid arthritis is based on similarities in disease and response to therapy in these patient populations and published studies.115,146 Because of the high frequency of adverse effects in children receiving sulfasalazine for the management of systemic course juvenile rheumatoid arthritis, use of the drug in children with this type of arthritis is not recommended.146 (See Pediatric Precautions.)
Sulfasalazine has been used with some success in the treatment of granulomatous colitis† and scleroderma†, and was reportedly beneficial in the treatment of collagenous colitis† in one patient.109
⬆ ⬇Sulfasalazine conventional and delayed-release tablets are administered orally.145,146 The total daily dosage should be divided into equally divided doses, and, if possible, doses should be administered after meals.145,146
Delayed-release sulfasalazine tablets should be swallowed whole.146
For the management of ulcerative colitis, the interval between doses of sulfasalazine given as conventional or delayed-release tablets should not exceed 8 hours.145,146 The response to sulfasalazine in ulcerative colitis patients can be evaluated by clinical criteria (e.g., presence of fever, weight changes, degree and frequency of diarrhea and bleeding) as well as by sigmoidoscopy and evaluation of biopsy samples.145,146 Continuation of sulfasalazine therapy may be necessary even when clinical symptoms, including diarrhea, have been controlled.145,146 When endoscopic examination confirms satisfactory improvement, sulfasalazine dosage may be decreased to a maintenance dosage.145,146 If diarrhea recurs, dosage should be increased to previously effective dosage.145,146 Patients with ulcerative colitis should be advised that the disease rarely remits completely, and that continued use of maintenance dosages of sulfasalazine may decrease the risk of relapse.145,146
The usual initial adult dosage of sulfasalazine given as conventional or delayed-release tablets for the management of ulcerative colitis is 3-4 g daily given in equally divided doses.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. Although dosage as high as 12 g daily has been given, dosage exceeding 4 g daily is accompanied by an increased incidence of adverse effects. Some clinicians recommend that dosage exceeding 4 g daily be avoided unless the serum concentration of total sulfapyridine and the phenotype of the patient are known. The usual adult 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 when possible to prevent adverse effects. The efficacy of maintenance therapy appears to be dose related, but the potential value of dosages greater than 2 g daily must be weighed against the risks of increased adverse effects and the necessity for more careful monitoring of the patient.114
When sulfasalazine is given as conventional or delayed-release tablets for the management of ulcerative colitis in children 6 years of age or older, the usual initial dosage is 40-60 mg/kg daily in 3-6 divided doses and the usual maintenance dosage is 30 mg/kg daily in 4 divided doses.145,146
When sulfasalazine is used for the management of mildly to moderately active Crohn's disease†, a daily dosage of 3-6 g, given in divided doses as conventional or delayed-release tablets, has been recommended for adults.158,159,161,162,168 Sulfasalazine (1.5-3 g daily), given as conventional or delayed-release tablets also has been used for maintenance therapy in Crohn's disease,160,168 although such dosages do not appear to be more effective than placebo when used in patients with medically-induced remission.168
Sulfasalazine, given as an initial dosage of 25-40 mg/kg daily and increased to 50-75 mg/kg daily (maximum daily dosage of 4 g), has been used in a limited number of pediatric patients with Crohn's disease† (i.e., mild ileal, ileocecal, ileocolonic, or colonic disease). 164,165,166 Limited data from a retrospective comparative study indicate that efficacy in maintaining remission of Crohn's disease is similar in children receiving sulfasalazine to those receiving oral mesalamine delayed-release tablets.166 However, some patients preferred mesalamine to sulfasalazine because of ease and frequency of administration and better tolerance.166
Rheumatoid Arthritis in Adults
For the management of rheumatoid arthritis, the interval between doses of sulfasalazine given as delayed-release tablets usually is 12 hours.146
The usual adult dosage of sulfasalazine given as delayed-release tablets for the management of rheumatoid arthritis is 2-3 g daily given in equally divided doses.146 154,155 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 exceeding 2 g daily should be carefully monitored.146
The usual dosage of sulfasalazine given as delayed-release tablets for the management of polyarticular course juvenile rheumatoid arthritis in children 6 years of age and older is 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 sulfasalazine therapy in children 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
⬆ ⬇Onset of adverse effects generally occurs within a few days to 12 weeks following initiation of sulfasalazine therapy, especially if dosage exceeds 4 g daily.
Clinical experience to date indicates that the incidence of sulfasalazine-induced adverse effects in patients with ulcerative colitis generally is similar to that reported in patients with rheumatoid arthritis, although there is a greater incidence of some reactions.146
The most frequent adverse effects associated with sulfasalazine therapy in patients with ulcerative colitis are anorexia, headache, nausea, vomiting, gastric distress, and apparently reversible oligospermia.145,146 Other adverse effects reported in patients with ulcerative colitis include pruritus, urticaria, rash, fever, Heinz body anemia, hemolytic anemia, and cyanosis.145,146
Adverse effects reported in patients with rheumatoid arthritis receiving sulfasalazine include nausea, dyspepsia, headache, abdominal pain, vomiting, fever, dizziness, stomatitis, rash, pruritus, abnormal liver function test results, leukopenia, and thrombocytopenia;146 reversible immunoglobulin suppression, rarely accompanied by clinical findings, has been observed in sulfasalazine-treated patients with rheumatoid arthritis.146 It appears that there are no drug-induced adverse effects that are specific to patients with rheumatoid arthritis; however, rash occurs more frequently in patients with rheumatoid arthritis than in those with ulcerative colitis, occurring in 13 or 3.3% of patients with rheumatoid arthritis or ulcerative colitis, respectively.146
An increased incidence of adverse effects has been reported in patients receiving sulfasalazine daily dosages of 4 g or more or those with serum total sulfapyridine concentrations exceeding 50 mcg/mL.145,146 The ability to acetylate sulfasalazine may influence the onset and severity of adverse effects. In one study, 86% of patients exhibiting adverse effects were slow acetylators of sulfapyridine.
Nausea,145,146 vomiting,145,146 gastric distress,145,146 and anorexia145,146 occur in 8-33% of patients receiving sulfasalazine. Diarrhea, bloody diarrhea, neutropenic enterocolitis, hepatitis, hepatic failure, and pancreatitis have also been reported with sulfasalazine or other sulfonamides.145,146
GI symptoms occurring after the first few days of sulfasalazine therapy are probably secondary to high serum concentrations of total sulfapyridine and may be alleviated by halving the dose and gradually increasing it over several days. If symptoms persist, the drug should be discontinued for 5-7 days, and therapy reinstituted at a lower daily dosage.
There have been isolated reports of sulfasalazine delayed-release tablets passing intact through the GI tract of some patients,146 possibly because of a lack of intestinal esterases capable of disintegrating the enteric coating. The drug should be discontinued immediately in such patients.146
Hypersensitivity reactions, including 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, have been reported with sulfasalazine or other sulfonamides.145,146
Sulfasalazine should be used with caution in patients with severe allergy or bronchial asthma.145,146
If a hypersensitivity reaction occurs during sulfasalazine therapy, the drug should be discontinued immediately.145,146
Desensitization to sulfasalazine has been used when reinstitution of sulfasalazine therapy is considered necessary in patients who have had a hypersensitivity reaction to the drug;117,118,145,146 however, 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 If manifestations of sensitivity recur, the drug should be discontinued.145,146
A few cases of pulmonary eosinophilia and at least one fatality from fibrosing alveolitis have been reported in patients receiving sulfasalazine.
Sulfasalazine may impart an orange-yellow color to alkaline urine and skin, and patients should be advised of this effect.145,146
Precautions and Contraindications
Sulfasalazine shares the toxic potentials of the sulfonamides, and the usual precautions of sulfonamide therapy should be observed. (See Cautions in the Sulfonamides General Statement 8:12.20.)
Sulfasalazine should be used in patients with hepatic or renal damage or with blood dyscrasias only after critical appraisal.145,146 Fatalities related to hypersensitivity reactions, blood dyscrasias (e.g., agranulocytosis, aplastic anemia), renal and liver damage, irreversible neuromuscular and CNS changes, and fibrosing alveolitis have been reported in patients receiving the drug.145,146
The presence of clinical signs such as sore throat, fever, pallor, purpura, or jaundice may indicate myelosuppression, hemolysis, or hepatotoxicity.145,146
Complete blood cell counts (CBCs), with differentials, and liver function tests should be performed prior to initiation of sulfasalazine therapy and every 2 weeks during the first 3 months of therapy.145,146 These tests should then be performed once monthly during the second 3 months of therapy and once every 3 months thereafter and as clinically indicated.145,146 In addition urinalysis (with microscopic examination) should be done frequently and other renal function tests should be evaluated periodically during sulfasalazine therapy.145,146 The drug can be discontinued while awaiting results of blood tests.145,146
Adequate fluid intake must be maintained during sulfasalazine therapy to reduce the risk of crystalluria and stone formation.145,146
Patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency should be monitored closely for signs of hemolytic anemia; this adverse effect frequently is dose related.145,146
Sulfasalazine is contraindicated in individuals hypersensitive to sulfasalazine, its metabolites, sulfonamides, or salicylates.145,146 The drug also is contraindicated in individuals with intestinal or urinary tract obstruction or porphyria.145,146
Safety and efficacy of sulfasalazine conventional or delayed-release tablets in children younger than 2 years of age with ulcerative colitis have not been established.145,146
Safety and efficacy of sulfasalazine delayed-release tablets for the 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 the management of juvenile rheumatoid arthritis generally are similar to those observed in adults with rheumatoid arthritis.146 However, sulfasalazine therapy is associated with a high frequency of serum sickness-like syndrome in children with systemic course juvenile rheumatoid arthritis.146 This syndrome, which frequently is severe, presents as fever, nausea, vomiting, headache, rash, and abnormalities in liver function test results.146 Therefore, use of sulfasalazine in patients with systemic course juvenile rheumatoid arthritis is not recommended.146
Sulfasalazine, given as an initial dosage of 25-40 mg/kg daily and increased to 50-75 mg/kg daily (maximum daily dosage of 4 g), has been used in a limited number of pediatric patients with Crohn's disease† (i.e., mild ileal, ileocecal, ileocolonic, or colonic disease). 164,165,166 Limited data from a retrospective comparative study indicate that efficacy in maintaining remission of Crohn's disease is similar in children receiving sulfasalazine to those receiving oral mesalamine delayed-release tablets.166 However, some patients preferred mesalamine to sulfasalazine because of ease and frequency of administration and better tolerance.166
Prolonged plasma elimination half-lives of sulfasalazine, sulfapyridine, and their metabolites have been reported in geriatric patients with rheumatoid arthritis.145,146 The clinical importance of these effects are not known.145,146
Mutagenicity and Carcinogenicity
In carcinogenicity studies evaluating sulfasalazine in rats and mice, an increased incidence of urinary bladder transitional cell papillomas was observed in male rats and transitional cell papilloma of the kidney was observed in some female rats.145,146 In addition, an increased incidence of hepatocellular adenoma or carcinoma was observed in male and female mice.145,146
Sulfasalazine was not mutagenic in the Ames test or in a mouse lymphoma cell assay; however, the drug showed equivocal mutagenic response in some other tests, including the micronucleus assay of mouse and rat bone marrow and mouse peripheral red blood cell, and the sister chromatid exchange, chromosomal aberration, and micronucleus assays in human lymphocytes.145,146
Pregnancy, Fertility, and Lactation
Reproduction studies in rats and rabbits using sulfasalazine dosages up to 6 times the usual human dosage have not revealed evidence of harm to the fetus.145,146
Sulfasalazine has been used for the treatment of inflammatory bowel disease, including Crohn's disease and ulcerative colitis, during pregnancy.122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,145,146 Although fetal abnormalities occasionally have been reported in infants born to women with inflammatory bowel disease who received sulfasalazine alone or combined with corticosteroids during pregnancy,126,129,134,137 most evidence indicates that sulfasalazine is not associated with a substantial risk of teratogenicity and that the potential benefits of therapy with the drug generally appear to outweigh the possible risks in pregnant women with this disease.122,123,124,125,126,127,128,129,130,131,132,133,135,136,144,145,146 Although most experience with the use of sulfasalazine in pregnancy has been in women with inflammatory bowel disease, safety of the drug in pregnant women with rheumatoid arthritis is not expected to differ from that in inflammatory bowel disease and sulfasalazine therapy generally can be continued in pregnant women with rheumatoid arthritis.156 Some clinicians consider sulfasalazine the disease-modifying antirheumatic drug (DMARD) of choice in women who are planning to become pregnant or who are pregnant.156
The risk of sulfasalazine-induced kernicterus in neonates born to women who received the drug during the last trimester appears to be low.122,123,124,125,126,127,130,132,133,135,144 Agranulocytosis has been reported in an infant whose mother received sulfasalazine and corticosteroid therapy throughout pregnancy.145,146 The effect of the drug on subsequent growth development and functional maturation in children whose mothers received sulfasalazine during pregnancy has not been determined.145,146
Because there are no adequate and controlled studies to date using sulfasalazine in pregnant women, the drug should be used during pregnancy only when clearly needed.124,145,146
Impairment of male fertility was observed in reproduction studies in rats using sulfasalazine dosages of 800 mg/kg daily.139,145,146 Oligospermia, abnormal sperm forms, impaired sperm motility, and infertility have occurred in men receiving sulfasalazine; however, these effects appear to be reversible following discontinuance of the drug.108,110,115,123,139,140,141,142,143 These effects appear to be caused by effects of sulfapyridine, not 5-aminosalicylic acid (mesalamine), on sperm maturation.139,140,142,143,145,146
Sulfasalazine should be used with caution in nursing women since sulfonamides are distributed into milk.145,146
⬆ ⬇Sulfasalazine shares the potential drug interactions of the sulfonamides. In addition, sulfasalazine may interact with other agents.
It has been postulated that concomitant use of anti-infectives may alter the action of sulfasalazine by altering intestinal flora and consequently sulfasalazine metabolism.
Concomitant use of sulfasalazine and digoxin may result in decreased absorption of digoxin.145,146
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 patients.111,112,113 Several mechanisms appear to be involved, including inhibition of hepatic folate metabolism, intestinal transport of folic acid, and jejunal brush-border folate conjugase.111,112,113
Some clinicians suggest that 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 supplements.113
Sulfasalazine chelates iron, altering distribution of sulfasalazine in the intestinal lumen, interfering with its absorption and resulting in lower blood concentrations of sulfasalazine.
Concomitant use of sulfasalazine and methotrexate in patients with rheumatoid arthritis does not appear to affect the pharmacokinetics of either drug.146 However, results of 2 controlled studies in patients with rheumatoid arthritis have shown an increased incidence of adverse GI effects (mainly nausea) in patients receiving concomitant therapy with sulfasalazine (2 g daily) and methotrexate (7.5 mg weekly) when compared with such incidence associated with administration of either drug alone.146
⬆ ⬇Although the precise mechanism of action of sulfasalazine in the management of ulcerative colitis has not been determined, one possible mechanism is that sulfasalazine serves 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. Once these agents have reached the colon, therapeutic effect may result from antibacterial action of sulfapyridine and/or topical anti-inflammatory action of 5-aminosalicylic acid. (For additional information on the anti-inflammatory action of 5-aminosalicylic acid, see Pharmacology in Mesalamine 56:36.) Other actions that may explain the activity of sulfasalazine include changes in organizational patterns in intestinal flora, reduction in Clostridium and Escherichia coli in the stools, inhibition of the synthesis of prostaglandins known to elicit diarrhea and affect mucosal transport, alteration in the secretion and absorption of fluids and electrolytes by the colon, and/or immunosuppression. Although it has been proposed that the therapeutic effects may also be related to the affinity of the drug for connective tissue and serosal membranes, ulcerative colitis principally affects mucosa that has very little connective tissue.
The relative contribution of sulfasalazine and its major metabolites to the management of rheumatoid arthritis is not known.146
About 10-15% of a dose of sulfasalazine is absorbed as unchanged drug from the small intestine. Part of the absorbed sulfasalazine is apparently excreted via the bile into the intestine. The remainder 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). Sulfapyridine is rapidly absorbed from the colon. Only a small portion of the 5-aminosalicylic acid present in the colon is absorbed.
Following administration of a single 2-g oral dose of sulfasalazine to healthy adults, peak serum sulfasalazine concentrations occur within 1.5-6 hours and average 14 mcg/mL. Peak serum sulfapyridine concentrations occur within 6-24 hours and average 21 mcg/mL. Following administration of a single 2-g oral dose of delayed-release sulfasalazine, peak serum sulfasalazine concentrations occur within 3-12 hours and average 6 mcg/mL, and peak sulfapyridine concentrations occur within 12-24 hours and average 13 mcg/mL. Peak plasma concentrations of sulfapyridine and 5-aminosalicylic acid usually occur about 10 hours after dosing; the longer time to achieve peak plasma concentrations of the metabolites versus the parent drug probably is associated with GI transit time to the lower intestine where metabolism of sulfasalazine occurs.146
The 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. In one study of colitis patients receiving sulfasalazine in doses ranging from 3-6 g daily, mean steady-state serum concentrations in fast acetylators were 17.6 mcg of sulfasalazine per mL, 31 mcg of total sulfapyridine per mL, and 1 mcg of 5-aminosalicylic acid per mL. In slow acetylators, mean steady-state serum concentrations were 18.7 mcg of sulfasalazine per mL, 53.7 mcg of total sulfapyridine per mL, and 1 mcg of 5-aminosalicylic acid per mL.
Serum concentrations of total sulfapyridine in excess of 50 mcg/mL appear to correlate with adverse effects, while concentrations of 20-50 mcg of total sulfapyridine per mL appear to correlate with clinical improvement.
Serum concentrations of 5-aminosalicylic acid range from 0-4 mcg/mL in patients with ulcerative colitis receiving sulfasalazine.
In animals, relatively high concentrations of sulfasalazine are present in serous fluid, liver, and the intestinal wall. Sulfapyridine is distributed to most body tissues. The apparent steady-state volume of distribution of sulfasalazine following IV administration reportedly is about 7.5 L.146 Only very small amounts of unchanged sulfasalazine are distributed into milk, but sulfapyridine concentrations in milk are about 30-60% of those in serum.145,146 Unchanged sulfasalazine, sulfapyridine and its metabolites, and 5-aminosalicylic acid and its acetylated metabolite cross the placenta.100,124,125,135
Sulfasalazine, sulfapyridine, and acetylsulfapyridine (principal metabolite of sulfapyridine) are about 99, 70, and 90% bound, respectively, to plasma proteins, mainly albumin.146
In one study in healthy individuals receiving 4-g doses of sulfasalazine, the mean serum half-life of sulfasalazine was reported to be 5.7 hours following a single dose and 7.6 hours following multiple doses. The half-life of sulfapyridine was reported to be 8.4 hours following a single dose, and 10.4 hours following multiple doses of sulfasalazine.
Sulfasalazine is cleaved by intestinal flora in the colon to form sulfapyridine and 5-aminosalicylic acid. (See Pharmacokinetics: Absorption.) Following absorption, sulfapyridine undergoes hepatic N 4-acetylation (to form acetylsulfapyridine) and ring hydroxylation followed by conjugation with glucuronic acid. The rate of metabolism of sulfapyridine and acetylsulfapyridine depends on the acetylator phenotype of the patient.146 The mean plasma half-life of sulfapyridine in fast acetylators or slow acetylators is 10.4 or 14.8 hours, respectively.146 Sulfapyridine also can be metabolized to 5-hydroxy-sulfapyridine and N -acetyl-5-hydroxy-sulfapyridine.146 A small portion of 5-aminosalicylic acid is absorbed and undergoes N 4-acetylation in the liver and intestine; the major portion is excreted in the feces. 146
In geriatric patients with rheumatoid arthritis, the half-life of sulfasalazine and its metabolites may be increased.145,146
Most of a dose of sulfasalazine is excreted in the urine. Generally, 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. One study has shown urinary excretion of total sulfapyridine to be higher in patients in remission as compared with unimproved patients. Although total fecal excretion of sulfasalazine and its metabolites depends on GI transit time and the activity of the intestinal bacteria, one study has shown fecal excretion to account for about 5% of a daily dose (primarily as sulfapyridine metabolites).
Following IV administration, the calculated clearance of sulfasalazine is about 17 mL/minute; renal clearance of the drug is approximately 37% of the total clearance.
Sulfasalazine is synthesized by diazotization of sulfapyridine and coupling of the diazonium salt with salicylic acid.115,116 Sulfasalazine generally is considered a prodrug since the diazo bond is cleaved in vivo to provide sulfapyridine and 5-aminosalicylic acid (mesalamine).116 Sulfasalazine occurs as a bright yellow or brownish-yellow, odorless, fine powder and has solubilities of less than 0.1 mg/mL in water and approximately 0.34 mg/mL in alcohol at 25°C.
Commercially available sulfasalazine conventional tablets and sulfasalazine delayed-release tablets should be stored at a controlled room temperature of 25°C, but may be exposed to temperatures ranging from 15-30°C.145,146
Additional Information
For further information on the chemistry, mechanism of action, pharmacokinetics, uses, cautions, and drug interactions of sulfasalazine, see the Sulfonamides General Statement 8:12.20. The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
⬆ ⬇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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 500 mg* | Azulfidine® (scored) | |
Tablets, delayed-release (enteric-coated), film-coated | 500 mg* | Azulfidine® EN-tabs® | Pfizer |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
⬆ ⬇ ⬆Only references cited for selected revisions after 1984 are available electronically.
100. Azad Khan AK, Truelove SC. Placental and mammary transfer of sulphasalazine. Br Med J . 1979; 2:1553. [PubMed 43760][PubMedCentral]
101. Anthonisen P, Barany F, Folkenberg O et al. The clinical effect of salazosulphapyridine (Salazopyrin®) in Crohn's disease: a controlled double-blind study. Scand J Gastroenterol . 1974; 9:549-54. [PubMed 4153646]
102. Summers RW, Switz DM, Sessions JT Jr et al. National Cooperative Crohn's Disease Study: results of drug treatment. Gastroenterology . 1979; 77(4 Part 2):847-69. [PubMed 38176]
103. Van Hees PAM, Van Lier HJJ, Van Eltern PH et al. Effect of sulphasalazine in patients with active Crohn's disease: a controlled double-blind study. Gut . 1981; 22:404-9. [PubMed 6114023][PubMedCentral]
104. Lennard-Jones JE. Sulphasalazine in asymptomatic Crohn's disease: a multicentre trial. Gut . 1977; 18:69-72. [PubMed 14057][PubMedCentral]
105. Malchow H, Ewe K, Brandes JW et al. European Cooperative Crohn's Disease Study (ECCDS): results of drug treatment. Gastroenterology . 1984; 86:249-66. [PubMed 6140202]
106. Singleton JW, Summers RW, Kern F Jr et al. A trial of sulfasalazine as adjunctive therapy in Crohn's disease. Gastroenterology . 1979; 77(4 Part 2):887-97. [PubMed 38179]
107. Sack DM, Peppercorn MA. Drug therapy of inflammatory bowel disease. Pharmacotherapy . 1983; 3:158-76. [PubMed 6136027]
108. Peppercorn MA. Sulfasalazine: pharmacology, clinical use, toxicity, and related new drug development. Ann Intern Med . 1984; 3:377-86.
109. Weidner N, Smith J, Pattee B. Sulfasalazine in treatment of collagenous colitis: case report and review of the literature. Am J Med . 1984; 77:162-6. [PubMed 6146259]
110. Toovey S, Hudson E, Hendry WF et al. Sulphasalazine and male infertility: reversibility and possible mechanism. Gut . 1981; 22:445-51. [PubMed 6114897][PubMedCentral]
111. Franklin JL, Rosenberg IH. Impaired folic acid absorption in inflammatory bowel disease: effects of salicylazosulfapyridine (azulfidine). Gastroenterology . 1973; 64:517-25. [PubMed 4144775]
112. Reisenauer AM, Halsted CH. Human jejunal brush border folate conjugase: characterisitics and inhibition by salicylazosulfapyridine. Biochim Biophys Acta . 1981; 659:62-9. [PubMed 6113848]
113. Halsted CH, Gandhi G, Tamura T. Sulfasalazine inhibits the absorption of folates in ulcerative colitis. N Engl J Med . 1981; 305:1513-7. [PubMed 6117796]
114. Azad Khan AK, Howes DT, Piris J et al. Optimum dose of sulphasalazine for maintenance treatment in ulcerative colitis. Gut . 1980; 21:232-40. [PubMed 6105118][PubMedCentral]
115. Imundo LF, Jacobs JC. sulfasalazine therapy for juvenile rheumatoid arthritis. J Rheumatol . 1996; 23:360-6. [PubMed 8882047]
116. Klotz U. Clinical pharmacokinetics of sulphasalazine, its metabolites and other prodrugs of 5-aminosalicylic acid. Clin Pharmacokinet . 1985; 10:285-302. [PubMed 2864155]
117. Purdy BH, Philips DM, Summers RW. Desensitization for sulfasalazine skin rash. Ann Intern Med . 1984; 100:512-4. [PubMed 6142671]
118. Taffet SL, Das KM. Desensitization of patients with inflammatory bowel disease to sulfasalazine. Am J Med . 1982; 73:520-4. [PubMed 6127032]
119. Pullar T, Hunter JA, Capell HA. Which component of sulphasalazine is active in rheumatoid arthritis? Br Med J . 1985; 290:1535-8.
120. Neumann VC, Grindulis KA, Hubball S et al. Comparison between penicillamine and sulphasalazine in rheumatoid arthritis: Leeds-Birmingham trial. BMJ . 1983; 287:1089-102. [PubMed 6414580][PubMedCentral]
121. Pullar T, Hunter JA, Capell HA. Sulphasalazine in rheumatoid arthritis: a double blind comparison of sulphasalazine with placebo and sodium aurothiomalate. BMJ . 1983; 287:1102-4. [PubMed 6138117][PubMedCentral]
122. Mogadam M, Dobbins WO III, Korelitz BI et al. Pregnancy in inflammatory bowel disease: effect of sulfasalazine and corticosteroids on fetal outcome. Gastroenterology . 1981; 80:72-6. [PubMed 6108894]
123. Jarnerot G. Fertility, sterility, and pregnancy in chronic inflammatory bowel disease. Scand J Gastroenterol . 1982; 17:1-4. [PubMed 6127785]
124. Donaldson RM Jr. Management of medical problems in pregnancy—inflammatory bowel disease. N Engl J Med . 1985; 312:1616-9. [PubMed 2860564]
125. Esbjorner E, Jarnerot G, Wranne L. Sulphasalazine and sulphapyridine serum levels in children to mothers treated with sulphasalazine during pregnancy and lactation. Acta Paediatr Scand . 1987; 76:137-42. [PubMed 2882643]
126. Lewis JH, Weingold AB. The use of gastrointestinal drugs during pregnancy and lactation. Am J Gastroenterol . 1985; 80:912-23. [PubMed 2864852]
127. Korelitz BI. Pregnancy, fertility, and inflammatory bowel disease. Am J Gastroenterol . 1985; 80:365-70. [PubMed 2859802]
128. Warsof SL. Medical and surgical treatment of inflammatory bowel disease in pregnancy. Clin Obstet Gynecol . 1983; 26:822-31. [PubMed 6141016]
129. Baiocco PJ, Korelitz BI. The influence of inflammatory bowel disease and its treatment on pregnancy and fetal outcome. J Clin Gastroenterol . 1984; 6:211-6. [PubMed 6144706]
130. Khosla R, Willoughby CP, Jewel DP. Crohn's disease and pregnancy. Gut . 1984; 25:52-6. [PubMed 6140209][PubMedCentral]
131. Gluckmann RF. Sulfasalazine, IBD, and pregnancy. Gastroenterology . 1981; 81:194. [PubMed 6113185]
132. Mogadam M. Sulfasalazine, IBD, and pregnancy. Gastroenterology . 1981; 81:194.
133. Willoughby CP, Truelove SC. Ulcerative colitis and pregnancy. Gut . 1980; 21:469-74. [PubMed 6107262][PubMedCentral]
134. Newman NM, Correy JF. Possible teratogenicity of sulphasalazine. Med J Aust . 1983; 1:528-9. [PubMed 6133211]
135. Jarnerot G, Into-Malmberg MB, Esbjorner E. Placental transfer of sulphasalazine and sulphapyridine and some of its metabolites. Scand J Gastroenterol . 1981; 16:693-7. [PubMed 6119765]
136. Levy N, Roisman I, Teodor I. Ulcerative colitis in pregnancy in Israel. Dis Colon Rectum . 1981; 24:351-4. [PubMed 6114823]
137. Craxi A, Pagliarello F. Possible embryotoxicity of sulfasalazine. Arch Intern Med . 1980; 140:1674. [PubMed 6109522]
138. Jarnerot G, Into-Malmberg MB. Sulphasalazine treatment during breast feeding. Scand J Gastrenterol . 1979; 14:869-71.
139. O'Morain C, Smethurst P, Dore CJ. Reversible male infertility due to sulphasalazine: studies in man and rat. Gut . 1984; 25:1078-84. [PubMed 6148293][PubMedCentral]
140. Riley SA, Lecarpentier J, Mani V et al. Sulphasalazine induced seminal abnormalities in ulcerative colitis: results of mesalazine substitution. Gut . 1987; 28:1008-12. [PubMed 2889648][PubMedCentral]
141. Ragni G, Bianchi Porro G, Ruspa M et al. Abnormal semen quality and low serum testosterone in men with inflammatory bowel disease treated for a long time with sulfasalazine. Andrologia . 1984; 16:162-7. [PubMed 6146274]
142. Cann PA, Holdsworth CD. Reversal of male infertility on changing treatment from sulphasalazine to 5-aminosalicylic acid. Lancet . 1984; 1:1119. [PubMed 6144844]
143. Shaffer JL, Kershaw A, Berrisford MH. Sulphasalazine-induced infertility reversed on transfer to 5-aminosalicylic acid. Lancet . 1984; 1:1240. [PubMed 6144952]
144. Vender RJ, Spiro HM. Inflammatory bowel disease and pregnancy. J Clin Gastroenterol . 1982; 4:231-49. [PubMed 6124570]
145. Pharmacia & Upjohn. Azulfidine® prescribing information. New York, NY; 2008 Jul.
146. Pharmacia & Upjohn. Azulfidine EN-tabs® (sulfasalazine) delayed-release tablets prescribing information. New York, NY; 2008 Jul.
147. ten Wolde S, Breedveld FC, Hermans J et al. Randomised placebo-controlled study of stopping second-line drugs in rheumatoid arthritis. Lancet . 1996; 347:347-52. [PubMed 8598699]
148. Boers M, Verhoeven AC, Markusse HM et al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet . 1997; 350:309-18. [PubMed 9251634]
149. O'Dell JR, Haire CE, Erikson N et al. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. N Engl J Med . 1996; 334:1287-91. [PubMed 8609945]
150. Rains CP, Noble S, Faulds D. Sulfasalazine: a review of its pharmacological properties and therapeutic efficacy in the treatment of rheumatoid arthritis. Drugs . 1995; 50:137-56. [PubMed 7588084]
151. Emery P. Rheumatoid arthritis: not yet curable with early intensive therapy. Lancet . 1997; 350:304-5. [PubMed 9251629]
152. Gómez-Reino JJ. Long-term therapy for rheumatoid arthritis. Lancet . 1996; 347:343-4. [PubMed 8598695]
153. Wollheim FA. Disease modifying drugs in rheumatoid arthritis: encouraging signs but effects not proved. BMJ . 1997; 314:766-7. [PubMed 9080990][PubMedCentral]
154. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum . 2002; 46:328-46. [PubMed 11840435]
155. Anon. Drugs for rheumatoid arthritis. Med Lett Drugs Ther . 2000; 42:57-64. [PubMed 10887424]
156. Janssen NM, Genta MS. The effects of immunosuppressive and anti-inflammatory medications on fertility, pregnancy, and lactation. Arch Intern Med . 2000; 160:610-9. [PubMed 10724046]
157. Lang KA and Peppercorn MA. Medical therapy for Crohn's disease. In: Kirsner JB, ed. Inflammatory bowel disease. 5th ed. Philadelphia, PA: WB Saunders; 2000:557-77.
158. Hanauer SB, Sandborn W, and the Practice Parameters Committee of the American College of Gastroenterology. Management of Crohn's disease in adults: Practice Guidelines. Am J Gastroenterol . 2001; 96:635-43. [PubMed 11280528]
159. Sandborn WJ, Feagan BG. Review article: mild to moderate Crohn's disease defining the basis for a new treatment algorithm. Aliment Pharmacol Ther . 2003; 18:263-77. [PubMed 12895211]
160. Biancone L, Tosti V, Fina D et al. Review article: maintenance treatment of Crohn's disease. Aliment Pharmacol Ther . 2003; 17(Suppl. 2):31-37. [PubMed 12786610]
161. Hanauer SB, Preemt DH. The state of the art in the management of inflammatory bowel disease. Rev Gastroenterol Disord . 2003; 3:81-92. [PubMed 12776005]
162. Hanauer SB. Inflammatory bowel disease. N Engl J Med . 1996; 334:841-8. [PubMed 8596552]
163. Steinhart AH, Hemphill D, Greenberg GR. Sulfasalazine and mesalazine for the maintenance therapy of Crohn's disease: a meta-analysis. Am J Gastroenterol . 1994; 89:2116-24. [PubMed 7977225]
164. Kirschner BS. Differences in the management of inflammatory bowel disease in children and adolescents compared to adults. Neth J Med . 1998;53 :S13-8. [PubMed 9883009]
165. Grand RJ, Ramakrishna J, Calenda KA. Therapeutic strategies for pediatric Crohn disease. Clin Invest Med . 1996;19:373-80. [PubMed 8889277]
166. Barden L, Lipson A, Pert P et al. Mesalazine in childhood inflammatory bowel disease. Aliment Pharmacol Ther . 1989; 3:597-603. [PubMed 2577501]
167. Feagan BG. Maintenance therapy for inflammatory bowel disease. Am J Gastroenterol . 2003 Dec; 98(12 Suppl): S6-S17.
168. Sandborn WJ. Evidence-based treatment algorithm for mild to moderate Crohn's disease. Am J Gastroenterol . 2003; 98(12 Suppl):S1-5. [PubMedCentral]
169. Löfberg R. Review article: medical treatment of mild to moderately active Crohn's disease. Aliment Pharmacol Ther . 2003; 17(Suppl 2):18-22.
170. Sack DM, Peppercorn MA. Drug therapy of inflammatory bowel disease. Pharmacotherapy . 1983; 3:158-76. [PubMed 6136027]