Azulfidine

A

Generic Name: Sulfasalazine
Class: Sulfonamides
VA Class: AM650
CAS Number: 599-79-1

Introduction

Prodrug converted in vivo to sulfapyridine (a sulfonamide anti-infective) and 5-aminosalicylic acid (mesalamine; anti-inflammatory agent).116

Uses for Azulfidine Ulcerative Colitis

Adjunct for management of mild to moderate ulcerative colitis.145 146

Crohn’s Disease

Management of active Crohn’s disease†.101 102 103 105 107 108

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

Does not appear to be useful for maintenance therapy once a remission has been attained or following surgical resection.102 104 107 108 157

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

Has been used in conjunction with other DMARDs (e.g., azathioprine, gold compounds, hydroxychloroquine, methotrexate, penicillamine) and/or systemic corticosteroids.148 149 150

Juvenile Arthritis

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 Administration Oral Administration

Administer orally, preferably after meals.145 146

Delayed-release tablets should be swallowed whole.146

Maintain adequate fluid intake to prevent crystalluria and stone formation.145 146

Dosage Pediatric Patients Ulcerative Colitis Oral

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

Crohn’s Disease† Oral

Initiate therapy with 25–40 mg/kg daily and increase to 50–75 mg/kg daily (maximum daily dosage 4 g).164 165

Juvenile Arthritis Polyarticular Course Oral

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 ? 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

Adults Ulcerative Colitis Oral

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

Crohn’s Disease† Oral

Mildly to moderately active disease: 3–6 g daily (as conventional or delayed-release tablets) has been used.158 159 161 162 168

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

Rheumatoid Arthritis Oral

Delayed-release tablets: 2–3 g daily given in equally divided doses every 12 hours.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 >2 g daily should be carefully monitored.146

Prescribing Limits Pediatric Patients Juvenile Arthritis Oral

Maximum 2 g daily.146

Crohn’s Disease† Oral

Maximum 4 g daily.164

Cautions for Azulfidine Contraindications

Hypersensitivity to sulfasalazine, its metabolites, sulfonamides, or salicylates.145 146

Intestinal or urinary tract obstruction.145 146

Porphyria.145 146

Warnings/Precautions Warnings Hematologic Effects

Fatalities associated with agranulocytosis, aplastic anemia, or other blood dyscrasias have been reported with sulfasalazine.145 146

Clinical signs such as sore throat, fever, pallor, purpura, or jaundice may indicate myelosuppression, hemolysis, or hepatotoxicity.145 146

Use in patients with blood dyscrasias only after critical appraisal.145 146

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

Patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency should be monitored closely for signs of hemolytic anemia.145 146

Impaired Fertility

Oligospermia and infertility reported in men treated with sulfasalazine; effects were reversed when the drug was discontinued145 .146

Sensitivity Reactions Hypersensitivity Reactions

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

Incidence of hypersensitivity reactions appears to increase with increased sulfonamide dosage.b Fatalities related to hypersensitivity to sulfasalazine have been reported.146

Use with caution in patients with severe allergy or bronchial asthma.145 146

If a hypersensitivity reaction occurs, discontinue sulfasalazine immediately and treat appropriately.145 146

Desensitization

Desensitization to sulfasalazine has been used when reinitiation of the drug was considered necessary in a patient who had a hypersensitivity reaction.117 118 145 146

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

If symptoms of sensitivity recur, the drug should be discontinued.145 146

Cross-hypersensitivity

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

General Precautions Renal Effects

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

Use in patients with renal damage only after critical appraisal.145 146

Perform urinalysis (with microscopic examination) frequently and other renal function tests periodically during sulfasalazine therapy.145 146

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

Hepatic Effects

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

Use in patients with hepatic damage only after critical appraisal.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

Specific Populations Pregnancy

Category B.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

Lactation

Distributed into milk.145 146 Use caution.145 146 b

Pediatric Use

Safety and efficacy not established for management of ulcerative colitis in children <2 years of age.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

Hepatic Impairment

Use with caution.145 146

Renal Impairment

Use with caution.145 146 (See Renal Effects under Cautions.)

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 Specific Drugs

Drug

Interaction

Comments

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

Anti-infectives

Possibility that concomitant anti-infectives may alter the action of sulfasalazine by altering intestinal flora and consequently sulfasalazine metabolisma

Digoxin

Possible decreased GI absorption of digoxin145 146 b

If used concomitantly, monitor to ensure adequate digoxin concentrationsb

Folic acid

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

Iron

Sulfasalazine chelates iron, altering distribution of sulfasalazine in the intestinal lumen, interfering with its absorption and resulting in lower blood concentrations of sulfasalazinea

Methotrexate

No evidence of pharmacokinetic interaction in patients with rheumatoid arthritis;146 possible increased risk of GI effects (especially nausea)146

Azulfidine Pharmacokinetics Absorption Bioavailability

About 10–15% of a sulfasalazine dose is absorbed as unchanged drug from the small intestine.145 146 a

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

Plasma Concentrations

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

Distribution Extent

In animals, relatively high concentrations of sulfasalazine are present in serous fluid, liver, and the intestinal wall.a Sulfapyridine is distributed to most body tissues.a

Unchanged sulfasalazine, sulfapyridine and its metabolites, and 5-aminosalicylic acid and its acetylated metabolite cross the placenta.100 124 125 135

Only small amounts of unchanged sulfasalazine are distributed into milk, but sulfapyridine concentrations in milk are about 30–60% of concurrent serum concentrations.145 146

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

Elimination Metabolism

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

Elimination Route

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

Half-life

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

Special Populations

In geriatric patients with rheumatoid arthritis, half-life of sulfasalazine and its metabolites may be increased.145 146

Stability Storage Oral Tablets, Conventional and Delayed-release

25°C (may be exposed to 15–30°C).145 146

ActionsActions

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

Importance of taking sulfasalazine in evenly divided doses, preferably after meals,145 146 and to swallow delayed-release tablets whole.146

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.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Sulfasalazine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

500 mg*

Azulfidine (scored)

Pfizer

Tablets, delayed-release (enteric-coated), film-coated

500 mg*

Azulfidine EN-tabs

Pfizer

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Azulfidine 500MG Tablets (PFIZER U.S.): 100/$68.99 or 300/$182.97

Azulfidine EN-tabs 500MG Enteric-coated Tablets (PFIZER U.S.): 100/$82.99 or 300/$226.96

Sulfasalazine 500MG Enteric-coated Tablets (GREENSTONE): 100/$37.99 or 200/$69.97

Sulfasalazine 500MG Tablets (GREENSTONE): 100/$18.99 or 300/$45.96

Sulfazine EC 500MG Enteric-coated Tablets (QUALITEST): 60/$24.99 or 180/$57.99

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions August 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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