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Sulfasalazine: Drug information

Sulfasalazine: Drug information
(For additional information see "Sulfasalazine: Patient drug information" and see "Sulfasalazine: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Azulfidine;
  • Azulfidine EN-tabs
Brand Names: Canada
  • PMS-Sulfasalazine;
  • Salazopyrin
Pharmacologic Category
  • 5-Aminosalicylic Acid Derivative;
  • Antirheumatic, Disease Modifying
Dosing: Adult
Ankylosing spondylitis

Ankylosing spondylitis (off-label use): Oral: Immediate and delayed release: Initial: 500 mg once daily; may increase up to 2 to 3 g/day in divided doses; if intolerance occurs, decrease dose by 500 mg each week as needed (Ref).

Crohn disease, mild to moderately active

Crohn disease, mild to moderately active (off-label use): Oral: Immediate and delayed release: 3 to 6 g/day in divided doses for up to 16 weeks (Ref).

Psoriatic arthritis

Psoriatic arthritis (off-label use): Oral: Immediate and delayed release: Initial: 500 mg once daily; may increase up to 2 to 3 g/day in divided doses (Ref).

Rheumatoid arthritis

Rheumatoid arthritis:

Note: May be used as an alternative to methotrexate in disease-modifying antirheumatic drug (DMARD)–naive patients with moderate to high disease activity, or as adjunctive therapy in patients whose treatment targets have not been met despite maximally tolerated methotrexate therapy. In DMARD-naive patients with low disease activity, sulfasalazine may be used as an alternative to hydroxychloroquine for initial therapy (Ref).

Oral: Delayed release: Initial: 500 mg once or twice daily; increase by 500 mg each week up to a maintenance dose of 1 g twice daily. May increase further to a maximum of 3 g/day if response to 2 g/day is inadequate after 12 weeks.

Ulcerative colitis, mildly to moderately active

Ulcerative colitis, mildly to moderately active (alternative agent):

Note: Reserved for patients who cannot tolerate preferred agents; if used, may have additional benefits in patients who have concurrent inflammatory arthritis. Supplement folic acid during therapy (Ref).

Induction of remission: Oral: Immediate and delayed release: 3 to 4 g/day in 3 to 4 divided doses; may initiate at 1 to 2 g/day to improve GI tolerance. Doses >4 g/day may increase the risk of toxicity (Ref).

Maintenance of remission: Oral: Immediate and delayed release: 2 to 4 g/day in 3 to 4 divided doses once endoscopic exam confirms improvement (Ref).

Dosage adjustment: If intolerance occurs (eg, GI upset, headache, hematologic toxicity, rash), reduce dosage by 50% and gradually increase to target dose over several days. If intolerance persists, stop therapy for 5 to 7 days and reintroduce at a lower daily dose.

Desensitization regimen: For patients who may be sensitive to treatment, it is suggested to start with a total dose of 50 to 250 mg daily and double it every 4 to 7 days until the desired therapeutic level is achieved. Discontinue if symptoms of sensitivity occur. Do not attempt in patients with a history of agranulocytosis or those who have had a previous anaphylactoid reaction on sulfasalazine therapy

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Note: Use with caution along with appropriate monitoring of kidney function in patients with kidney impairment or on dialysis, as prompt identification and management of acute kidney injury is key (Ref). Ensure adequate hydration in order to prevent crystalluria and stone formation (Ref). Immediate- or delayed-release tablets may be used based on required dose and dosage form availability.

Kidney impairment prior to treatment initiation:

eGFR ≥60 mL/minute/1.73 m2: No dosage adjustment necessary (Ref).

eGFR <60 mL/minute/1.73 m2:

Inflammatory bowel disease (Crohn disease, ulcerative colitis): Oral: Data on the safety of sulfasalazine treatment in patients with preexisting kidney disease is lacking. It may be reasonable to avoid use, if possible, in patients with preexisting impairment (Ref). If necessary, use with caution and utilize the lowest effective dose; monitor kidney function frequently, especially during flares of inflammatory bowel disease, which could precipitate dehydration (Ref).

Rheumatic conditions (eg, arthritis, ankylosing spondylitis, psoriatic arthritis): Oral: Initiate therapy at the low end of the dosage range; gradually titrate based on tolerability and response, not to exceed the usual maximum recommended dose for patients with normal kidney function (Ref).

Hemodialysis, intermittent (thrice weekly): Sulfasalazine is not dialyzable; sulfapyridine metabolite is dialyzable (62%) (Ref):

Inflammatory bowel disease (Crohn disease, ulcerative colitis): Oral: Data on the safety of sulfasalazine treatment in patients with end-stage kidney disease (ESKD) is lacking (Ref). Use with caution and utilize the lowest effective dose (Ref).

Rheumatic conditions (eg, arthritis, ankylosing spondylitis, psoriatic arthritis): Oral: Initial: 250 to 500 mg once daily; gradually titrate based on tolerability and response (Ref). Doses up to 1 g/day have been well tolerated in patients with ESKD receiving hemodialysis (Ref); there is no efficacy or safety data available for doses >1 g/day.

Peritoneal dialysis: Sulfasalazine unlikely to be dialyzed (>99% protein bound) (Ref); dialyzability of sulfapyridine metabolite unknown (has not been studied):

Inflammatory bowel disease (Crohn disease, ulcerative colitis): Oral: Data on the safety of sulfasalazine treatment in patients with ESKD is lacking (Ref). Use with caution and utilize the lowest effective dose (Ref).

Rheumatic conditions (eg, arthritis, ankylosing spondylitis, psoriatic arthritis): Oral: Initial: 250 to 500 mg once daily; gradually titrate based on tolerability and response (Ref). Doses up to 1 g/day have been well tolerated in patients with ESKD receiving hemodialysis (Ref); there is no efficacy or safety data available for doses >1 g/day.

Nephrotoxicity during treatment: Nephrotoxicity is most often due to acute or chronic interstitial nephritis, which may occur within the first 12 months or after several years. Interstitial nephritis is idiosyncratic and not dose-related (Ref). Acute kidney injury due to sulfasalazine-induced crystalluria has also been reported (Ref). Permanently discontinue therapy in patients who experience sulfasalazine-induced nephrotoxicity. Additional measures (eg, corticosteroids, hydration) may be necessary depending on the underlying pathology of the kidney injury (Ref).

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling; use with extreme caution.

Dosing: Older Adult

Refer to adult dosing.

Dosing: Pediatric

(For additional information see "Sulfasalazine: Pediatric drug information")

Inflammatory bowel disease

Inflammatory bowel disease (eg, ulcerative colitis; Crohn disease):

Weight-directed dosing: Children and Adolescents:

Induction: Crohn disease, ulcerative colitis: Oral: 40 to 70 mg/kg/day in 3 to 6 divided doses; in some cases, higher induction doses up to 100 mg/kg/day may be required; maximum daily dose: 4,000 mg/day (Ref)

Maintenance: Ulcerative colitis: Oral: 30 to 70 mg/kg/day in 3 to 6 divided doses; maximum daily dose: 4,000 mg/day; effective induction dose should be transitioned as the initial maintenance dose; may consider dose reduction once remission sustained for several months (Ref).

Fixed dosing (Ref): Children ≥25 kg and Adolescents: Note: Consider dose reduction or use of enteric-coated tablet in patients experiencing adverse gastrointestinal effects with uncoated tablet.

Acute attacks:

25 to <35 kg: Oral: 500 mg 3 times daily

35 to 50 kg: Oral: 1,000 mg 2 to 3 times daily

Maintenance of remission:

25 to <35 kg: Oral: 500 mg 2 times daily

35 to 50 kg: Oral: 500 mg 2 to 3 times daily

Juvenile idiopathic arthritis

Juvenile idiopathic arthritis: Children and Adolescents 6 to 16 years: Oral: Enteric-coated tablet: 30 to 50 mg/kg/day in 2 divided doses; maximum daily dose: 2,000 mg/day (Ref); Note: Although it is an FDA-labeled indication, the use of sulfasalazine for treatment of JIA is not included as a therapeutic option by experts (Ref).

Desensitization regimen

Desensitization regimen: Children ≥6 years and Adolescents: For patients who may be sensitive to treatment, it is suggested to start with a lower total dose, for example when treating inflammatory bowel disease; lower initial doses of 50 to 250 mg daily is suggested (usual is 1,500 to 3,000 mg/day) and double it every 4 to 7 days until the desired dose is achieved. Discontinue if symptoms of sensitivity occur. Do not attempt in patients with a history of agranulocytosis or those who have had a previous anaphylactoid reaction on sulfasalazine therapy.

Dosing: Kidney Impairment: Pediatric

There are no dosage adjustments provided in manufacturer's labeling; use with extreme caution.

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in manufacturer's labeling; use with extreme caution.

Adverse Reactions (Significant): Considerations
Blood dyscrasias

Various blood dyscrasias have been reported, including agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, and immune thrombocytopenia, often as part of a multisystemic disease (drug reaction with eosinophilia and systemic symptoms [DRESS]) (Ref). Although most cases resolve upon drug discontinuation, there are reports of fatal agranulocytosis associated with sulfasalazine (Ref).

Mechanism: Non–dose-related; immune thrombocytopenia may occur due to hapten-dependent antibodies, platelet-reactive autoantibodies or drug-dependent antibodies (Ref). Agranulocytosis is a host immune response to the reactive metabolite of sulfasalazine, namely sulfapyridine (Ref). Dose-related; most cases of leukopenia may be dose-related.

Onset: Delayed; symptoms usually develop within first 3 months of treatment (Ref).

Risk factors:

• G6PD deficiency: Limited data to support an association between sulfasalazine and development of hemolytic anemia in G6PD-deficient patients (Ref)

• Agranulocytosis is associated with HLA-B*08:01 and HLA-A*31:01 in European patients (Ref)

GI effects

Nausea, vomiting, diarrhea, and abdominal pain are commonly associated with sulfasalazine and may lead to drug discontinuation (Ref).

Mechanism: Dose-related; increased blood concentration of active metabolite of sulfasalazine (sulfapyridine) (Ref).

Onset: Delayed; nausea occurs within first few days of initiation or dose increase and is usually transient (Ref).

Risk factors:

• Increased GI intolerance with uncoated tablets (use of enteric-coated formulation may help to improve GI tolerance) (Ref)

• Slow acetylator phenotype (Ref)

Hypersensitivity reactions (delayed)

Delayed hypersensitivity reactions may occur with sulfasalazine ranging from maculopapular skin rash (Ref)to severe cutaneous adverse reactions (SCARs). SCARs include acute generalized exanthematous pustulosis, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) (Ref). In some cases, predominant hepatotoxicity (Ref), pulmonary toxicity (including eosinophilic pneumonitis, pulmonary alveolitis [fibrosing], and interstitial fibrosis) (Ref), or interstitial nephritis (Ref) is noted, although these are usually part of DRESS. Discontinuation of sulfasalazine leads to resolution of symptoms in most patients (Ref). However, in some cases of fulminant hepatitis, liver transplantation and fatalities have been described (Ref).

Mechanism: Delayed hypersensitivity reactions: Non–dose-related, immunologic or idiosyncratic (Ref). SCARs are T-cell mediated (Ref).

Onset: Delayed hypersensitivity reactions: Varied. SCARs usually occur 1 to 8 weeks after initiation (Ref), but may occur more rapidly (often within 1 day) upon reexposure (Ref). Hepatotoxicity occurs within 6 weeks after sulfasalazine initiation (Ref). Interstitial fibrosis has occurred more than 4 years after starting sulfasalazine (Ref).

Risk factors:

• Cross-reactivity may occur in patients with a history of a hypersensitivity reaction to sulfonamide antibiotics (eg, sulfamethoxazole/trimethoprim) (Ref)

• Increased risk of serious skin reactions in patients with rheumatoid arthritis compared to patients with inflammatory bowel disease (Ref)

• DRESS is associated with HLA-B*13:01 in Chinese Han population (Ref)

• In Japanese patients, an association between HLA-A*11:01 with sulfonamide-related (including salazosulfapyridine) SCARs have been described (Ref)

• Sulfasalazine was also identified as a significant cause of SJS/TEN in registration databases from Asian countries (Ref)

• Viral reactivation is frequently associated with sulfasalazine DRESS and relapsing course, in particular HHV-6, HHV-7, Epstein-Barr virus, and cytomegalovirus (Ref)

• Autoimmune sequelae have been associated with sulfasalazine DRESS (Ref)

• Increased toxicity in adult-onset Still disease and systemic juvenile idiopathic arthritis (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults unless otherwise specified.

>10%:

Dermatologic: Skin rash (rheumatoid arthritis: 13%; ulcerative colitis: ≤3%)

Gastrointestinal: Anorexia (ulcerative colitis: ~33%), dyspepsia (rheumatoid arthritis: 13%), gastric distress (ulcerative colitis: ~33%), nausea (rheumatoid arthritis: 19%; ulcerative colitis: ~33%), vomiting (rheumatoid arthritis: 8%; ulcerative colitis: ~33%)

Genitourinary: Oligospermia (reversible; ulcerative colitis: ~33%)

Nervous system: Headache (rheumatoid arthritis: 9%; ulcerative colitis: ~33%)

1% to 10%:

Dermatologic: Pruritus (≤4%), urticaria (ulcerative colitis: ≤3%)

Gastrointestinal: Abdominal pain (rheumatoid arthritis: 8%), stomatitis (rheumatoid arthritis: 4%)

Hematologic & oncologic: Acquired Heinz body anemia (ulcerative colitis: ≤3%), hemolytic anemia (ulcerative colitis: ≤3%), immunoglobulin abnormality (suppression: 10%), leukopenia (rheumatoid arthritis: 3%), thrombocytopenia (rheumatoid arthritis: 1%)

Hepatic: Abnormal hepatic function tests (rheumatoid arthritis: 4%)

Nervous system: Dizziness (rheumatoid arthritis: 4%)

Respiratory: Cyanosis (ulcerative colitis: ≤3%)

Miscellaneous: Fever (≤5%)

Frequency not defined (includes reactions reported with mesalamine or other sulfonamides):

Cardiovascular: Hypersensitivity myocarditis, pericarditis (with or without cardiac tamponade), polyarteritis nodosa, vasculitis

Dermatologic: Alopecia, erythema multiforme, parapsoriasis varioliformis acuta, skin discoloration, skin photosensitivity

Gastrointestinal: Bloody diarrhea, diarrhea (Amos 1986), neutropenic enterocolitis, pancreatitis

Genitourinary: Crystalluria, hematuria, nephrotic syndrome, proteinuria, toxic nephrosis (with oliguria and anuria), urinary tract infection, urine discoloration

Hematologic & oncologic: Agranulocytosis (Wadelius 2018), aplastic anemia, eosinophilia, hemolytic-uremic syndrome, hypoprothrombinemia, megaloblastic anemia, methemoglobinemia, myelodysplastic syndrome, neutropenia (congenital), purpuric disease

Hepatic: Fulminant hepatitis, hepatitis

Hypersensitivity: Serum sickness

Immunologic: Serum sickness-like reaction (children with juvenile rheumatoid arthritis have frequent and severe reaction)

Nervous system: Ataxia, cauda equina syndrome, depression, drowsiness, Guillain-Barre syndrome, hallucination, insomnia, meningitis, peripheral neuropathy, seizure, transverse myelitis, vertigo

Neuromuscular & skeletal: Arthralgia, lupus-like syndrome, rhabdomyolysis, transient lesions of the posterior spinal column

Ophthalmic: Conjunctival injection, injected sclera, periorbital edema

Otic: Hearing loss, tinnitus

Renal: Interstitial nephritis (Augusto 2009)

Respiratory: Eosinophilic pneumonitis (Parry 2002), pleurisy, pulmonary alveolitis (fibrosing) (Leino 1991)

Postmarketing (includes reactions reported with mesalamine or other sulfonamides):

Cardiovascular: Kawasaki syndrome, myocarditis (Jeremic 2015)

Dermatologic: Acute generalized exanthematous pustulosis (Choon 2018), exfoliative dermatitis, pallor, Stevens-Johnson syndrome (Zizi 2015), toxic epidermal necrolysis (Shahidi-Dadras 2021)

Endocrine & metabolic: Folate deficiency

Gastrointestinal: Cholestasis

Hematologic & oncologic: Hematologic disease (pseudomononucleosis), purpuric rash

Hepatic: Cholestatic hepatitis, cholestatic jaundice, hepatic cirrhosis, hepatic failure, hepatic necrosis, hepatotoxicity (idiosyncratic) (Chalasani 2021), jaundice

Hypersensitivity: Anaphylaxis, angioedema (Cildag 2017)

Immunologic: Drug reaction with eosinophilia and systemic symptoms (Sil 2021)

Infection: Sepsis, severe infection

Nervous system: Intracranial hypertension (Tan 2019)

Renal: Nephrolithiasis

Respiratory: Interstitial fibrosis (Kerget 2018), oropharyngeal pain, pneumonia

Contraindications

Hypersensitivity to sulfasalazine, its metabolites, sulfonamides, salicylates, or any component of the formulation; intestinal or urinary obstruction; porphyria

Note: Although the FDA-approved product labeling states this medication is contraindicated in patients with hypersensitivity to sulfonamide-containing drugs, the scientific basis of this cross-sensitivity has been challenged. See “Warnings/Precautions” for more detail.

Canadian labeling: Additional contraindications (not in US labeling): Severe renal impairment (GFR <30 mL/minute/1.73 m2); severe hepatic impairment; use in pediatric patients <2 years of age; patients in whom acute asthmatic attacks, urticaria, rhinitis, or other allergic manifestations are precipitated by acetyl salicylic acid (ASA) or other NSAIDs

Warnings/Precautions

Concerns related to adverse effects:

• CNS effects: Deaths from irreversible neuromuscular and CNS changes have been reported.

• Folate deficiency: May decrease folic acid absorption.

• Infections: Serious infections (some fatal), including sepsis and pneumonia, have been reported. Infections may be associated with agranulocytosis, neutropenia, or myelosuppression. Monitor for signs/symptoms of infection during and after sulfasalazine therapy and promptly evaluate if infection occurs; discontinue therapy for serious infections. Use cautiously in patients with a history of recurring or chronic infections or with underlying conditions or concomitant therapy which may predispose them to infectious complications.

• Sulfonamide ("sulfa") allergy: Traditionally, concerns for cross-reactivity have extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur, or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides and antibiotic sulfonamides. A nonantibiotic sulfonamide compound which contains the arylamine structure and therefore may cross-react with antibiotic sulfonamides is sulfasalazine (Zawodniak 2010). T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (SJS/TEN), some clinicians choose to avoid exposure to these classes.

Disease-related concerns:

• Allergies/asthma: Use with caution in patients with severe allergies or bronchial asthma.

• Hepatic impairment: Use with extreme caution in patients with impaired hepatic function.

• Renal impairment: Use with caution in patients with renal impairment. Maintain adequate hydration to prevent crystalluria and stone formation.

Special populations:

• Slow acetylators: Patients classified as slow acetylators may be at increased risk for adverse reactions due to a prolonged half-life of sulfapyrazine (metabolite of sulfasalazine).

Dosage form specific issues:

• Appropriate use: Delayed release: Use in patients with ulcerative colitis who cannot take uncoated sulfasalazine tablets because of GI intolerance, and in whom there is evidence that this intolerance is not primarily the result of high blood levels of sulfapyridine and its metabolites (eg, patients experiencing nausea and vomiting with the first few doses of the drug, patients in whom a reduction in dosage does not alleviate the adverse GI effects).

• Enteric-coated tablets: Discontinue if tablets are noted to pass without disintegrating.

Other warnings/precautions:

• Skin/urine discoloration: May cause skin and urine discoloration (orange/yellow).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral:

Azulfidine: 500 mg

Azulfidine: 500 mg [DSC] [scored]

Generic: 500 mg

Tablet Delayed Release, Oral:

Azulfidine EN-tabs: 500 mg

Generic: 500 mg

Generic Equivalent Available: US

Yes

Pricing: US

Tablet, EC (Azulfidine EN-tabs Oral)

500 mg (per each): $2.37

Tablet, EC (sulfaSALAzine Oral)

500 mg (per each): $0.44

Tablets (Azulfidine Oral)

500 mg (per each): $1.91

Tablets (sulfaSALAzine Oral)

500 mg (per each): $0.24 - $2.40

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Salazopyrin: 500 mg

Generic: 500 mg

Tablet Delayed Release, Oral:

Salazopyrin: 500 mg

Generic: 500 mg

Administration: Adult

Oral: Administer tablets in evenly divided doses, preferably after meals. Delayed-release tablets should be swallowed whole; do not chew or crush.

Bariatric surgery: Tablet, delayed release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Delayed-release tablet should be swallowed whole. Do not chew or crush. IR tablet is available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery.

Administration: Pediatric

Oral: Tablets should be administered in evenly divided doses, preferably after meals. Do not crush enteric-coated tablets.

Use: Labeled Indications

Juvenile rheumatoid arthritis: Delayed release: Treatment of pediatric patients with polyarticular-course juvenile rheumatoid arthritis who have responded inadequately to salicylates or other NSAIDs.

Rheumatoid arthritis: Delayed release: Treatment of rheumatoid arthritis in patients who have responded inadequately to salicylates or other NSAIDs.

Ulcerative colitis, mildly to moderately active: Immediate and delayed release: Treatment of mild to moderate ulcerative colitis; adjunctive therapy in severe ulcerative colitis; prolongation of the remission period between acute attacks of ulcerative colitis.

Limitations of use: Based on the American Gastroenterological Association (AGA) guidelines on the management of moderate to severe ulcerative colitis, if remission is achieved with concomitant biologic agents or immunomodulators, sulfasalazine should not be continued for maintenance of remission (AGA [Feuerstein 2020]).

Use: Off-Label: Adult

Ankylosing spondylitis; Crohn disease, mild to moderately active; Psoriatic arthritis

Medication Safety Issues
Sound-alike/look-alike issues:

SulfaSALAzine may be confused with cefuroxime, salsalate, sulfADIAZINE

Azulfidine may be confused with Augmentin, azaTHIOprine

Metabolism/Transport Effects

Substrate of BCRP/ABCG2

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Cardiac Glycosides: 5-Aminosalicylic Acid Derivatives may decrease the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy

COVID-19 Vaccines: SulfaSALAzine may diminish the therapeutic effect of COVID-19 Vaccines. Management: Rheumatology guidelines recommend holding sulfasalazine for 1 to 2 weeks after vaccine administration as permitted by the underlying disease. These guidelines consider sulfasalazine to be an immunomodulatory or immunosuppressive medication. Risk D: Consider therapy modification

Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Risk C: Monitor therapy

Darolutamide: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Elacestrant: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Eltrombopag: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Encorafenib: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Folic Acid: SulfaSALAzine may decrease the serum concentration of Folic Acid. Risk C: Monitor therapy

Futibatinib: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Gilteritinib: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Leflunomide: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Leniolisib: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combination

Local Anesthetics: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. Risk C: Monitor therapy

Methenamine: May enhance the adverse/toxic effect of SulfaSALAzine. Specifically, the combination may result in the formation of an insoluble precipitate in the urine. Risk X: Avoid combination

Methotrexate: SulfaSALAzine may enhance the hepatotoxic effect of Methotrexate. Risk C: Monitor therapy

Methylfolate: SulfaSALAzine may decrease the serum concentration of Methylfolate. Risk C: Monitor therapy

Myelosuppressive Agents: 5-Aminosalicylic Acid Derivatives may enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the nephrotoxic effect of 5-Aminosalicylic Acid Derivatives. Risk C: Monitor therapy

Osimertinib: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Oteseconazole: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Pacritinib: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combination

Pretomanid: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. Risk C: Monitor therapy

Regorafenib: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Riluzole: SulfaSALAzine may enhance the adverse/toxic effect of Riluzole. Specifically, the risk of hepatotoxicity may be increased. Management: Consider alternatives to sulfasalazine in patients receiving treatment with riluzole due to the potential for additive hepatotoxicity. Risk D: Consider therapy modification

Rolapitant: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Management: Monitor patients receiving rolapitant for increased exposure to and/or effects of BCRP/ABCG2 substrates. Use the lowest effective rosuvastatin dose when used in combination with rolapitant. Risk C: Monitor therapy

Sodium Nitrite: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor therapy

Sparsentan: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combination

Tafamidis: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Taurursodiol: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combination

Tedizolid: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Teriflunomide: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Thiopurine Analogs: 5-Aminosalicylic Acid Derivatives may enhance the myelosuppressive effect of Thiopurine Analogs. 5-Aminosalicylic Acid Derivatives may increase serum concentrations of the active metabolite(s) of Thiopurine Analogs. Specifically, exposure to the active 6-thioguanine nucleotides (6-TGN) may be increased. Risk C: Monitor therapy

Varicella Virus-Containing Vaccines: 5-Aminosalicylic Acid Derivatives may enhance the adverse/toxic effect of Varicella Virus-Containing Vaccines. The primary concern is the potential development of Reye's Syndrome, a condition that has been associated with the use of salicylates in children with varicella infections. Management: Avoid administration of salicylates for at least 6 weeks after adminstration of a varicella virus-containing vaccine. Risk D: Consider therapy modification

Vitamin K Antagonists (eg, warfarin): 5-Aminosalicylic Acid Derivatives may enhance the anticoagulant effect of Vitamin K Antagonists. 5-Aminosalicylic Acid Derivatives may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Voxilaprevir: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combination

Reproductive Considerations

Sulfasalazine maintenance doses for the management of inflammatory bowel disease may be continued in women planning a pregnancy. A 3- to 6-month remission prior to conception reduces the risk of flare-up during pregnancy (AGA [Mahadevan 2019]). Based on available information, sulfasalazine can be continued in females with rheumatic and musculoskeletal diseases who are planning a pregnancy. Conception should be planned during a period of quiescent/low disease activity (ACR [Sammaritano 2020]). Supplementation with folic acid is recommended (ACR [Sammaritano 2020]; AGA [Mahadevan 2019]).

Sulfasalazine may cause oligospermia and reversible infertility in males; however, there is no data which suggest it would be teratogenic. Based on available information, sulfasalazine can be continued in males with rheumatic and musculoskeletal diseases who are planning to father a child. A semen analysis should be considered if conception does not occur (ACR [Sammaritano 2020]).

Pregnancy Considerations

Sulfasalazine and sulfapyridine cross the placenta.

Based on available data, an increase in fetal malformations has not been observed following maternal use of sulfasalazine for the treatment of inflammatory bowel disease. Cases of neural tube defects have been reported (causation undetermined). Agranulocytosis was noted in an infant following maternal use of sulfasalazine during pregnancy. Although sulfapyridine has poor bilirubin-displacing ability, a potential for kernicterus in the newborn exists.

Aminosalicylates may be continued at prepregnancy maintenance doses for the management of inflammatory bowel disease; however, sulfasalazine is not the preferred drug in this class for use in pregnant women (AGA [Mahadevan 2019]). Based on available information, sulfasalazine can be continued during pregnancy in females with rheumatic and musculoskeletal diseases (ACR [Sammaritano 2020]). Sulfasalazine is known to inhibit the absorption and metabolism of folic acid and may diminish the effects of folic acid supplementation. Supplementation with folic acid is recommended (ACR [Sammaritano 2020]; AGA [Mahadevan 2019]).

Breastfeeding Considerations

Sulfasalazine and sulfapyridine are present in breast milk.

Sulfasalazine concentrations are insignificant; however, sulfapyridine concentrations are ~30% to 60% of the maternal serum. In one case report, sulfapyridine appeared in breast milk within 4 hours of the initial maternal dose and remained fairly constant over the dosing interval. Acetylsulfapyridine was also present in some breast milk samples (Berlin 1980).

One episode of bloody diarrhea was first observed in a 2-month old exclusively breastfed infant. The symptoms reappeared 2 weeks later with up to 6 episodes/day, and continued until 3 months of age. The mother had been taking sulfasalazine for 5 years. Within 72 hours of discontinuing therapy, bloody stools stopped in the infant. Although maternal plasma concentrations were in the therapeutic range, the mother was determined to be a slow acetylator. Sulfapyridine was detected in the infant; milk samples were not obtained (Branski 1986). The manufacturer notes that although sulfapyridine has poor bilirubin-displacing ability, exposure may cause kernicterus in the newborn.

The manufacturer recommends that caution be exercised when administering sulfasalazine to breastfeeding women. Based on available information, sulfasalazine is considered compatible for use in females with inflammatory bowel disease or rheumatic and musculoskeletal diseases who are breastfeeding (ACR [Sammaritano 2020]; AGA [Mahadevan 2019]). However, sulfasalazine is not the preferred drug in this class for use in lactating women with inflammatory bowel disease (AGA [Mahadevan 2019]). Breastfeeding during therapy should be avoided if the infant is premature, ill, has hyperbilirubinemia, or G-6-PD deficiency. Infants should be monitored for diarrhea (WHO 2002).

Dietary Considerations

Sulfasalazine impairs folate absorption. Adequate fluid intake is required to prevent crystalluria and stone formation.

Monitoring Parameters

Manufacturer's labeling: CBC with differential and LFTs (prior to therapy, then every other week for first 3 months of therapy, followed by every month for the second 3 months, then once every 3 months thereafter or as clinically indicated); periodic urinalysis and renal/LFTs; stool frequency; signs of infection, dermatologic toxicity (eg, skin rash, mucosal lesions), hypersensitivity reactions, or blood dyscrasias (eg, rash, sore throat, fever, pallor, purpura).

Alternate recommendations: Rheumatoid arthritis: Complete blood count, serum creatinine, and LFTs: Baseline and every 2 to 4 weeks for 3 months after initiation or following dose increases, then every 8 to 12 weeks during 3 to 6 months of treatment, followed by every 12 weeks beyond 6 months of treatment; monitor more frequently if clinically indicated (ACR [Singh 2016]; ACR [Fraenkel 2021]).

Reference Range

Sulfapyridine concentrations >50 mcg/mL are associated with increased adverse events.

Mechanism of Action

5-aminosalicylic acid (5-ASA) is the active component of sulfasalazine; the specific mechanism of action of 5-ASA is unknown; however, it is thought that it modulates local chemical mediators of the inflammatory response, especially leukotrienes, and is also postulated to be a free radical scavenger or an inhibitor of tumor necrosis factor (TNF); action appears topical rather than systemic

Pharmacokinetics (Adult Data Unless Noted)

Onset of action: Rheumatoid arthritis: >4 weeks; Ulcerative colitis: >3 to 4 weeks

Absorption: Oral: Sulfasalazine: <15% as parent drug

Protein binding: Sulfasalazine: >99% to albumin; Sulfapyridine: ~70% to albumin; Acetylsulfapyridine (AcSP): ~90% to plasma proteins

Distribution: Vd: Sulfasalazine: 7.5 ± 1.6 L

Metabolism: Via colonic intestinal flora to sulfapyridine and 5-aminosalicylic acid (5-ASA). Following absorption, sulfapyridine undergoes acetylation to form AcSP and ring hydroxylation while 5-ASA undergoes N-acetylation (non-acetylation phenotype dependent process); rate of metabolism via acetylation dependent on acetylation phenotype

Bioavailability: Sulfasalazine: <15%; Sulfapyridine: ~60%; 5-aminosalicylic acid: ~10% to 30%

Half-life elimination: Sulfasalazine: 7.6 ± 3.4 hours (prolonged in older adults); Sulfapyridine: 14.8 hours (slow acetylators) and 10.4 hours (fast acetylators)

Time to peak: Sulfasalazine: 3 to 12 hours (mean: 6 hours); Sulfapyridine and 5-aminosalicylic acid (5-ASA): ~10 hours

Excretion: Primarily urine (as unchanged drug, conjugates, and acetylated metabolites); feces (small amounts)

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Older adult: Elderly patients with rheumatoid arthritis showed a prolonged plasma half-life for sulfasalazine, sulfapyridine, and their metabolites.

Acetylator status: SP metabolism is mediated by polymorphic enzymes such that 2 distinct populations of slow and fast metabolizer exist. Slow acetylator phenotype (~60% of white patients) display a prolonged plasma half-life and an accumulation of higher plasma levels of SP than fast acetylators.

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AE) United Arab Emirates: Salazopyrin;
  • (AR) Argentina: Azulfidine en-tabs | Flogostop;
  • (AT) Austria: Salazopyrin;
  • (AU) Australia: Pyralin | Salazopyrin;
  • (BD) Bangladesh: Reumazin | Salazine | Salazopyrin | Sulfacol | Sulfazin | Zulfidin;
  • (BE) Belgium: Salazopyrine | Salazopyrine ec;
  • (BG) Bulgaria: Salazopyrin | Sulfaenterin | Sulfasalazin;
  • (BR) Brazil: Azulfin | Salazoprin;
  • (CH) Switzerland: Salazopyrin | Salazopyrin en;
  • (CL) Chile: Azulfidine | Azulfidine EN | Eurozina Re;
  • (CO) Colombia: Rosulfan | Salazin | Salazopyrin | Sulfasalazina;
  • (CZ) Czech Republic: Salazopyrin en | Sulfasalazin;
  • (DE) Germany: Azulfidine | Colo-pleon | Pleon ra | Salazopyrina | Salazopyrine | Salazopyrine ra | Sulfasalazin | Sulfasalazin hexal | Sulfasalazin-Heyl;
  • (DK) Denmark: Sulfasalazin Medac;
  • (DO) Dominican Republic: Azulfidine;
  • (EC) Ecuador: Falazine;
  • (EE) Estonia: Salazopyrin | Sulfasalasin;
  • (EG) Egypt: Colosalazine ec | Salazo | Salazopyrin;
  • (ES) Spain: Salazopyrina;
  • (FI) Finland: Gastropyrin | Salazopyrin | Salopyr | Sulfasalazin Medac;
  • (FR) France: Salazopyrine;
  • (GB) United Kingdom: Salazopyrin | Sulazine | Sulphasalazine | Sulphasalazine aps | Sulphasalazine dc | Ucine;
  • (GR) Greece: Salopyrin;
  • (HK) Hong Kong: Pms-sulfasalazine | Salazopyrin | Saridine E | Sulphasalazine | Zopyrin;
  • (HR) Croatia: Salazopyrin en | Sulfasalazin | Sulfasalazin krka | Sulfasalzin Krka;
  • (HU) Hungary: Salazopyrin;
  • (ID) Indonesia: Lazafin | Sulcolon | Sulfitis;
  • (IE) Ireland: Salazopyrin;
  • (IL) Israel: Salazine | Salazopyrin;
  • (IN) India: Dalazosaz | Iwata | Ra zin | Saaz | Salazar | Salazin | Salazopyrin | Sazo | Sazo EN | Zemosal;
  • (IT) Italy: Salazopyrin en;
  • (JO) Jordan: Salazopyrin;
  • (JP) Japan: Asasurfan | Azulfidine EN | Eminapyrin | Lanofen | Safildine en | Salazopyrin | Salazosulfapyridine | Slama | Soaresin;
  • (KE) Kenya: Salazopyrin en;
  • (KR) Korea, Republic of: Azasulfan | Salazine | Salazopyrin | Salazopyrin en | Saludine | Sarazopyrin en | Saromeien | Sazopine | Seltasin | Zopyrin;
  • (KW) Kuwait: Salazopyrin | Salazopyrin en;
  • (LB) Lebanon: Salazopyrin | Salazopyrine EN;
  • (LT) Lithuania: Salazidin gr | Salazopyrin | Sulfasalazin;
  • (LU) Luxembourg: Salazopyrine;
  • (LV) Latvia: Pleon ra | Salazopyrin | Salazopyrin en | Sulfasalazin | Sulfasalazin Heyl;
  • (MA) Morocco: Salazopyrine;
  • (MX) Mexico: Andagun | Azulfidina | Lafasul;
  • (MY) Malaysia: Salazine | Sazo | Sazo EN;
  • (NL) Netherlands: Salazopyrin | Salazopyrine | Salazosulfapyr | Sulfasalazine Gf | Sulfasalazine Mylan;
  • (NO) Norway: Salazopyrin | Salazopyrin en | Sulfasalazine ec;
  • (NZ) New Zealand: Salazopyrin;
  • (PE) Peru: Azulfidine en 500 mg | Disalazin | Galazine | Lafazin | Sulfasalazina;
  • (PK) Pakistan: Salazine | Salazodine | Salazopyrin | Sulfasal;
  • (PL) Poland: Azulfidine | Salazopyrin | Salazopyrin en | Sulfasalazin;
  • (PR) Puerto Rico: Azulfidine | Azulfidine en-tabs | Sulfazine | Sulfazine ec;
  • (PT) Portugal: Salazopirina | Salazopirina en;
  • (RO) Romania: Sulfasalazin;
  • (RU) Russian Federation: Sulfasalazin | Sulfasalazine en | Sulfasalazine nativ;
  • (SA) Saudi Arabia: Pms-sulfasalazine | Salazopyrin | Salazopyrin en;
  • (SE) Sweden: Salazopyrin | Salazopyrin en | Salazopyrina | Sulfasalazin Medac;
  • (SG) Singapore: Pms-sulfasalazine | Salazopyrin | Salazopyrin en;
  • (SI) Slovenia: Sulfasalazin;
  • (SK) Slovakia: Sulfasalazin;
  • (TH) Thailand: Salazine | Salazopyrin | Saridine | Sulsa | Zaladine;
  • (TN) Tunisia: Salasopyrine | Salazopyrine;
  • (TR) Turkey: Salazopyrin;
  • (TW) Taiwan: Bomecon | Salazine | Salazopyrin;
  • (UA) Ukraine: Salazopyrin | Sulfasalazin;
  • (UY) Uruguay: Azulfidine | Salazodin;
  • (VE) Venezuela, Bolivarian Republic of: Azulfidine;
  • (ZA) South Africa: Salazopyrin;
  • (ZW) Zimbabwe: Salazopyrin
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