(sul fa SAL a zeen)
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Azulfidine: 500 mg [scored]
Generic: 500 mg
Tablet Delayed Release, Oral:
Azulfidine EN-tabs: 500 mg
Generic: 500 mg
Brand Names: U.S.
- Azulfidine EN-tabs
- 5-Aminosalicylic Acid Derivative
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
Oral: 10% to 15% as unchanged drug from the small intestine; upon administration, the drug is split into sulfapyridine and 5-aminosalicylic acid (5-ASA) in the colon
Vd: Sulfasalazine ~7.5 L
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
Primarily urine (as unchanged drug, conjugates, and acetylated metabolites); feces (small amounts)
Onset of Action
JIA: Minimum trial of 3 months is necessary; Ulcerative colitis: >3 to 4 weeks
Time to Peak
Sulfasalazine: 3 to 12 hours (mean: 6 hours); Serum sulfapyridine (active metabolite): Within 6 to 24 hours
Sulfasalazine: 5.7 to 10 hours (prolonged in elderly); Sulfapyridine: 14.8 hours (slow acetylators) and 10.4 hours (fast acetylators)
Sulfasalazine: >99% to albumin; Sulfapyridine: ~70% to albumin; Acetylsulfapyridine (AcSP): ~90% to plasma proteins
Special Populations: Elderly
Elderly patients with rheumatoid arthritis showed a prolonged plasma half-life for sulfasalazine, sulfinpyridine, and their metabolites. The clinical impact of this is unknown.
Special Populations Note
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. The clinical implications of this are unclear; however, slow acetylators may experience a higher incidence of adverse reactions.
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 nonsteroidal anti-inflammatory drugs (NSAIDs).
Rheumatoid arthritis: Delayed release: Treatment of patients with rheumatoid arthritis who have responded inadequately to salicylates or other NSAIDs.
Ulcerative colitis: 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.
Canadian labeling: Adjunctive therapy in severe ulcerative colitis, distal ulcerative colitis or proctitis, and Crohn disease; enteric coated tablets are also used for rheumatoid arthritis unsuccessfully treated with first-line therapy
Ankylosing spondylitis, Crohn disease, psoriasis, psoriatic arthritis
Hypersensitivity to sulfasalazine, sulfa drugs, salicylates, or any component of the formulation; intestinal or urinary obstruction; porphyria
Note: Although the FDA approved product labeling states this medication is contraindicated with other sulfonamide-containing drug classes, the scientific basis of this statement has been challenged. See “Warnings/Precautions” for more detail.
Canadian labeling: Additional contraindications (not in U.S. 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
Rheumatoid arthritis: Oral: Enteric coated tablet: Initial: 0.5 to 1 g daily; increase weekly to maintenance dose of 2 g daily in 2 divided doses; maximum: 3 g daily (if response to 2 g daily is inadequate after 12 weeks of treatment)
Ulcerative colitis: Oral:
Initial: 3 to 4 g daily in evenly divided doses at ≤8-hour intervals; may initiate therapy with 1 to 2 g daily to reduce GI intolerance. Note: American College of Gastroenterology guideline recommendations: Titrate to 4 to 6 g daily in 4 divided doses (Kornbluth, 2010).
Maintenance dose: 2 g daily in evenly divided doses at ≤8-hour intervals; if GI intolerance occurs reduce dosage by 50% and gradually increase to target dose after several days. If GI intolerance persists, stop drug for 5 to 7 days and reintroduce at a lower daily dose.
Crohn disease, active mild/moderate, ileocolonic or colonic disease (off-label use): Oral: 3 to 6 g daily in divided doses (Lichtenstein, 2009)
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 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
Rheumatoid arthritis: Oral: Enteric coated tablet: Initial: 500 mg daily; increase dose weekly by 500 mg (total daily dose given in 2 divided doses) to maintenance dose of 1 g twice daily; if inadequate response to 1 g twice daily after 2 months, may increase dose to 3 g daily. Clinical improvement usually observed 1 to 2 months after initiating therapy. Concurrent use of analgesics and/or anti-inflammatory agents is recommended until therapeutic effect of sulfasalazine is observed.
Ulcerative colitis, inflammatory bowel disease, Crohn disease: Oral: Note: Consider dose reduction or use of enteric coated tablet in patients experiencing adverse gastrointestinal effects with uncoated tablet.
Acute attacks: Severe: 1 to 2 g 3 to 4 times daily; mild to moderate: 1 g 3 to 4 times daily
Maintenance of remission: 1 g 2 to 3 times daily; continue dose indefinitely unless patient experiences adverse effects. In the event patient condition worsens, increase dose to 1 to 2 g 3 to 4 times daily.
Refer to adult dosing.
Juvenile rheumatoid arthritis: Children ≥6 years: Oral: Enteric coated tablet: 30 to 50 mg/kg/day in 2 divided doses; Initial: Begin with 1/4 to 1/3 of expected maintenance dose; increase weekly; maximum: 2 g daily typically
Ulcerative colitis: Children ≥6 years: Oral: Initial: 40 to 60 mg/kg/day in 3 to 6 divided doses; maintenance dose: 30 mg/kg/day in 4 divided doses
Desensitization regimen: Refer to adult dosing for patients who may be sensitive to treatment.
Ulcerative colitis, inflammatory bowel disease, Crohn disease: Oral: Note: Consider dose reduction or use of enteric coated tablet in patients experiencing adverse gastrointestinal effects with uncoated tablet.
Body weight 25 to <35 kg: 500 mg 3 times daily
Body weight 35 to 50 kg: 1 g 2 to 3 times daily
Maintenance of remission:
Body weight 25 to <35 kg: 500 mg 2 times daily
Body weight 35 to 50 kg: 500 mg 2 to 3 times daily
Dosing: Renal Impairment
There are no dosage adjustments provided in the manufacturer's labeling; use with extreme caution. Canadian labeling contraindicates use in severe impairment (GFR <30 mL/minute/1.73 m2).
Dosing: Hepatic Impairment
There are no dosage adjustments provided in the manufacturer's labeling; use with extreme caution. Canadian labeling contraindicates use in severe impairment.
A 100 mg/mL oral suspension may be made with tablets. Place twenty 500 mg tablets in a mortar and add a small amount of a 1:1 mixture of Ora-Sweet® and Ora-Plus® to cover the tablets. Let soak for 20-30 minutes. Crush the tablets and mix to a uniform paste; mix while adding the vehicle in equal proportions to almost 100 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add sufficient quantity of vehicle to make 100 mL. Label "shake well". Stable 91 days under refrigeration or at room temperature.Lingertat-Walsh K, Walker SE, Law S, et al, "Stability of Sulfasalazine Oral Suspension," Can J Hosp Pharm, 2006, 59(4):194-200.
Tablets should be administered in evenly divided doses, preferably after meals. Enteric coated tablets should be swallowed whole.
Sulfasalazine impairs folate absorption. Adequate fluid intake is required to prevent crystalluria and stone formation.
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Cardiac Glycosides: 5-ASA Derivatives may decrease the serum concentration of Cardiac Glycosides. Monitor therapy
Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Monitor therapy
Eltrombopag: May increase the serum concentration of BCRP/ABCG2 Substrates. Monitor therapy
Folic Acid: SulfaSALAzine may decrease the serum concentration of Folic Acid. Monitor therapy
Heparin: 5-ASA Derivatives may enhance the adverse/toxic effect of Heparin. Specifically, the risk for bleeding/bruising may be increased. Monitor therapy
Heparin (Low Molecular Weight): 5-ASA Derivatives may enhance the adverse/toxic effect of Heparin (Low Molecular Weight). Specifically, the risk for bleeding/bruising may be increased. Monitor therapy
Methotrexate: SulfaSALAzine may enhance the hepatotoxic effect of Methotrexate. Monitor therapy
Methylfolate: SulfaSALAzine may decrease the serum concentration of Methylfolate. 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. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when nitric oxide is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine. Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May enhance the nephrotoxic effect of 5-ASA Derivatives. Monitor therapy
Osimertinib: May increase the serum concentration of BCRP/ABCG2 Substrates. 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. Monitor therapy
Regorafenib: May increase the serum concentration of BCRP/ABCG2 Substrates. Monitor therapy
Rolapitant: May increase the serum concentration of BCRP/ABCG2 Substrates. 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. 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. Monitor therapy
Teriflunomide: May increase the serum concentration of BCRP/ABCG2 Substrates. Monitor therapy
Tetracaine (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Monitor therapy
Thiopurine Analogs: 5-ASA Derivatives may decrease the metabolism of Thiopurine Analogs. Monitor therapy
Varicella Virus-Containing Vaccines: 5-ASA 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. Consider therapy modification
Reports of possible interference with measurements, by liquid chromatography, of urinary normetanephrine causing a false-positive test result have been observed in patients exposed to sulfasalazine or its metabolite, mesalamine/mesalazine.
Central nervous system: Headache (RA 9%)
Dermatologic: Skin rash (RA 13%)
Gastrointestinal: Nausea (RA 19%), dyspepsia (RA 13%), anorexia, gastric distress, vomiting
Genitourinary: Oligospermia (reversible)
1% to 10%:
Central nervous system: Dizziness
Dermatologic: Pruritus (RA 4%), urticaria
Gastrointestinal: Abdominal pain (RA 8%), stomatitis (RA 4%)
Hematologic & oncologic: Leukopenia (RA 3%), thrombocytopenia (RA 1%), Heinz body anemia, hemolytic anemia
Hepatic: Abnormal hepatic function tests (RA 4%)
<1% (limited to important or life-threatening; includes reactions reported with mesalamine or other sulfonamides): Agranulocytosis, alopecia, anaphylaxis, angioedema, aplastic anemia, arthralgia, cauda equina syndrome, cholestatic hepatitis, cholestatic jaundice, conjunctival injection, crystalluria, depression, diarrhea, DRESS syndrome, drowsiness, eosinophilia, exfoliative dermatitis, folate deficiency, fulminant hepatitis, Guillain-Barré syndrome, hallucination, hearing loss, hematologic abnormality, hematologic disease (pseudomononucleosis), hematuria, hemolytic-uremic syndrome, hepatic cirrhosis, hepatic failure, hepatic necrosis, hepatitis, hepatotoxicity (idiosyncratic) (Chalasani, 2014), hypoglycemia, hypoprothrombinemia, injected sclera, insomnia, interstitial nephritis, interstitial pulmonary disease, jaundice, Kawasaki syndrome (single case report), lupus-like syndrome, megaloblastic anemia, meningitis, methemoglobinemia, myelitis, myelodysplastic syndrome, myocarditis (allergic), nephritis, nephrolithiasis, nephrotic syndrome, neutropenia (congenital), neutropenic enterocolitis, oropharyngeal pain, pancreatitis, parapsoriasis varioliformis acuta, periarteritis nodosa, pericarditis, periorbital edema, peripheral neuropathy, pleurisy, pneumonia, pneumonitis, proteinuria, pulmonary alveolitis, purpura, renal disease (acute), rhabdomyolysis, seizure, sepsis, serum sickness-like reaction (children with JRA have frequent and severe reaction), skin discoloration, skin photosensitivity, Stevens-Johnson syndrome, thyroid function impairment, toxic epidermal necrolysis, toxic nephrosis, urine discoloration, vasculitis
Concerns related to adverse effects:
• Blood dyscrasias: Fatalities associated with severe reactions including agranulocytosis, aplastic anemia, and other blood dyscrasias have occurred; discontinue use at first sign of rash or signs of serious adverse reactions. The presence of clinical signs such as sore throat, fever, pallor, or purpura may be indicative of a serious blood disorder. Use with extreme caution in patients with blood dyscrasias; monitor complete blood counts frequently.
• CNS effects: Deaths from irreversible neuromuscular and central nervous system changes have been reported.
• Dermatologic reactions: Severe skin reactions (some fatal), including Stevens-Johnson syndrome (SJS), exfoliative dermatitis, and toxic epidermal necrolysis (TEN) have occurred with sulfonamides (including sulfasalazine), most commonly during the first month of treatment; discontinue use at first sign of skin rash, mucosal lesions, or any other sign of dermatologic toxicity.
• Fibrosing alveolitis: Deaths from fibrosing alveolitis have been reported.
• Folate deficiency: May decrease folic acid absorption.
• GI effects: Nausea, vomiting, and abdominal discomfort commonly occur; titration of dose and/or using the enteric coated formulation may decrease GI adverse effects.
• Hepatic necrosis: Fatalities associated with hepatic damage have occurred; discontinue use at first sign of jaundice or hepatotoxicity.
• Hypersensitivity reactions: Severe and life-threatening reactions, including drug rash with eosinophilia and systemic symptoms (DRESS) syndrome have been reported. Fever or lymphadenopathy may be present prior to rash development. Other severe hypersensitivity reactions may include internal organ involvement, such as hepatitis, nephritis, myocarditis, mononucleosis-like syndrome, hematologic abnormalities (including hematophagic histiocytosis), and/or pneumonitis including eosinophilic infiltration. Discontinue treatment for severe reactions and evaluate promptly.
• 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.
• Oligospermia: In males, oligospermia (rare) and infertility has been reported; usually reverses upon discontinuation.
• 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 (Stevens-Johnson syndrome/TEN), some clinicians choose to avoid exposure to these classes.
• Allergies/asthma: Use with caution in patients with severe allergies or bronchial asthma.
• G6PD deficiency: Use with caution in patients with G6PD deficiency; hemolytic anemia may occur.
• Hepatic impairment: Use with extreme caution in patients with impaired hepatic function. Canadian labeling contraindicates use in severe impairment.
• Renal impairment: Use with extreme caution in patients with renal impairment. Canadian labeling contraindicates use in severe impairment (GFR <30 mL/minute/1.73 m2). Maintain adequate hydration to prevent crystalluria and stone formation.
• 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:
• Enteric-coated tablets: Discontinue if tablets are noted to pass without disintegrating.
CBC with differential and liver function tests (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/liver function tests (Canadian labeling also recommends renal function tests [including urinalysis] prior to therapy and monthly for first 3 months); stool frequency; signs of infection, dermatologic toxicity, or hypersensitivity reactions
Pregnancy Risk Factor
Adverse events have not been observed in animal reproduction studies. Sulfasalazine and sulfapyridine cross the placenta; a potential for kernicterus in the newborn exists. Agranulocytosis was noted in an infant following maternal use of sulfasalazine during pregnancy. Additionally, cases of neural tube defects have been reported (causation undetermined); sulfasalazine is known to inhibit the absorption and metabolism of folic acid and may diminish the effects of folic acid supplementation. 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 or ulcerative colitis. When treatment for inflammatory bowel disease is needed during pregnancy, sulfasalazine may be used, although supplementation with folic acid is recommended (Habal, 2012; Mahadevan, 2009; Mottet, 2007).
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience heartburn or lack of appetite. Have patient report immediately to prescriber signs of infection, signs of a severe sulfonamide reaction (rash; red, swollen, blistered, or peeling skin; red or irritated eyes; sores in your mouth, throat, nose, or eyes; fever, chills, or sore throat; cough that is new or worse; loss of strength and energy; any bruising or bleeding; or signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), tablet shell in stool, severe loss of strength and energy, severe abdominal pain, bloody diarrhea, severe nausea, severe vomiting, skin discoloration, angina, arrhythmia, urinary retention, change in amount of urine passed, enlarged lymph nodes, hearing loss, depression, muscle pain, burning or numbness feeling, seizures, severe dizziness, severe headache, shortness of breath, abnormal gait, bruising, bleeding, pale skin, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.