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Drug Reference

sulfasalazine

Aminosalicylate anti-inflammatory· Brands: Salazopyrin, Salazopyrin EN-Tabs, Azulfidine, SulfazinePOPR

Mechanism of action
Sulfasalazine is a prodrug that links 5-aminosalicylic acid (mesalazine) to sulfapyridine by an azo bond. About 20 to 30% of an oral dose is absorbed unchanged from the small intestine; the remainder reaches the colon, where bacterial azo reductases split the bond and release the two moieties. In inflammatory bowel disease the 5-aminosalicylic acid moiety is the active component. It acts topically on colonic mucosa: it inhibits cyclo-oxygenase and lipoxygenase to reduce prostaglandin and leukotriene synthesis, scavenges reactive oxygen species, blocks nuclear factor kappa B activation and pro-inflammatory cytokine release, and reduces neutrophil chemotaxis and adhesion. In rheumatoid arthritis and related rheumatic disease the antirheumatic effect is attributed largely to sulfapyridine, whose mechanism is not fully defined but is thought to involve immunomodulation and reduced cytokine signalling; the 5-aminosalicylic acid moiety contributes little there because it is poorly absorbed. Sulfapyridine also weakly inhibits folate metabolism, which may explain the macrocytosis seen in some patients.
Pharmacokinetics
After oral administration, sulfasalazine is about 20 to 30% absorbed from the small intestine; the unabsorbed fraction passes to the colon, where colonic bacteria cleave the azo bond. The absorbed intact drug undergoes enterohepatic circulation and is largely excreted unchanged in bile and urine. Sulfapyridine is well absorbed from the colon, about 70% protein bound, and metabolised mainly by N-acetyltransferase 2 (NAT2) and by ring hydroxylation. Acetylation phenotype matters clinically: slow acetylators reach higher plasma sulfapyridine concentrations and report more dose-related adverse effects. Sulfapyridine has a plasma half-life of roughly 6 to 10 hours, prolonged in slow acetylators and in renal impairment. 5-Aminosalicylic acid is only partly absorbed from the colon and is acetylated to acetyl-5-ASA; most is excreted in faeces, and the absorbed portion is cleared renally. Peak plasma concentrations occur about 3 to 12 hours after a dose, later with enteric-coated tablets. Sulfapyridine crosses the placenta and appears in breast milk. Steady state is reached in about 2 to 5 days with immediate-release tablets and up to a week with enteric-coated formulations, while full clinical benefit in rheumatic disease takes 6 to 12 weeks.
Indications & dosing

Ulcerative colitis, active mild to moderate disease

Start low and titrate to response. Enteric-coated or modified-release tablets reduce upper gut intolerance. Allow several weeks for full effect. Teaching example only.

  • adult · PO: 500–1000 mg QDS · Start low and titrate to response. Enteric-coated or modified-release tablets reduce upper gut intolerance. Allow several weeks for full effect. Teaching example only.

Ulcerative colitis, maintenance of remission

Usual maintenance 2 g daily in divided doses. Stop if no benefit after an adequate trial. Folic acid 5 mg daily is commonly co-prescribed because sulfasalazine inhibits folate absorption.

  • adult · PO: 500–1000 mg QDS · Usual maintenance 2 g daily in divided doses. Stop if no benefit after an adequate trial. Folic acid 5 mg daily is commonly co-prescribed because sulfasalazine inhibits folate absorption.

Rheumatoid arthritis

Begin 500 mg once daily, increase weekly as tolerated to 2 to 3 g daily. Full benefit may take up to 3 months. Monitor FBC, renal and liver function. Not a monotherapy of first choice in many current guidelines.

  • adult · PO: 500–1000 mg BD · Begin 500 mg once daily, increase weekly as tolerated to 2 to 3 g daily. Full benefit may take up to 3 months. Monitor FBC, renal and liver function. Not a monotherapy of first choice in many current guidelines.

Juvenile idiopathic arthritisoff-label

Typical total 30 to 50 mg/kg daily in divided doses, capped at 2 g daily. Licensing varies between regions. Specialist paediatric rheumatology supervision. Monitor blood counts and liver function.

  • pediatric · PO: 15–25 mg/kg/dose BD · Typical total 30 to 50 mg/kg daily in divided doses, capped at 2 g daily. Licensing varies between regions. Specialist paediatric rheumatology supervision. Monitor blood counts and liver function.

Ulcerative colitis in childrenoff-label

Typical total 40 to 60 mg/kg daily in divided doses, capped at 4 g daily for induction and lower for maintenance. Age and regional licensing restrictions apply.

  • pediatric · PO: 10–15 mg/kg/dose QDS · Typical total 40 to 60 mg/kg daily in divided doses, capped at 4 g daily for induction and lower for maintenance. Age and regional licensing restrictions apply.

Ankylosing spondylitis and other spondyloarthropathiesoff-label

Titrate from 500 mg daily to 2 to 3 g daily. Evidence of benefit is mainly for peripheral joint disease; limited effect on axial symptoms. Off-label in some regions.

  • adult · PO: 500–1000 mg BD · Titrate from 500 mg daily to 2 to 3 g daily. Evidence of benefit is mainly for peripheral joint disease; limited effect on axial symptoms. Off-label in some regions.
Contraindications & precautions
  • Hypersensitivity to sulfasalazine, other sulfonamides or salicylates · Includes previous anaphylaxis, DRESS, Stevens-Johnson syndrome or other severe cutaneous reaction to any sulfonamide or salicylate. Cross-reactivity between sulfonamides is a class concern.
  • Acute porphyria · Sulfasalazine is regarded as unsafe in acute porphyria because it may precipitate an attack.
  • Infants under 2 months of age · Sulfonamide component can displace bilirubin from albumin and risk kernicterus. Use in older infants and children follows specialist paediatric protocols.
  • Severe renal impairment · Reduced clearance increases systemic exposure and the risk of crystalluria and blood dyscrasias. Seek specialist advice and monitor renal function closely if use is judged necessary.
  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency · Risk of haemolytic anaemia. Test before starting where ancestry or history suggests deficiency; avoid unless benefit outweighs risk.
  • Pre-existing blood dyscrasias or marked anaemia · Sulfasalazine can cause leucopenia, agranulocytosis, aplastic anaemia and megaloblastic anaemia; baseline full blood count is required and monitoring intervals are set locally.
  • Breastfeeding a premature, jaundiced or G6PD-deficient infant · Small amounts pass into breast milk. Avoid in these infant groups because of kernicterus and haemolysis risk. In healthy term infants, use only after weighing benefit and risk.
  • Check baseline full blood count, urea and electrolytes, liver function tests and, where relevant, G6PD status before starting, then repeat monitoring as local protocols advise, particularly in the first months of treatment.
  • Advise patients to report promptly sore throat, fever, mouth ulcers, rash, unexplained bruising or bleeding, or jaundice, and to stop the drug and seek urgent review since these may signal blood dyscrasia or hepatotoxicity.
  • Take with or after food to reduce nausea, and maintain a good fluid intake to limit crystalluria. Enteric-coated tablets must be swallowed whole, not crushed or chewed.
  • Withdraw immediately and do not rechallenge if a severe cutaneous reaction, pulmonary hypersensitivity or acute hepatitis is suspected.
  • Warn men about reversible oligospermia and reduced fertility, and give folic acid supplementation where indicated because sulfasalazine impairs folate absorption.
  • Use in pregnancy only when clearly needed with folic acid cover, and avoid in infants under 2 months and in breastfeeding of premature, jaundiced or G6PD-deficient infants.
Adverse effects
  • Nausea, vomiting, anorexia, dyspepsia and abdominal discomfort
  • Headache
  • Rash, urticaria and pruritus
  • Yellow-orange discolouration of urine, skin and soft contact lenses
  • Reversible oligospermia and reduced male fertility
  • Blood dyscrasias: leucopenia, agranulocytosis, thrombocytopenia, aplastic anaemia, megaloblastic anaemiaserious
  • Haemolytic anaemia, particularly in G6PD deficiencyserious
  • Hepatotoxicity, including hepatitis and hepatic failureserious
  • Pulmonary hypersensitivity: eosinophilic pneumonitis, fibrosing alveolitisserious
  • Severe cutaneous adverse reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESSserious
Interactions
  • warfarinmajorIf co-prescription is necessary, monitor INR frequently, especially after starting or stopping sulfasalazine. Consider reducing the warfarin dose to maintain the target INR. Advise the patient to report signs of bleeding such as bruising, black stools, or blood in urine. Alternative therapy with less interaction potential may be considered.
Renal & hepatic adjustment
  • eGFR 60+: No specific dose adjustment is needed. Monitor renal function, full blood count and liver function as per local protocol.
  • eGFR 30–59: No specific dose adjustment is established. Use with caution and monitor renal function and for sulfasalazine toxicity because active metabolites may accumulate. Consider an alternative if renal function declines.
  • eGFR 0–29: Avoid in severe renal impairment. There are no established dose adjustments, and accumulation of sulfapyridine and its metabolites increases the risk of toxicity. (avoid)
  • Hepatic impairment (mild): No specific dose adjustment is established. Use with caution and monitor liver function tests and for adverse effects.
  • Hepatic impairment (moderate): Use with caution, consider a lower starting dose and slower titration, and monitor liver function tests closely. Specialist advice may be needed.
  • Hepatic impairment (severe): Avoid in severe hepatic impairment because of the risk of altered metabolism and increased toxicity. No established dose adjustment exists. (avoid)
Monitoring, pregnancy & toxicity
  • Full blood count and leucocyte differential · Baseline, then regularly; often every 2 to 4 weeks for the first 3 months, then at least 3-monthly, following local protocol.
  • Liver function tests · Baseline and periodically, especially during the first 3 months and if symptoms suggest hepatotoxicity.
  • Renal function (eGFR, creatinine, urea) · Baseline and periodically; more often in existing renal impairment or if dehydration or other nephrotoxic drugs are used.
  • Symptoms of blood dyscrasia or hypersensitivity (sore throat, fever, rash, mouth ulcers, bruising, bleeding) · At every review; arrange urgent full blood count if any occur.
  • Disease activity and adherence · At each clinical review to confirm continued benefit and appropriate dose.
  • Methaemoglobin or haemolysis if clinically suspected · If cyanosis, unexplained dyspnoea, anaemia or dark urine occurs.
  • Pregnancy: Sulfasalazine is generally considered compatible with pregnancy and is often continued to maintain control of inflammatory bowel disease or inflammatory arthritis. Use the lowest effective dose, supplement folic acid as advised locally, and monitor for disease flare and adverse effects. Specialist review is recommended before or during pregnancy. Practice varies by region and formulary.
  • Toxicity: Acute overdose can cause nausea, vomiting, abdominal pain, dizziness, drowsiness, headache, and, less commonly, haematuria or crystalluria. · There is no specific antidote. Give supportive care, consider activated charcoal if presentation is within 1 to 2 hours and the airway is protected, ensure adequate hydration, and monitor renal function, full blood count, liver function and methaemoglobin. Seek toxicology advice.
  • Toxicity: Methaemoglobinaemia may cause cyanosis, dyspnoea, tachycardia, confusion or dark brown blood. · Stop sulfasalazine, give oxygen, and consider methylene blue only for severe or symptomatic cases and if G6PD deficiency has been excluded. Seek toxicology advice.
  • Toxicity: Haematological toxicity including agranulocytosis, neutropenia, thrombocytopenia, haemolytic anaemia or megaloblastic anaemia may present with fever, sore throat, mouth ulcers, bruising, bleeding, pallor or fatigue. · Stop the drug immediately, obtain urgent full blood count and differential, and provide supportive care. Do not rechallenge after a severe blood dyscrasia. Seek haematology advice.
  • Toxicity: Hypersensitivity reactions include rash, fever, eosinophilia, hepatitis, pneumonitis or a lupus-like syndrome. · Stop the drug, assess severity, treat supportively, and consider corticosteroids for severe systemic reactions under specialist guidance. Avoid rechallenge after a serious hypersensitivity reaction.
Clinical notes
Uses include induction and maintenance of remission in mild to moderate ulcerative colitis, selected Crohn's colitis, and disease-modifying therapy in rheumatoid arthritis, juvenile idiopathic arthritis and peripheral spondyloarthritis. A teaching example: in rheumatoid arthritis, start 500 mg once daily with food and increase stepwise over about four weeks to 2 to 3 g daily in divided doses; in ulcerative colitis, 1 to 2 g four times daily for active disease, and 500 mg four times daily to 2 g daily for maintenance, with a maximum of 4 g daily. Doses vary widely between countries and formularies and must be checked locally. Give with food and plenty of fluid, and swallow enteric-coated tablets whole. Before starting, record full blood count, renal and liver function, and consider G6PD status. Monitoring schedules differ by region; a common approach is blood count, renal and liver function at baseline, every 2 to 4 weeks for the first three months, then at longer intervals. Advise patients to stop and seek urgent advice for sore throat, fever, rash, mouth ulcers, unexplained bruising or bleeding, jaundice or dark urine. Common effects are nausea, diarrhoea, headache and rash. Serious effects include agranulocytosis, aplastic anaemia, hepatotoxicity, interstitial nephritis, pulmonary reactions and DRESS. Reversible oligospermia and male infertility occur and usually resolve within about three months of stopping. Avoid in sulfonamide or salicylate hypersensitivity, severe renal or hepatic impairment, and porphyria; use with caution in G6PD deficiency. Interactions include increased methotrexate and thiopurine toxicity, reduced digoxin and folate absorption, and possible potentiation of warfarin. It is generally considered compatible with pregnancy and breastfeeding, with folate supplementation advised.

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BNF; local formulary; current manufacturer prescribing information (SmPC or package insert); national DMARD monitoring guidance