Sulfasalazine for Inflammatory Bowel Disease

Sulfasalazine is a prodrug of mesalazine joined to sulfapyridine. Colonic bacteria split it to release both parts. Mesalazine provides the anti-inflammatory effect in the colon, and sulfapyridine causes most adverse effects. It is a low-cost treatment for mild to moderate ulcerative colitis and for colonic Crohn disease, and it is also used in inflammatory arthritis.

Classification. Aminosalicylate; anti-inflammatory; conventional DMARD.

Mechanism. Cleaved by bacterial azoreductases in the colon into 5-aminosalicylic acid (anti-inflammatory) and sulfapyridine (absorbed systemically). Inhibits prostaglandin and leukotriene synthesis and inflammatory cell activity.

Pharmacodynamics. Onset in colitis over 2 to 4 weeks; maximum effect by 8 weeks.

Pharmacokinetics. About 10% to 30% of the parent drug is absorbed in the small bowel; the rest reaches the colon. Sulfapyridine is nearly fully absorbed and its half-life depends on acetylator status (slow acetylators have higher levels and more toxicity).

Metabolism. Sulfapyridine is acetylated by N-acetyltransferase; 5-aminosalicylic acid is mostly excreted in faeces.

Adult oral doses unless stated. Start low and increase gradually to reduce nausea.

Active ulcerative colitis, mild to moderate.

• Start 500 mg twice daily; increase by 500 mg daily each week.

• Usual treatment dose 2 to 4 g daily in four divided doses.

• Maximum 6 g daily in severe disease (limited by adverse effects).

• Continue until remission, usually 4 to 8 weeks.

Maintenance of remission in ulcerative colitis. 2 g daily in two divided doses (1 g twice daily); some patients need 3 g.

Crohn disease (colonic). 3 to 6 g daily in divided doses; less effective than for ulcerative colitis, and ineffective in small bowel disease.

Rheumatoid arthritis and spondyloarthritis (reference). Enteric-coated 500 mg daily, increased weekly to 1 g twice daily.

Children.

• Active disease: 40 to 60 mg/kg daily in divided doses.

• Maintenance: 20 to 30 mg/kg daily.

• Maximum 4 g daily.

• Under 2 years: contraindicated.

Kidney and liver adjustment.

• Kidney impairment: use with caution; reduce the dose and monitor if GFR is under 30 mL/min.

• Liver impairment: avoid in severe impairment.

Contraindications.

• Hypersensitivity to sulfonamides or salicylates.

• Porphyria; severe liver or kidney impairment.

• Children under 2 years.

• Intestinal or urinary obstruction.

Common adverse effects. Nausea, vomiting, anorexia, headache, rash, abdominal discomfort, orange discolouration of urine and skin, and reversible oligospermia with male infertility.

Serious adverse effects.

• Blood dyscrasias: agranulocytosis, aplastic anaemia, haemolytic anaemia (G6PD deficiency), thrombocytopenia, macrocytosis.

• Hepatotoxicity, including fulminant hepatitis.

• Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS.

• Interstitial nephritis; pneumonitis and pulmonary eosinophilia.

• Lupus-like syndrome.

Major interactions.

• Azathioprine and mercaptopurine: additive myelosuppression.

• Methotrexate: additive toxicity; folate deficiency.

• Digoxin: reduced absorption.

• Warfarin: effect may increase; monitor INR.

• Sulfonylureas: increased hypoglycaemia risk.

• Folic acid antagonists (trimethoprim): additive folate depletion.

• Cyclosporine: reduced levels.

Special groups.

• Pregnancy: acceptable; give folic acid 5 mg daily before conception and in pregnancy.

• Breastfeeding: low levels in milk; compatible in healthy full-term infants; avoid in preterm or jaundiced infants or those with G6PD deficiency.

• Children: dose by weight under specialist care.

• Older adults: monitor blood counts.

• G6PD deficiency: risk of haemolysis; test before starting where prevalent.

• Kidney impairment: reduce the dose.

• Liver impairment: avoid.

• Regional: low cost and widely available; the most accessible aminosalicylate in East Africa.

Formulations. Tablets 500 mg; enteric-coated tablets 500 mg; oral suspension 250 mg in 5 mL.

Administration.

• Take after meals with a full glass of water to lessen nausea.

• Swallow enteric-coated tablets whole.

• Maintain fluid intake of at least 1.5 to 2 litres daily to prevent crystalluria.

• Advise on harmless orange colouration of urine; soft contact lenses may stain.

Baseline. Full blood count, liver and kidney function, G6PD status where indicated, and folate level.

Monitoring.

• Full blood count and liver tests every 2 weeks for the first 3 months, then monthly for 3 months, then every 3 months.

• Kidney function every 6 months.

• Disease activity and symptoms.

• Advise patients to report sore throat, fever, bruising or rash at once.

Therapeutic drug monitoring. Not applicable.

Stopping. No taper is needed. Stop for blood dyscrasia, hepatitis, severe rash or hypersensitivity.

Referral and escalation. Refer for failure to respond within 4 to 8 weeks, intolerance, or acute severe colitis requiring admission. Surveillance colonoscopy after 8 years of colitis.