Mesalazine

Mesalazine (5-aminosalicylic acid) is the first-line anti-inflammatory treatment for mild to moderate ulcerative colitis and is used to maintain remission. Its benefit in Crohn disease is limited. It acts locally on the gut lining, and the formulation determines where it is released.

Classification. Aminosalicylate; anti-inflammatory for inflammatory bowel disease.

Mechanism. Inhibits cyclo-oxygenase and lipoxygenase pathways, reducing prostaglandin and leukotriene production. It also scavenges reactive oxygen species and activates the PPAR-gamma nuclear receptor and inhibits NF-kappa B signalling.

Pharmacodynamics. Response in active ulcerative colitis begins within 2 to 4 weeks, with maximum effect by 8 weeks. Maintenance reduces relapse and may lower colorectal cancer risk.

Pharmacokinetics. Oral free mesalazine is absorbed rapidly in the upper gut, so formulations delay or time release to reach the colon. About 20% to 30% of delayed-release doses is absorbed; the rest acts locally. Half-life 1 hour for free drug; the acetylated metabolite is longer.

Metabolism. Acetylated by N-acetyltransferase in the gut wall and liver to inactive N-acetyl-5-aminosalicylic acid; excreted in urine and faeces.

Adult doses unless stated.

Mild to moderate ulcerative colitis, active (oral).

• 2.4 to 4.8 g daily as a single daily dose or divided twice to three times daily, for 8 weeks.

• Use the higher dose (4.8 g) for moderate disease or when response is poor.

Distal ulcerative colitis or proctitis, active (rectal).

• Proctitis: 1 g suppository once daily at night, for 4 to 6 weeks.

• Proctosigmoiditis: 1 g enema or foam once daily at night, for 4 to 6 weeks.

• Combining oral (2.4 g) and rectal therapy is more effective than either alone.

Maintenance of remission in ulcerative colitis.

• Oral 1.2 to 2.4 g daily, usually once daily.

• Rectal 1 g two to three times weekly for distal disease.

Crohn disease. Limited benefit; oral 2.4 to 4 g daily may be tried for mild ileocolonic disease, or after surgery, although other agents are preferred.

Children.

• Active disease: 30 to 50 mg/kg daily in two or three divided doses, maximum 4 g daily.

• Maintenance: 15 to 30 mg/kg daily, maximum 2 g daily.

• Use specialist-directed doses.

Kidney and liver adjustment.

• Kidney impairment: avoid in moderate to severe impairment (GFR under 30 mL/min); use with caution if GFR is 30 to 60 mL/min.

• Liver impairment: avoid in severe impairment.

Contraindications. Hypersensitivity to salicylates or aminosalicylates; severe kidney impairment (GFR under 30 mL/min); severe liver impairment; active peptic ulcer in some labels; children under 2 years for some preparations.

Common adverse effects. Headache, nausea, abdominal pain, diarrhoea, flatulence, rash and dizziness.

Serious adverse effects.

• Interstitial nephritis and kidney impairment, sometimes delayed.

• Paradoxical worsening of colitis, with bloody diarrhoea, fever and cramp, after starting.

• Pancreatitis, hepatitis and cholestasis.

• Blood dyscrasias: neutropenia, agranulocytosis, aplastic anaemia and thrombocytopenia.

• Pericarditis and myocarditis; lupus-like syndrome; drug rash with eosinophilia (rare).

Major interactions.

• Azathioprine and mercaptopurine: increased risk of leukopenia and myelosuppression; monitor blood counts.

• Nephrotoxic drugs (NSAIDs, aminoglycosides): increased kidney risk.

• Warfarin: effect may be slightly reduced; monitor INR.

• Lactulose and drugs lowering colonic pH may impair release of pH-dependent formulations.

• Digoxin: absorption may be reduced.

Special groups.

• Pregnancy: continue if needed to control disease; relapse is a greater risk than the drug. Supplement folic acid 5 mg daily where sulfasalazine is used; for mesalazine, usual folic acid 400 micrograms.

• Breastfeeding: low levels in milk; compatible; watch for infant diarrhoea.

• Children: dose by weight under specialist care.

• Older adults: monitor kidney function.

• Kidney impairment: avoid in moderate to severe impairment.

• Liver impairment: avoid in severe impairment.

• Regional: availability varies and may be limited in East Africa; sulfasalazine is a cheaper alternative for ulcerative colitis.

Formulations. Delayed-release tablets 400 mg, 800 mg and 1.2 g; prolonged-release tablets 500 mg and 1 g; granules 1 g and 2 g sachets; suppositories 500 mg and 1 g; enema 1 g and 4 g in 60 to 100 mL; foam enema 1 g in each dose.

Administration.

• Swallow tablets whole; do not crush or chew modified-release forms.

• Granules: place on the tongue and swallow with water, without chewing.

• Take with or without food, once daily dosing is as effective as divided dosing.

• Rectal products: empty the bowel first; insert at bedtime and lie on the left side; retain overnight.

• Different brands release at different sites and are not interchangeable; keep the same product.

Baseline. Kidney function, full blood count and liver function; urinalysis.

Monitoring.

• Kidney function (creatinine, eGFR) before treatment, at 3 months, then every 6 to 12 months for life.

• Full blood count and liver tests if on thiopurines or if symptoms arise.

• Disease activity: stool frequency, bleeding, faecal calprotectin.

• Urine protein.

Therapeutic drug monitoring. Not applicable.

Stopping. No taper is needed. Stop for kidney impairment, blood dyscrasia, pancreatitis or hypersensitivity. Relapse risk rises after stopping.

Referral and escalation. Refer if there is no response to oral plus rectal therapy at 4 to 8 weeks, or for severe disease (more than 6 bloody stools daily with fever, tachycardia or raised inflammatory markers). Urgent admission for acute severe colitis. Surveillance colonoscopy after 8 years of colitis.