LACTOLOGY FOUNDATION

Mesalazine (ATC A07EC02)

ATC class and general pharmacology

Mesalazine (mesalamine, 5-aminosalicylic acid, 5-ASA) is classified under ATC code A07EC02, within the alimentary tract and metabolism group (A), antidiarrheals, intestinal anti-inflammatory/anti-infective agents (A07), intestinal anti-inflammatory agents (A07E), and the aminosalicylic acid and similar agents subclass (A07EC), alongside sulfasalazine (A07EC01), olsalazine (A07EC03), and balsalazide (A07EC04) (PubChem; RxReasoner). Chemically, mesalazine is the single active molecule 5-amino-2-hydroxybenzoic acid, structurally related to the salicylates and to phenacetin; unlike sulfasalazine, it lacks a sulfapyridine carrier moiety, and represents the isolated therapeutic component historically identified within the sulfasalazine prodrug (DrugBank; PMC).pmc.ncbi.nlm.nih+3

Because unmodified 5-ASA is rapidly and near-completely absorbed in the proximal small intestine, therapeutic mesalazine formulations depend on specialised colonic-delivery technologies — pH-dependent Eudragit coatings, ethylcellulose-controlled microgranules, or azo-bonded prodrug carriers (as in olsalazine and balsalazide) — engineered to release the active moiety at or beyond the terminal ileum and colon, where the topical anti-inflammatory effect is exerted (Salofalk SmPC, Indonesian regulatory dossier; DrugBank). Systemic plasma concentrations of mesalazine are consequently low and of limited relevance to therapeutic efficacy, functioning instead chiefly as a safety-monitoring parameter.registrasiobat.pom.go+1

The precise mechanism of anti-inflammatory action remains incompletely elucidated. Proposed pathways include inhibition of cyclooxygenase- and lipoxygenase-dependent arachidonic acid metabolism, thereby reducing colonic production of prostaglandins and leukotrienes (particularly leukotriene B4); inhibition of platelet-activating factor synthesis; scavenging of reactive oxygen free radicals; suppression of nuclear factor kappa-B (NF-κB) activation and downstream pro-inflammatory cytokine transcription (including interleukin-1, interleukin-2, and TNF-α); inhibition of leukocyte chemotaxis and antibody synthesis by plasma cells; and direct activation of peroxisome proliferator-activated receptor gamma (PPAR-γ) in colonic and rectal epithelium (DrugBank; MIT OpenCourseWare pharmacology lecture). A 2025 finding additionally identified tubulin binding and microtubule stabilisation as a novel mechanistic candidate.ocw.mit+2

Mesalazine is metabolised both pre-systemically within the intestinal mucosa and systemically in the liver, principally via N-acetyltransferase-1 (NAT-1), to the pharmacologically inactive metabolite N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). Elimination occurs predominantly via the faecal route, with renal excretion (mainly as N-Ac-5-ASA) accounting for approximately 20–50% depending on formulation and route of administration, and a minor biliary contribution (Health Canada product monograph; DrugBank). Systemic exposure increases by up to two-fold in elderly patients relative to younger adults, reflecting age-related decline in renal clearance.geneesmiddeleninformatiebank+2

Clinically, mesalazine is indicated for induction and maintenance of remission in mild-to-moderate ulcerative colitis and is used off-label in selected cases of Crohn's disease. Standard oral maintenance doses range from approximately 1.5 to 4.8 g/day depending on formulation and disease activity, with rectal preparations (suppositories, enemas, foam) available for distal disease (RxReasoner; Salofalk SmPC). The improved tolerability profile relative to sulfasalazine — attributable to the absence of the sulfapyridine carrier — has permitted use of substantially higher 5-ASA doses in clinical practice.ncbi.nlm.nih+2

Toxicological profile

Mesalazine demonstrates low acute toxicity. Animal studies have shown that single oral doses up to 5 g/kg in pigs and a single intravenous dose of 920 mg/kg in rats were not lethal, and human overdose experience — including reports of patients receiving 8 g/day for a month — has not documented significant hepatic or renal toxicity from acute exposure. As an aminosalicylate structurally related to acetylsalicylic acid, overdose may nonetheless mimic classic salicylate toxicity, with tinnitus, vertigo, headache, confusion, drowsiness, hyperventilation, acid-base disturbance, pulmonary oedema, dehydration, electrolyte imbalance, hypoglycaemia, and hyperthermia; no specific antidote exists, and management is supportive with close monitoring of renal function and fluid/electrolyte correction (EU SmPC; Health Canada product monograph).pdf.hres+2

The dominant and most clinically consequential toxicological concern with mesalazine is nephrotoxicity, occurring at meaningfully higher rates than with sulfasalazine. A pharmacovigilance comparison of adverse drug reaction reports submitted to the UK Committee on Safety of Medicines (1991–1998) found that interstitial nephritis was reported exclusively for mesalazine (11.1 reports per million prescriptions) with no comparable reports for sulfasalazine, and that pancreatitis was reported roughly seven times more frequently for mesalazine than sulfasalazine (odds ratio 7.0; 95% CI 2.6–18.6). Mesalazine-induced nephrotoxicity manifests principally as acute or chronic tubulointerstitial nephritis, and less commonly as minimal change nephropathy or nephrotic syndrome; estimates of incidence range from approximately 1 in 100 patients for any renal function abnormality to fewer than 1 in 500 for clinically significant interstitial nephritis, with some more recent estimates as low as 1 in 4,000 patient-years (PMC; MDU Journal). The pathogenic mechanism is considered idiosyncratic and dose-independent, more likely a delayed, cell-mediated hypersensitivity response than classic type I hypersensitivity, and has been linked in genome-wide association studies to specific HLA regions, with a disproportionate incidence in male patients (PMC pediatric case review; PMC).pmc.ncbi.nlm.nih+3

Clinical presentation of mesalazine nephrotoxicity is typically insidious: most cases present within the first 12 months of therapy (occasionally after several years), often with asymptomatic reduction in glomerular filtration rate unaccompanied by pyuria, eosinophilia, or skin rash — in contrast to classic drug-induced interstitial nephritis (PubMed; droracle.ai clinical summary). Renal function recovery following drug withdrawal occurs in approximately 85% of cases if nephrotoxicity is diagnosed within 10 months of treatment initiation, but only partial recovery (in roughly one-third of cases) is achieved if diagnosis is delayed to 18 months, and a retrospective cohort of 151 patients found nearly 10% ultimately required renal replacement therapy (PMC; MDU Journal). In paediatric ulcerative colitis populations, mesalazine-induced kidney injury has been reported to occur predominantly in boys and may progress to end-stage renal disease if not identified promptly. Consequently, professional guidelines (British Society of Gastroenterology, British National Formulary) recommend baseline renal function assessment prior to initiation, followed by monitoring at approximately three months and then annually, with more frequent surveillance in patients with pre-existing renal impairment or concurrent nephrotoxic drug exposure (e.g., NSAIDs, azathioprine) (MDU Journal; Health Canada product monograph). Notably, a 2019 analysis (Jairath et al.) challenged the magnitude of this risk, finding no clear increase in nephrotoxicity attributable to 5-ASA therapy in a broader dataset, illustrating ongoing debate regarding absolute risk quantification.pubmed.ncbi.nlm.nih+6

Additional toxicological signals include pancreatitis (more frequent than with sulfasalazine), hepatotoxicity (elevated liver enzymes and, rarely, hepatic failure, particularly in patients with pre-existing liver disease), cardiac hypersensitivity reactions (myocarditis and pericarditis, reported rarely), serious blood dyscrasias, nephrolithiasis (including stones of up to 100% mesalazine composition), and severe cutaneous adverse reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, which mandate immediate drug discontinuation (EU SmPC; FDA Verification Portal; Health Canada product monograph). A systematic safety review additionally reported respiratory symptoms, musculoskeletal complaints, and sexual dysfunction as attributed adverse events, without a clear dose-dependent relationship. Mesalazine also produces a harmless red-brown urine discoloration upon contact with sodium hypochlorite bleach and may modestly increase renal and haematological toxicity of concomitant methotrexate through additive effects and diminished folate absorption.onlinelibrary.wiley+3

Lactation pharmacology and infant exposure

Mesalazine is poorly absorbed from the intestine — particularly when administered rectally — resulting in low systemic plasma concentrations and correspondingly low transfer into human milk. Approximately 1% of an orally administered mesalazine dose is estimated to be excreted into breast milk. Measured breast milk concentrations of unmetabolised 5-ASA in treated patients range from 4–40 ng/mL, whereas concentrations of its inactive metabolite N-acetyl-5-ASA are approximately 1,000-fold higher, at 5.0–14.9 μg/mL — a consistent finding replicated across multiple independent pharmacokinetic investigations (PMC; e-lactation).pmc.ncbi.nlm.nih+2

Using standard weight-adjusted infant exposure calculations (assuming average milk intake of 150 mL/kg/day), the resulting infant dose of 5-ASA equates to approximately 0.0006–0.006 mg/kg, corresponding to a relative infant dose well below 10% of the maternal weight-adjusted therapeutic dose — the conventional threshold below which an exposure is generally considered clinically insignificant (PMC; DrLact). Because N-acetyl-5-ASA is pharmacologically inactive in treating inflammatory bowel disease, it is considered unlikely to exert a therapeutic or toxic effect on the nursing infant, although dedicated infant-outcome studies of this specific metabolite have not been conducted.pmc.ncbi.nlm.nih+1

Clinical experience across more than 120 documented infants of mesalazine-treated mothers has not identified serious adverse effects attributable to milk exposure, with isolated case reports of watery or bloody diarrhoea representing the principal reported concern (e-lactation; Academic OUP — IBD Journal). In one well-documented case, a breastfed infant developed watery diarrhoea within 12 hours of the mother's first rectal mesalazine dose (500 mg twice daily); the diarrhoea resolved after cessation and recurred within 10 hours on each of four subsequent re-challenges, providing relatively strong evidence for a causal, dose-independent allergic-type reaction in that infant. A separate case report raised a theoretical concern of infant renal insufficiency following high-dose maternal oral mesalazine (4 g/day) during mid-pregnancy, though this occurred in the antenatal rather than purely lactational context. A larger case-control study comparing 121 infants exposed to mesalamine, olsalazine, or sulfasalazine via breast milk (mean exposure duration 5.3 months) against 121 unexposed control infants found no significant difference in the frequency or nature of maternally reported adverse events over a mean follow-up of approximately 22 months, providing reassuring population-level evidence (Drugs.com/LactMed — Balsalazide monograph, citing Moretti 1989; DrLact).academic.oup+2

Because mesalazine lacks the sulfapyridine moiety present in sulfasalazine, the sulfonamide-related risks of neonatal haemolysis and bilirubin displacement (kernicterus) that apply to sulfasalazine and its metabolites are not clinically relevant to mesalazine exposure via lactation (Academic OUP — IBD Journal; DrLact). No published data indicate that mesalazine adversely affects milk production or lactation performance.ncbi.nlm.nih+2

Lactological safety assessment and clinical recommendations

Mesalazine is broadly regarded by specialist consensus as compatible with breastfeeding, supported by an extensive body of expert guidance spanning gastroenterology and obstetric medicine literature (Huang 2016, Nguyen 2016, van der Woude 2015, Mahadevan 2015, Schulz 2014, Nielsen 2014, Yarur 2013, Van Assche 2010, among others). Independent lactation-risk classification systems (e.g., DrLact) assign mesalazine derivatives among the safest categories for breastfeeding use, and UK hospital-based patient guidance explicitly instructs mothers to continue breastfeeding as normal while on therapy, without requiring routine infant hospital monitoring (DrLact; Leicester Hospitals patient information).leicestershospitals.nhs+2

Based on the convergent pharmacokinetic and clinical-outcome evidence, the following lactological safety assessment and clinical recommendations are proposed:

• Overall risk categorisation: Very low to low risk to the term, healthy breastfed infant. Given the minimal relative infant dose (well under 10%) and the reassuring case-control follow-up data, discontinuation of breastfeeding is not warranted on the basis of maternal mesalazine therapy alone (PMC; e-lactation).pmc.ncbi.nlm.nih+1
• Preferred agent within the aminosalicylate class during lactation: Because mesalazine avoids the sulfapyridine-related haemolysis and bilirubin-displacement risks associated with sulfasalazine, several authors specifically recommend non-sulfonamide-containing 5-ASA derivatives (mesalazine, olsalazine) as preferable choices for lactating patients who require an aminosalicylate (DrLact; Academic OUP — IBD Journal).academic.oup+1
• Infant clinical monitoring: Breastfeeding mothers and clinicians should be advised to observe the infant for watery or bloody diarrhoea, particularly following initiation or dose changes, since this represents the most consistently reported (albeit uncommon) adverse effect in exposed infants (Academic OUP — IBD Journal; Leicester Hospitals patient information).academic.oup+1
• Response to suspected infant reaction: If diarrhoea or other suspected drug-related symptoms occur in the breastfed infant, temporary discontinuation of maternal mesalazine (or breastfeeding) allows rapid symptom resolution in reported cases; re-challenge should be approached cautiously given documented recurrence on rechallenge in at least one case.academic.oup
• Maternal renal monitoring independent of lactation status: Given the drug's dominant idiosyncratic nephrotoxicity risk (interstitial nephritis, minimal change nephropathy), lactating mothers on mesalazine should continue routine maternal renal function surveillance (serum creatinine at baseline, at approximately three months, and annually thereafter, or per local gastroenterology society guidance), since maternal renal impairment could indirectly affect the mother's capacity for infant care (MDU Journal; PubMed).pubmed.ncbi.nlm.nih+1
• Dose considerations: No lactation-specific dose adjustment has been established or is generally recommended; the maternal dose required for disease control should be maintained, as the placental/lactational transfer of 5-ASA is not meaningfully dose-proportional at the doses used clinically.e-lactation
• Premature or vulnerable infants: Although the sulfonamide-specific risks of sulfasalazine do not apply, general caution and closer clinical observation remain prudent in premature infants or those with underlying gastrointestinal vulnerability, given the limited infant-outcome data specifically addressing this subgroup.pmc.ncbi.nlm.nih

In summary, the pharmacokinetic profile of mesalazine — characterised by minimal systemic absorption, low milk transfer of the active moiety, and a relative infant dose well below the conventional threshold of concern — together with reassuring case-control outcome data, supports continuation of breastfeeding during maternal mesalazine therapy in the substantial majority of cases, with targeted monitoring for gastrointestinal symptoms in the infant and maintenance of standard maternal nephrotoxicity surveillance independent of lactation status.