What are the adverse effects of mesalazine (5-aminosalicylic acid)?

Mesalazine Adverse Effects

Mesalazine is generally well tolerated with adverse events similar to placebo, but clinicians must monitor for rare serious complications including interstitial nephritis, hepatotoxicity, cardiac toxicity, and severe cutaneous reactions. 1, 2

Common Adverse Effects

The most frequently reported adverse effects from clinical trials include:

• Gastrointestinal symptoms: Flatulence/gas (6%), diarrhea (3%), nausea (2%), abdominal pain, and worsening ulcerative colitis 1, 2
• Systemic symptoms: Headache (2%), fever, fatigue, and flu-like symptoms 1, 2
• Musculoskeletal: Leg/joint pain and arthralgia 2, 3
• Dermatologic: Rash (1%) and hair loss 2

These common adverse effects occur at rates similar to placebo and rarely necessitate treatment discontinuation. 1

Serious Adverse Effects Requiring Monitoring

Renal Complications

• Interstitial nephritis is the most clinically significant rare adverse effect, potentially leading to acute or chronic renal failure 1, 2
• Nephrolithiasis with 100% mesalazine-content stones (radiotransparent, undetectable by standard radiography or CT) 2
• Nephrogenic diabetes insipidus and nephrotoxicity have been reported 2, 4
• Baseline renal function should be evaluated before initiating therapy, with periodic monitoring throughout treatment 3, 4

Hepatotoxicity

• Elevated liver enzymes and hepatic failure can occur, particularly in patients with pre-existing liver disease 2, 5
• Chronic hepatitis has been documented after prolonged mesalazine exposure (21 months in one case), with autoantibodies and elevated IgG levels 5
• Baseline liver function tests should be obtained, with additional testing performed if symptoms develop 3

Cardiac Toxicity

• Myocarditis and pericarditis are rare but serious hypersensitivity reactions 2, 3
• These typically present as part of a broader hypersensitivity syndrome 2

Severe Cutaneous Adverse Reactions

• Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported 2
• Discontinue mesalazine immediately at first signs of severe cutaneous reactions 2
• Photosensitivity occurs, particularly in patients with pre-existing atopic dermatitis or eczema; advise sun avoidance and protective measures 2

Hematologic Toxicity

• Agranulocytosis, aplastic anemia, leukopenia, neutropenia, pancytopenia, and thrombocytopenia are rare but documented 2
• Risk increases with concurrent use of azathioprine or 6-mercaptopurine; monitor complete blood counts if combination therapy cannot be avoided 2

Other Serious Reactions

• Pancreatitis 2, 3
• Respiratory complications: Fibrosing alveolitis, pleurisy/pleuritis, and pneumonitis 2, 3
• Intracranial hypertension 2
• Reversible oligospermia 2

Mesalamine-Induced Acute Intolerance Syndrome

Approximately 3% of patients develop acute intolerance that mimics a flare of colitis, including bloody diarrhea, abdominal cramping, and fever. 1, 3, 6

• Recurrence of symptoms upon rechallenge confirms the diagnosis 1
• This represents a hypersensitivity reaction requiring permanent discontinuation 2

Dose-Dependent Relationship

High-dose mesalazine (>2.4 g/day) does not appear to have increased risk of adverse events compared to standard doses (≤2.4 g/day). 3

• This finding supports the use of higher doses when clinically indicated without additional safety concerns 3

Excipient vs. Active Component Intolerance

Distinguishing between 5-aminosalicylic acid intolerance and excipient intolerance is critical for management decisions. 6

• Excipient intolerance primarily presents with acute skin symptoms (rash, urticaria, angioedema) and can be managed by switching mesalamine formulations 6
• 5-ASA intolerance causes similar adverse reactions across all preparations and requires discontinuation of all mesalamine products 6

Drug Interactions

• Concurrent use with nephrotoxic agents (including NSAIDs) increases nephrotoxicity risk; monitor renal function closely 2
• Azathioprine or 6-mercaptopurine combination increases myelotoxicity risk; monitor complete blood counts if combination unavoidable 2
• Spuriously elevated urinary normetanephrine measurements occur with liquid chromatography/electrochemical detection; use alternative selective assays 2

Comparative Safety Profile

Mesalazine and balsalazide are significantly better tolerated than sulfasalazine, with lower rates of treatment discontinuation and fewer systemic adverse effects. 1

• Sulfasalazine causes adverse effects in 10-45% of patients (dose-dependent), including headache, nausea, diarrhea, rash, and rare serious reactions like Stevens-Johnson syndrome, hepatitis, and hematologic toxicity 1
• Olsalazine carries up to 20% risk of secretory diarrhea necessitating discontinuation 1

Clinical Monitoring Algorithm

1. Before initiating therapy: Obtain baseline renal function and liver function tests 3, 4
2. During therapy: Periodically assess renal function; perform additional testing (liver enzymes, complete blood counts) if symptoms develop 3, 4
3. Ensure adequate hydration to prevent nephrolithiasis 2
4. Discontinue immediately if severe cutaneous reactions, worsening colitis mimicking intolerance syndrome, or new organ dysfunction develops 2