What was the reason for the nimesulide (Nonsteroidal Anti-Inflammatory Drug (NSAID)) ban?

Nimesulide Ban: Hepatotoxicity Risk

Nimesulide was banned or restricted in multiple countries primarily due to its association with severe hepatotoxicity, including fatal fulminant hepatic failure, with the drug carrying a higher risk of liver injury compared to other NSAIDs. 1, 2, 3

Primary Reason for Ban: Severe Liver Injury

The core issue driving regulatory action against nimesulide centers on hepatotoxicity that can progress to death:

• Nimesulide is associated with the highest risk of acute serious liver injury among commonly used NSAIDs, with an adjusted odds ratio of 2.10 (95% CI 1.28-3.47) in a large Italian case-control study. 1

• Fatal hepatic failure has been documented in multiple case reports, with patients progressing from initial hepatitis to fulminant liver failure with encephalopathy and hepatorenal syndrome, resulting in death. 3, 4

• The drug exhibits a dose-dependent and duration-dependent hepatotoxicity pattern: risk increases dramatically with exposure >30 days (OR 12.55,95% CI 1.73-90.88) and at higher doses (OR 10.69,95% CI 4.02-28.44). 1

Clinical Spectrum of Nimesulide Liver Injury

The hepatotoxicity presents across a dangerous spectrum:

• Asymptomatic elevation of liver enzymes may occur, which typically reverses upon drug discontinuation. 5, 4

• Symptomatic hepatitis develops weeks after initiation (median 10 weeks, range 2-13 weeks), presenting with fatigue, nausea, and vomiting, with peak ALT levels reaching 15 times the upper limit of normal. 4

• Fulminant hepatic failure represents the most severe outcome, particularly when patients continue the drug despite symptoms, leading to encephalopathy, hepatorenal syndrome, and death within weeks. 4

Comparative Risk Among NSAIDs

While all NSAIDs carry hepatotoxicity risk, nimesulide stands out:

• General NSAID hepatotoxicity incidence ranges from 0.29-9 per 100,000 patients in clinical studies, but liver-related hospitalizations occur at higher rates (3-23 per 100,000). 2

• Nimesulide's risk exceeds other commonly used NSAIDs: ibuprofen carries an OR of 1.92 (95% CI 1.13-3.26) at recommended doses, and ketoprofen ≥150 mg has an OR of 4.65 (95% CI 1.33-10.00), both substantially lower than nimesulide's risk profile. 1

• Historical precedent exists: other NSAIDs including bromfenac, ibufenac, and benoxaprofen were previously withdrawn from markets worldwide due to hepatotoxicity. 2

Regulatory Actions and Geographic Variation

The controversy surrounding nimesulide led to disparate regulatory responses:

• Nimesulide was never marketed in some countries (including the United States) and was subsequently withdrawn in others due to accumulating evidence of severe hepatotoxicity. 2

• The drug remains available in certain markets where it was initially approved, creating ongoing debate about the actual risk-benefit profile. 2

Critical Clinical Pitfalls

Several factors compound the hepatotoxicity risk:

• Continued use despite symptoms dramatically worsens outcomes: the fatal case in the Israeli series involved a patient who continued nimesulide for 2 weeks after symptom onset, progressing to irreversible hepatic failure. 4

• Delayed presentation is common: symptoms typically emerge weeks after drug initiation (median 10 weeks), making causality assessment challenging and potentially delaying drug discontinuation. 4

• Under-reporting obscures true risk: asymptomatic cases and transient liver enzyme elevations are frequently unreported, along with non-compliance with pharmacovigilance criteria, making the actual hepatotoxicity incidence difficult to establish. 2

Renal Toxicity as Contributing Factor

Beyond hepatotoxicity, nimesulide carries standard NSAID renal risks:

• Prostaglandin inhibition decreases renal perfusion, leading to volume-dependent renal failure, particularly in volume-depleted states or when combined with ACE inhibitors, ARBs, or diuretics. 6

• High-risk populations include patients with pre-existing renal disease, heart failure, cirrhosis, advanced age (>60 years), or compromised fluid status. 6

• Immediate discontinuation is required if creatinine doubles from baseline or GFR drops below 20 mL/min/1.73 m². 6

Monitoring Requirements (Where Still Available)

In jurisdictions where nimesulide remains marketed, strict surveillance is essential:

• Baseline liver function tests (alkaline phosphatase, LDH, SGOT, SGPT) should be established before initiating therapy. 7

• Discontinue immediately if liver enzymes rise to 3 times the upper limit of normal, as hepatotoxicity can progress rapidly to fulminant failure. 7

• Monitoring liver enzymes after initiation is prudent given the documented risk of progression from asymptomatic elevation to fatal hepatic failure. 4