Is Relafen (nabumetone) safe to use in patients with Chronic Kidney Disease (CKD)?

Relafen (Nabumetone) Use in CKD

Relafen (nabumetone) should be avoided in patients with chronic kidney disease, particularly those with moderate to severe renal impairment, due to significant risks of acute kidney injury, worsening renal function, hyperkalemia, fluid retention, and hypertension. 1, 2

FDA-Mandated Restrictions and Warnings

The FDA label explicitly states that nabumetone is not recommended in patients with advanced renal disease. 1 If therapy must be initiated in this population, close monitoring of renal function is mandatory. 1

Dosing Adjustments Required by Renal Function:

• Moderate renal impairment (CrCl 30-49 mL/min): Maximum starting dose 750 mg once daily, with a 50% increase in unbound plasma levels of the active metabolite (6MNA). After careful monitoring, may increase to maximum 1,500 mg daily. 1

• Severe renal impairment (CrCl <30 mL/min): Maximum starting dose 500 mg once daily, with maximum daily dose of 1,000 mg after careful monitoring. 1

• Mild renal insufficiency (CrCl ≥50 mL/min): Generally no dosage adjustment necessary, though closer monitoring than normal renal function patients is required. 1

Mechanism of Nephrotoxicity

NSAIDs like nabumetone cause dose-dependent decreases in prostaglandin synthesis, leading to reduced renal blood flow and potential renal decompensation. 1 This is particularly dangerous in patients where renal prostaglandins play a compensatory role in maintaining renal perfusion. 1

Specific Renal Risks:

• Acute kidney injury through hemodynamic changes 2, 3
• Progressive loss of glomerular filtration rate with long-term use 2
• Electrolyte derangements including hyperkalemia 2
• Hypervolemia with worsening heart failure and hypertension 2
• Renal papillary necrosis with long-term administration 1
• Interstitial nephritis 4

High-Risk Patient Populations

Patients at greatest risk include those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, and the elderly. 1 The KDIGO guidelines emphasize avoiding NSAIDs in CKD patients, particularly when combined with other nephrotoxic agents or RAAS inhibitors. 5

Critical Drug Interactions:

The combination of NSAIDs with ACE inhibitors or ARBs (commonly prescribed in CKD for renoprotection) significantly increases the risk of acute kidney injury and hyperkalemia. 5 This "triple whammy" effect is amplified when diuretics are also used. 5

Clinical Evidence in CKD

While older studies suggested nabumetone had minimal renal effects in less than 1% of patients, 4 more recent evidence demonstrates that NSAIDs pose tangible risks for acute kidney injury, electrolyte imbalances, and blood pressure increases in CKD patients. 2, 3

The role of NSAIDs in causing progressive kidney disease is primarily associated with long-term usage in high cumulative dosages and combination with other agents. 3

Monitoring Requirements If Use Is Unavoidable

If nabumetone must be used despite CKD:

• Measure renal function before initiating therapy 1, 4
• Monitor serum creatinine and potassium within 2-4 weeks of initiation or dose changes 5
• Check for signs of fluid retention, worsening hypertension, and heart failure 1, 2
• Discontinue if creatinine increases >30% from baseline 5
• Use the lowest effective dose for the shortest possible duration 1

Safer Alternatives

For acute gout in CKD, low-dose colchicine or intra-articular/oral glucocorticoids are preferable to NSAIDs. 5 However, alternative analgesics including opioids, tramadol, gabapentin, and baclofen have weak efficacy evidence and significant harm profiles in CKD patients. 3

Common Pitfalls to Avoid

• Do not assume nabumetone is "safer" than other NSAIDs simply because it is a prodrug with a non-acidic structure—it still carries significant renal risks in CKD. 1, 2
• Do not prescribe NSAIDs concurrently with ACE inhibitors/ARBs and diuretics without extreme caution and close monitoring. 5
• Do not continue therapy if acute kidney injury develops—discontinuation typically leads to recovery to pretreatment state. 1
• Avoid in patients with CrCl <30 mL/min unless absolutely no alternatives exist and only with intensive monitoring. 1