What could cause reddish urine after three days of combined rosuvastatin and fenofibrate therapy and how should it be managed?

Rhabdomyolysis with Myoglobinuria: Immediate Discontinuation Required

The reddish-colored urine after 3 days of rosuvastatin and fenofibrate is most likely myoglobinuria from acute rhabdomyolysis, and both medications must be stopped immediately. 1, 2

Clinical Presentation and Diagnosis

This patient's presentation is consistent with drug-induced rhabdomyolysis manifesting as:

• Myoglobinuria causing the characteristic reddish-brown or tea-colored urine (not frank hematuria) 2, 3
• Rapid onset within 3 days of initiating combination therapy, which is typical for statin-fibrate induced muscle toxicity 2
• The combination of rosuvastatin and fenofibrate increases rhabdomyolysis risk despite fenofibrate being safer than gemfibrozil 1

Immediate Diagnostic Workup Required

• Creatine kinase (CK) level urgently—expect markedly elevated values (>10,000 IU/L in severe cases, with reported levels of 96,000-97,000 IU/L in documented fenofibrate-statin rhabdomyolysis) 2
• Serum creatinine and BUN to assess for acute kidney injury 2, 3
• Serum myoglobin (typically >2,000 ng/mL in rhabdomyolysis) and urine myoglobin to confirm myoglobinuria 4
• Serum potassium urgently, as hyperkalemia from muscle breakdown can cause fatal arrhythmias 2
• Urinalysis showing positive blood on dipstick without RBCs on microscopy (myoglobin cross-reacts with hemoglobin on dipstick) 2

Immediate Management Algorithm

Step 1: Drug Discontinuation

• Stop both rosuvastatin and fenofibrate immediately—do not wait for laboratory confirmation 2, 3
• Never restart this combination once rhabdomyolysis has occurred 2

Step 2: Aggressive Fluid Resuscitation

• Initiate intravenous normal saline at 200-300 mL/hour to maintain urine output >200-300 mL/hour 2
• Target urine output prevents myoglobin precipitation in renal tubules 2

Step 3: Urinary Alkalinization

• Add sodium bicarbonate to IV fluids to achieve urine pH >6.5, which increases myoglobin solubility and reduces tubular toxicity 2
• Combine with mannitol diuresis (forced alkaline-mannitol diuresis protocol) 2

Step 4: Monitor for Acute Renal Failure

• Serial creatinine measurements every 12-24 hours 2, 3
• Hemodialysis may be required if acute renal failure develops despite aggressive management 2, 3
• Both reported cases of fenofibrate-rosuvastatin rhabdomyolysis required temporary hemodialysis but achieved full renal recovery 2

Why This Combination Caused Rhabdomyolysis

While fenofibrate is significantly safer than gemfibrozil (15-fold lower rhabdomyolysis risk), the combination still carries meaningful risk: 1

• Pharmacokinetic interaction: Rosuvastatin plasma concentrations increase 1.56- to 1.88-fold when combined with fibrates due to inhibition of OATP1B1/3 hepatic uptake transporters 1
• Pharmacodynamic synergy: Both drugs independently cause muscle toxicity, and the combined risk exceeds the sum of individual risks 1
• Early onset: Rhabdomyolysis can occur within days of initiating combination therapy, as demonstrated in this case 2

Evidence on Safety Profile

The guideline evidence shows conflicting safety data that requires careful interpretation:

• Large trial data (FIELD, ACCORD) showed zero cases of rhabdomyolysis among ~1,000 patients on statin-fenofibrate combination, suggesting relative safety in controlled settings 1, 5
• However, case reports and FDA adverse event data document severe rhabdomyolysis with acute renal failure requiring hemodialysis in real-world practice 2, 3
• The discrepancy likely reflects patient selection in trials (excluding high-risk patients) versus real-world heterogeneous populations 2

Critical Risk Factors Present

Even though fenofibrate-statin is considered "remarkably safe" in guidelines, certain factors dramatically increase risk: 5

• Rapid initiation without gradual dose titration 5
• Potential unrecognized renal insufficiency (fenofibrate is contraindicated when CrCl <30 mL/min) 6
• High-dose statin use (rosuvastatin 10-40 mg range) 5

Long-Term Management After Recovery

Once CK normalizes and renal function recovers:

• Never rechallenge with the statin-fibrate combination 2
• If lipid management still required, use statin monotherapy alone at the lowest effective dose, starting weeks after full recovery 5
• Consider alternative agents such as ezetimibe or PCSK9 inhibitors if statin monotherapy insufficient 5
• If fibrate absolutely necessary, use fenofibrate monotherapy without any statin 1

Common Pitfall to Avoid

Do not assume this is benign hematuria or UTI—the 3-day temporal relationship to drug initiation and the specific drug combination make rhabdomyolysis the diagnosis until proven otherwise. 2 Delayed recognition and continued drug exposure can progress to irreversible acute tubular necrosis requiring permanent dialysis. 2, 3