Yes, a patient can safely be on Zetia (ezetimibe), Crestor (rosuvastatin), and fenofibrate simultaneously—this triple combination is FDA-approved and guideline-supported for specific clinical indications.
FDA-Approved Indication for Triple Therapy
The FDA explicitly approves ezetimibe in combination with fenofibrate for mixed hyperlipidemia, and separately approves ezetimibe with statins, making this triple combination permissible when clinically indicated. 1
When Triple Therapy Is Recommended
This combination should be used when patients have:
Mixed dyslipidemia with inadequate response to dual therapy: Elevated LDL-C, elevated triglycerides (>150 mg/dL), and low HDL-C that fails to respond to statin plus ezetimibe alone 2
Severe hypertriglyceridemia (≥500 mg/dL) despite statin-ezetimibe therapy: To reduce pancreatitis risk 2
LDL-C above goal despite maximally tolerated statin plus ezetimibe AND persistently elevated triglycerides 2
Safety Profile: Fenofibrate Is the Critical Choice
Fenofibrate is specifically preferred over gemfibrozil because it has a 15-fold lower risk of rhabdomyolysis when combined with statins (0.58 vs 8.6 cases per million prescriptions). 2
Key safety evidence:
Rosuvastatin can be combined with fenofibrate without dose restrictions, unlike gemfibrozil which requires limiting rosuvastatin to 10mg daily 2
The FIELD study demonstrated zero cases of rhabdomyolysis in approximately 1,000 patients on statin-fenofibrate combination therapy 2
Clinical trials show this combination is generally well-tolerated with efficacy superior to dual therapy 3, 4
Monitoring Requirements
Monitor these parameters closely:
Muscle symptoms: Check creatine kinase if myalgia develops 2, 1
Liver function: Perform testing as clinically indicated; consider withdrawal if ALT/AST ≥3x upper limit of normal persists 1
Renal function: Check before initiating fenofibrate, within 3 months, then every 6 months thereafter 2
Lipid panel: Assess efficacy at 4 weeks after initiation 1
High-Risk Patients Requiring Extra Vigilance
Exercise particular caution in: 2
- Elderly patients, especially thin or frail women
- Small body frame and frailty
- Renal impairment (combination therapy risk increases significantly)
- Diabetes combined with chronic renal failure
- Perioperative periods
- Patients on multiple medications
Critical Contraindications
Never substitute gemfibrozil for fenofibrate in this regimen—gemfibrozil is contraindicated with many statins and has 15-fold higher rhabdomyolysis risk. 2, 5
Avoid this combination if: 6, 1
- eGFR <30 mL/min/1.73 m² (fenofibrate contraindicated)
- Moderate to severe hepatic impairment
- History of hypersensitivity to any component
- Concurrent use of cyclosporine
Evidence Limitations
While statin-fibrate combination therapy has not consistently shown cardiovascular outcome benefits in broad populations 6, post-hoc analysis suggests potential benefit in specific subgroups (men with triglycerides ≥204 mg/dL and HDL ≤34 mg/dL) 6. The triple combination with ezetimibe added provides superior lipid parameter improvements compared to dual therapy 3, though long-term cardiovascular outcome data for triple therapy specifically are lacking.