What are the potential interactions between statins (HMG-CoA reductase inhibitors) and macrolide antibiotics (e.g. clarithromycin, erythromycin)?

Statin-Macrolide Drug Interactions

Direct Recommendation

Clarithromycin and erythromycin are contraindicated with lovastatin and simvastatin, and should be avoided with atorvastatin; if a macrolide is necessary in patients on these statins, temporarily discontinue the statin during antibiotic therapy or switch to azithromycin with a non-CYP3A4 metabolized statin like pravastatin, fluvastatin, or rosuvastatin. 1, 2

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Mechanism and Severity of Interaction

The interaction between macrolides and statins occurs through two primary mechanisms:

• CYP3A4 inhibition: Clarithromycin and erythromycin are potent inhibitors of the cytochrome P-450 3A4 enzyme, which metabolizes several statins 3, 2
• Transporter inhibition: These macrolides also inhibit hepatic uptake transporters OATP1B1 and OATP1B3, further increasing statin blood levels 4

The magnitude of interaction varies dramatically by statin:

• Simvastatin and lovastatin: >5-fold increase in drug exposure—FDA contraindicated 1, 4
• Atorvastatin: 2-4 fold increase in exposure—should be avoided 4
• Pitavastatin: 2-4 fold increase—withhold or reduce dose 4
• Pravastatin: ~2-fold increase—may continue with caution at ≤40 mg daily 4
• Fluvastatin and rosuvastatin: Minimal interaction—safe to continue 4

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Clinical Consequences

The statin-macrolide interaction can cause a spectrum of muscle toxicity:

• Mild myalgia: Non-specific muscle aches without significant CK elevation 2
• Moderate myopathy: Muscle pain with mild-to-moderate CK elevations 2
• Severe myositis: Muscle weakness, pain, and marked CK elevations 2
• Rhabdomyolysis: Life-threatening condition with myoglobinuria, acute renal failure, and CK levels >10 times upper limit of normal 2, 5, 6

Real-world evidence demonstrates serious consequences:

• All 16 reported cases of rhabdomyolysis from statin-macrolide interactions involved CYP3A4-metabolized statins (simvastatin, lovastatin, or atorvastatin) 4
• Cohort studies show a doubled risk of hospitalization for rhabdomyolysis when clarithromycin is combined with CYP3A4-metabolized statins compared to azithromycin 4
• Fatal outcomes have been reported, including one patient who died from infectious complications following rhabdomyolysis 5

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High-Risk Patient Populations

Certain patients face exponentially higher risk when statins and macrolides are combined:

• Advanced age >80 years, particularly frail elderly women 3, 2
• Chronic renal insufficiency, especially in diabetic patients 3, 2
• Small body frame and frailty 3, 2
• Polypharmacy with multiple interacting medications 3, 2
• Higher statin doses (risk is dose-dependent) 3, 2

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Management Algorithm

When Macrolide Antibiotic is Needed:

Step 1: Identify the current statin

• If on simvastatin or lovastatin: These combinations are FDA contraindicated—must avoid 1
• If on atorvastatin: Should be avoided due to substantial interaction risk 4
• If on pitavastatin: Withhold during macrolide course or reduce dose 4
• If on pravastatin: May continue with caution, limit dose to ≤40 mg daily 4
• If on fluvastatin or rosuvastatin: Safe to continue with monitoring 4

Step 2: Choose antibiotic strategy

• Preferred approach: Use azithromycin instead of clarithromycin/erythromycin (azithromycin has minimal CYP3A4 inhibition) 4
• Alternative: Temporarily discontinue the statin during the 7-14 day macrolide course 6
• If macrolide is mandatory: Switch to pravastatin (≤40 mg), fluvastatin, or rosuvastatin before starting macrolide 4

Step 3: Patient counseling and monitoring

• Instruct patients to immediately report muscle pain, tenderness, weakness, or dark urine 2
• Consider baseline CK measurement in high-risk patients 2
• Obtain CK levels if muscle symptoms develop 2
• Discontinue statin immediately if CK exceeds 10 times upper limit of normal or if severe myopathy develops 2

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Critical Pitfalls to Avoid

Common prescribing errors persist despite clear warnings:

• 63.5% of general practitioners co-prescribed high-risk statin-macrolide combinations at least once 7
• No evidence of prescribers avoiding erythromycin in patients on interacting statins 8
• Paradoxically, some patients on gemfibrozil-statin combinations (already high-risk) received even higher statin doses, compounding the danger 8

The interaction risk extends beyond the treatment period:

• Rhabdomyolysis cases have occurred 1-2 weeks after completion of macrolide therapy 6
• This delayed presentation occurs because statin levels remain elevated after CYP3A4 inhibition resolves 6

Multiple prescribers create dangerous gaps:

• Patients often receive prescriptions from different caregivers who may be unaware of the interaction 3
• Ensure patients understand the risk and can communicate it to all healthcare providers 3

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Practical Clinical Scenarios

Scenario 1: Patient on simvastatin 40 mg needs treatment for pneumonia

• Action: Prescribe azithromycin instead of clarithromycin, continue simvastatin with standard monitoring 4

Scenario 2: Patient on atorvastatin 80 mg requires clarithromycin for H. pylori eradication

• Action: Hold atorvastatin during the 14-day clarithromycin course, resume after completion with close monitoring for delayed muscle symptoms 4, 6

Scenario 3: Elderly patient with CKD on pravastatin 40 mg needs erythromycin

• Action: Continue pravastatin at current dose (do not exceed 40 mg), provide explicit warnings about muscle symptoms, consider baseline CK given high-risk profile 4, 2