Which medications have clinically important interactions with statins?

Clinically Important Statin Drug Interactions

The most critical drug interactions with statins involve medications that inhibit CYP3A4 or drug transporters (OATP1B1, P-glycoprotein), particularly cyclosporine, gemfibrozil, macrolide antibiotics (clarithromycin, erythromycin), azole antifungals (itraconazole, ketoconazole), and certain cardiovascular drugs (amiodarone, dronedarone, verapamil, diltiazem), all of which substantially increase myopathy risk. 1

High-Risk Interactions Requiring Dose Limits or Avoidance

Amiodarone

• Simvastatin must be limited to ≤20 mg daily when combined with amiodarone, based on data from the SEARCH trial showing 8.8-fold increased risk of myopathy/rhabdomyolysis (8 cases of myopathy and 7 cases of rhabdomyolysis with simvastatin 80 mg versus zero cases with 20 mg). 1
• Lovastatin should not exceed 40 mg daily with concurrent amiodarone use. 1
• Atorvastatin can be used without mandatory dose limits, though caution is warranted, as it shows less interaction potential than simvastatin despite CYP3A4 metabolism. 1
• Pravastatin, rosuvastatin, fluvastatin, and pitavastatin require no dose adjustments with amiodarone. 1

Gemfibrozil and Other Fibrates

• Gemfibrozil is contraindicated with all statins due to its potent inhibition of both CYP2C8 and OATP1B1, which dramatically increases statin exposure and myopathy risk. 1, 2
• Other fibrates (fenofibrate) may be combined with statins for mixed dyslipidemia, but this requires careful monitoring for muscle symptoms and creatine kinase elevation. 1
• The combination of statins with fibrates increases myopathy risk but is now considered an option with monitoring, rather than contraindicated as previously thought. 1

Macrolide Antibiotics and Azole Antifungals

• Strong CYP3A4 inhibitors (clarithromycin, erythromycin, itraconazole, ketoconazole) dramatically increase concentrations of simvastatin, lovastatin, and atorvastatin. 1
• Consider temporary statin discontinuation during short courses of these antibiotics/antifungals, or switch to pravastatin or rosuvastatin which are not CYP3A4 substrates. 2

Cyclosporine

• Cyclosporine inhibits multiple pathways (CYP3A4, P-glycoprotein, OATP1B1) and dramatically increases all statin concentrations. 2
• If statins must be used with cyclosporine, pravastatin or fluvastatin at the lowest effective doses are preferred, with intensive monitoring. 2

Calcium Channel Blockers

• Verapamil and diltiazem are moderate CYP3A4 inhibitors that increase simvastatin and lovastatin concentrations. 2
• Use cautiously with small doses of CYP3A4-dependent statins, or preferentially use pravastatin, rosuvastatin, or pitavastatin. 2

Colchicine-Statin Interactions

Rosuvastatin, fluvastatin, lovastatin, pitavastatin, or pravastatin are preferred when combining with colchicine, while atorvastatin and simvastatin require dose reductions and close monitoring. 1, 3

• Simvastatin-colchicine is the highest-risk combination, with 6 documented cases of myopathy including one death from rhabdomyolysis and multiorgan failure. 3, 4
• Both drugs independently cause myopathy and share CYP3A4 and P-glycoprotein pathways, creating synergistic muscle toxicity. 3
• When combining colchicine with any statin, reduce colchicine to loading doses ≤0.6-1.2 mg and maintenance doses of 0.3-0.6 mg daily. 1, 3
• For atorvastatin or simvastatin specifically, consider reducing the statin dose as well. 1, 3
• Rosuvastatin is safest as it avoids the CYP3A4/P-glycoprotein pathways. 3, 4

Niacin

• Niacin increases myopathy risk when combined with statins, though the absolute risk remains low. 1, 5
• This combination is used for resistant dyslipidemia but requires monitoring for muscle symptoms. 1

Cardiovascular Medications with Lower Risk

Sacubitril/Valsartan

• In vitro data show potential inhibition of OATP1B1, OATP1B3, OAT1, and OAT3 transporters. 1
• Atorvastatin exposure increased up to 2-fold (Cmax) and 1.3-fold (AUC), but no significant adverse events were reported in phase III trials. 1
• Lower doses of all statins may be considered when combined with sacubitril/valsartan, though no mandatory adjustments are currently required. 1

Ivabradine

• No clinically significant interaction with simvastatin has been demonstrated. 1
• Coadministration at approved doses is reasonable when clinically indicated. 1

Statin-Specific Interaction Profiles

High Interaction Risk (CYP3A4-Dependent)

• Simvastatin and lovastatin: Most vulnerable to CYP3A4 inhibitors; require the most stringent dose limits with interacting drugs. 1, 2
• Atorvastatin: CYP3A4-dependent but less prone to severe interactions than simvastatin/lovastatin. 1, 2

Low Interaction Risk (Non-CYP3A4 Pathways)

• Pravastatin: Excreted mainly unchanged; not significantly affected by CYP3A4 inhibitors. 2
• Rosuvastatin: Minimal CYP metabolism; safest option with most interacting drugs. 2
• Fluvastatin: Metabolized by CYP2C9; exposure increased <2-fold by CYP2C9 inhibitors. 2
• Pitavastatin: Minimal CYP metabolism; low interaction potential. 2

Monitoring and Management Algorithm

1. Before prescribing any statin, review all current medications for CYP3A4 inhibitors, fibrates, and other high-risk agents. 1

2. For patients on strong CYP3A4 inhibitors (cyclosporine, clarithromycin, itraconazole, ritonavir):

   • Choose pravastatin, rosuvastatin, or pitavastatin
   • Avoid simvastatin, lovastatin, and use atorvastatin cautiously 2

3. For patients on moderate CYP3A4 inhibitors (amiodarone, diltiazem, verapamil):

   • Limit simvastatin to ≤20 mg daily with amiodarone 1
   • Use small doses of CYP3A4-dependent statins or switch to non-CYP3A4 statins 2

4. For patients requiring colchicine:

   • Prefer rosuvastatin, fluvastatin, lovastatin, pitavastatin, or pravastatin 3
   • If using atorvastatin or simvastatin, reduce both drug doses 3
   • Reduce colchicine to 0.3-0.6 mg daily maintenance 3

5. Monitor at each clinical encounter and during care transitions for new interacting medications. 1

6. Educate patients to report muscle pain, weakness, or dark urine immediately, especially when new medications are added. 1

Critical Caveats

• The incidence of severe myopathy with statin monotherapy is extremely low (0.08% in clinical trials, <1 death per million prescriptions). 1, 6
• Most muscle complaints (≈5%) occur equally with placebo and active statin, suggesting they may not be drug-related. 1
• Myopathy risk is highest in patients with complex medical problems, multiple medications, advanced age, renal impairment, or low body weight. 1, 7
• Fatal rhabdomyolysis rates are equivalent among currently available statins (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin) when used appropriately. 1
• HIV medications represent another major category of statin interactions not covered here; consult specialized resources for this population. 1