Simvastatin and Amlodipine Interaction
When prescribing simvastatin with amlodipine, limit the simvastatin dose to a maximum of 20 mg daily due to a clinically significant pharmacokinetic interaction that increases simvastatin exposure by approximately 77% and raises myopathy risk. 1, 2
Mechanism and Magnitude of Interaction
Amlodipine increases simvastatin systemic exposure by 77% when 10 mg amlodipine is co-administered with 80 mg simvastatin, primarily through inhibition of CYP3A-mediated metabolism 2
The FDA drug label mandates dose restriction: simvastatin must not exceed 20 mg daily when combined with any dose of amlodipine 2
This interaction is classified as "minor" by the American Heart Association but requires mandatory dose restrictions due to increased myopathy risk 3
The 20 mg maximum is less restrictive than the 10 mg limit required with diltiazem or verapamil, which increase simvastatin AUC by 5-fold 1, 3
Clinical Management Algorithm
If currently on simvastatin >20 mg daily:
- Reduce simvastatin to 20 mg daily maximum when adding amlodipine 1, 2
- Monitor for muscle symptoms (myalgia, weakness) and check CPK if symptoms develop 4
If higher-intensity statin therapy is needed:
- Switch to atorvastatin, which has no significant interaction with amlodipine and requires no dose adjustment 1, 3
- Alternative statins without interaction include rosuvastatin, pravastatin, fluvastatin, or pitavastatin 1
If continuing simvastatin ≤20 mg with amlodipine:
- Check baseline liver enzymes and CPK before initiating combination 4
- Counsel patients to report muscle pain, tenderness, or weakness immediately 4
High-Risk Populations Requiring Extra Caution
Patients of Asian origin require special caution with any statin-calcium channel blocker combination 1
Elderly patients taking multiple concomitant medications are at increased risk for adverse effects 1
Patients with hepatic insufficiency have 40-60% increased amlodipine AUC and may require lower initial doses 2
Real-World Safety Data
A large secondary care analysis of 67,081 patients receiving combined amlodipine and simvastatin found muscular discomfort in only 6.20% of patients, which was actually lower than the 8.04% rate in patients on simvastatin alone 5
Despite the pharmacokinetic interaction, real-world evidence suggests the combination is generally well-tolerated when dose restrictions are followed 5
However, regulatory guidance must be followed regardless of observational data—the 20 mg maximum is mandatory per FDA labeling 2
Common Pitfalls to Avoid
Do not confuse amlodipine with diltiazem or verapamil—these non-dihydropyridine calcium channel blockers have much more potent interactions requiring a 10 mg simvastatin maximum 4, 1
Do not prescribe simvastatin 80 mg to any patient on amlodipine—this violates FDA labeling and significantly increases myopathy risk 2
Do not assume all statins interact similarly with amlodipine—atorvastatin, rosuvastatin, pravastatin, fluvastatin, and pitavastatin can be co-administered without dose adjustment 4, 1