Simvastatin and Ranolazine: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 4, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Ranolazine
Simvastatin
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
Here's what's going on. Ranolazine (Ranexa) slows down the liver enzyme that breaks down simvastatin (Zocor). When that happens, more simvastatin builds up in your body, roughly 80% more in one study. Higher statin levels raise the chance of muscle problems, including a rare but serious one called rhabdomyolysis, where muscle breaks down and can hurt your kidneys.
Watch for new or unusual muscle pain, tenderness, weakness, or dark (cola-colored) urine, and report those right away. The good news is your care team manages this easily, often by keeping the simvastatin dose lower. Don't stop either medicine on your own. Just check in with your pharmacist or doctor.
Mechanism: Ranolazine inhibits CYP3A4, reducing metabolism of simvastatin (a CYP3A4 substrate), increasing systemic exposure. Neither is a prodrug in a way that reverses this; the effect is increased statin exposure and myotoxicity risk.
- Magnitude: Simvastatin AUC increased ~80%; ranolazine SR 1000 mg BID raised simvastatin and simvastatin acid AUC 1.86- and 2.26-fold, Cmax 1.75- and 2.28-fold.
- Risk: Myopathy/rhabdomyolysis; case report at simvastatin 80 mg/day plus ranolazine 500 mg/day.
- Evidence: Probable; severity major.
- Management: Do not exceed simvastatin 20 mg/day with ranolazine. Monitor for muscle symptoms and CK if indicated.
What happens
Increased simvastatin exposure and increased risk of rhabdomyolysis
Interaction Deep Dive
Taking ranolazine together with simvastatin raises simvastatin exposure and heightens the likelihood of myopathy and rhabdomyolysis, a result of ranolazine blocking CYP3A4-mediated simvastatin metabolism. In one pharmacokinetic study, simvastatin exposure rose by roughly 80% when the two agents were given together 1. Rhabdomyolysis was reported in a case where ranolazine 500 mg/day was added for a patient who was already on simvastatin 80 mg/day 3. When coadministration of the two drugs cannot be avoided, simvastatin dosing should be capped at 20 mg/day 41. When ranolazine SR 1000 mg was administered twice daily for 7 days alongside simvastatin 80 mg on day 1 and on days 6 through 9, the AUC of simvastatin and simvastatin acid rose 1.86-fold and 2.26-fold, while their Cmax increased 1.75-fold and 2.28-fold, respectively 2.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated simvastatin metabolism
How to manage this interaction
This is manageable with the right dose and monitoring. Keep taking both medicines exactly as prescribed unless your care team tells you otherwise.
- Because ranolazine raises simvastatin levels, guidance is that the simvastatin dose should not exceed 20 mg per day when the two are used together. Your team may adjust and individualize your dose accordingly.
- Your team may watch you more closely for muscle symptoms.
- Report any new muscle pain, tenderness, weakness, or dark urine promptly.
Ask your pharmacist or prescriber to confirm your current simvastatin dose is appropriate with ranolazine.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
3 reports — tap to read
a) In a pharmacokinetic study, simvastatin exposure rose by roughly 80% when simvastatin was given together with ranolazine. Participants took ranolazine sustained-release 1000 mg twice daily for 7 days, and simvastatin 80 mg was given on day 1 and on days 6 through 9. The mean ratio (with ranolazine versus without ranolazine) for simvastatin was 1.86 for AUC and 1.75 for Cmax. The corresponding ratios for simvastatin acid (the beta-hydroxyacid of simvastatin) were 2.26 for AUC and 2.28 for Cmax 1.
b) Rhabdomyolysis was described in a 63-year-old patient after the combined use of ranolazine and simvastatin. This patient, with a medical history that included hyperlipidemia, coronary artery disease, chronic kidney disease, degenerative joint disease, and stroke, was admitted to the hospital reporting weakness in both legs that had begun 3 days prior. Alongside extended-release ranolazine 500 mg/day (which had been introduced 10 days before admission) and simvastatin 80 mg/day, his medications included furosemide, clopidogrel, hydralazine, metoprolol, isosorbide mononitrate, omeprazole, and nitroglycerin. Laboratory findings revealed elevations in creatine kinase (CK) (31,989 units/L; normal 55 to 170 units/L), CK-MB band, troponin, B-type natriuretic peptide, TSH, AST, ALT, and serum creatinine (SCr). The patient received a diagnosis of rhabdomyolysis. Both ranolazine and simvastatin were stopped. On days 4 and 7 of treatment, his CK and SCr levels had improved. By day 18 of hospitalization, serum CK was nearly undetectable and SCr stayed at baseline. On day 32, he was discharged, and no alternative agent for hyperlipidemia was prescribed. The Drug Interaction Probability Scale assigned the interaction between ranolazine and simvastatin a score of 5, denoting a probable link between the concurrent use of these agents and the rhabdomyolysis 3.
c) In a drug interaction study, giving ranolazine SR 1000 mg twice daily for 7 days together with simvastatin 80 mg on day 1 and days 6 to 9 raised the AUC of simvastatin and simvastatin acid by 1.86-fold and 2.26-fold and raised Cmax by 1.75-fold and 2.28-fold respectively 2.
Common questions
Can I take Simvastatin and Ranolazine together?
Ranolazine raises simvastatin levels and the risk of serious muscle damage, so simvastatin should be kept at no more than 20 mg per day when the two are combined. Keep taking both as prescribed and ask your care team to confirm your dose. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Simvastatin and Ranolazine interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How is the Simvastatin and Ranolazine interaction managed?
This is manageable with the right dose and monitoring. Keep taking both medicines exactly as prescribed unless your care team tells you otherwise. Because ranolazine raises simvastatin levels, guidance is that the simvastatin dose should not exceed 20 mg per day when the two are used together. Your team may adjust and individualize your dose accordingly. Your team may watch you more closely for mu… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Simvastatin or Ranolazine need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (4)
- Product Information: ZOCOR(R) oral tablets, simvastatin oral tablets. Organon & Co (per FDA), Jersey City, NJ, 2022. DailyMed
- Product Information: VYTORIN(R) oral tablets, ezetimibe simvastatin oral tablets. Organon LLC (per FDA), Jersey City, NJ, 2024. DailyMed
- Hylton AC & Ezekiel TO: Rhabdomyolysis in a patient receiving ranolazine and simvastatin. Am J Health Syst Pharm 2010; 67(21):1829-1831. PubMed
- Product Information: Ranexa(R) extended-release oral tablets, ranolazine extended-release oral tablets. Gilead Sciences, Inc. (per FDA), Foster City, CA, 2011. DailyMed
Keep reading about Ranolazine
Keep reading about Simvastatin
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