Simvastatin and Levoketoconazole: 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
Simvastatin
Levoketoconazole
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.
These two medicines should not be taken together. Your body uses a liver enzyme called CYP3A4 to break down simvastatin (a cholesterol drug). Levoketoconazole (Recorlev) blocks that enzyme, so simvastatin can build up to much higher levels than intended.
When statin levels get too high, the risk of muscle problems goes up. This can mean muscle pain, weakness, or in rare cases a serious muscle injury that affects the kidneys. Because this combination is contraindicated, the good news is your care team can manage it easily by choosing a different plan. Please talk with your pharmacist or doctor before taking both, and do not stop anything on your own.
Contraindicated combination. Levoketoconazole is a strong CYP3A4 inhibitor; simvastatin is a sensitive CYP3A4 substrate (not a prodrug in the relevant sense here). Inhibition markedly reduces simvastatin clearance, increasing its systemic exposure.
- Direction: Increased simvastatin AUC/Cmax and elevated statin-related toxicity risk.
- Magnitude: Study with felodipine showed AUC +1007%, Cmax +937%, illustrating the potency of CYP3A4 inhibition.
- Risk: Dose-dependent myopathy/rhabdomyolysis.
- Evidence: Probable.
- Management: Avoid coadministration. Select a non-CYP3A4-dependent statin or alternative lipid strategy per prescriber.
What happens
Increased CYP3A4 substrate exposure and an increased risk of sensitive CYP3A4 substrate-related adverse reaction
Interaction Deep Dive
The combination of levoketoconazole with sensitive CYP3A4 substrates is contraindicated. Because levoketoconazole inhibits CYP3A4, giving it together with a sensitive CYP3A4 substrate can raise the substrate's exposure and heighten the likelihood of adverse reactions related to that substrate. Findings from a drug interaction study showed that when levoketoconazole 400 mg once daily was administered alongside felodipine (a sensitive CYP3A4 substrate), felodipine AUC rose by 1007% and Cmax rose by 937%1.
Why it happens (mechanism)
Inhibition of CYP3A4-substrate metabolism by levoketoconazole
How to manage this interaction
This pairing is labeled contraindicated, so the usual approach is to avoid using them together rather than adjust the dose.
- Keep taking your medicines as prescribed until you have spoken with your care team. Do not stop on your own.
- Your prescriber may choose an alternative, such as a different cholesterol medicine that does not rely on the same liver enzyme, or a different treatment plan.
- Tell your pharmacist and doctor that you have been prescribed both drugs so they can sort out the safest option.
- Report any muscle pain, tenderness, weakness, or dark-colored urine right away.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) In a study of drug interactions, giving levoketoconazole 400 mg once daily together with felodipine (a sensitive CYP3A4 substrate) raised the felodipine AUC and Cmax by 1007% and 937%, respectively, when compared with felodipine given by itself (N=14) 1.
Common questions
Can I take Simvastatin and Levoketoconazole together?
Levoketoconazole strongly blocks the enzyme that clears simvastatin, so simvastatin can build up and raise the risk of serious muscle injury; this combination is contraindicated, so contact your pharmacist or doctor before taking both. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Simvastatin and Levoketoconazole interaction?
It is rated contraindicated. These should generally not be used together.
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 Levoketoconazole interaction managed?
This pairing is labeled contraindicated, so the usual approach is to avoid using them together rather than adjust the dose. Keep taking your medicines as prescribed until you have spoken with your care team. Do not stop on your own. Your prescriber may choose an alternative, such as a different cholesterol medicine that does not rely on the same liver enzyme, or a different treatment plan. Tell yo… 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 Levoketoconazole 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 (1)
- Product Information: RECORLEV(R) oral tablets, levoketoconazole oral tablets. Xeris Pharmaceuticals Inc (per FDA), Chicago, IL, 2023. DailyMed
Keep reading about Simvastatin
Keep reading about Levoketoconazole
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