Simvastatin and Larotrectinib: 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
Larotrectinib
No brand names on recordSimvastatin
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.
What's going on: Larotrectinib is a cancer medicine that can slow down a liver enzyme (called CYP3A4) that your body uses to break down simvastatin, a cholesterol medicine. When that enzyme is slowed, more simvastatin can build up in your blood than usual.
Higher simvastatin levels can raise the chance of statin side effects, especially muscle aches, weakness, or soreness, and rarely more serious muscle problems. The good news is your care team knows about this and can manage it. Please don't stop either medicine on your own. Just let your pharmacist or doctor know you take both, and tell them right away if you notice new muscle pain.
Mechanism: Larotrectinib is a moderate CYP3A4 inhibitor; simvastatin is a sensitive CYP3A4 substrate. Inhibition reduces simvastatin clearance, increasing plasma exposure and myotoxicity risk (myalgia, myopathy, rhabdomyolysis). Neither drug is a prodrug in a way that reverses this direction.
- Direction: increased simvastatin exposure (increases drug effect)
- Magnitude: larotrectinib raised midazolam AUC and Cmax ~1.7-fold; simvastatin-specific data not established
- Evidence: theoretical, extrapolated from index substrate
- Onset: unspecified
Management: Avoid coadministration if possible. If unavoidable, monitor for statin adverse effects; the simvastatin dose may need to be individualized by the care team, with consideration of an alternative statin less dependent on CYP3A4.
What happens
Increased sensitive CYP3A4 substrate exposure and increase in the incidence or severity of adverse reactions
Interaction Deep Dive
It is recommended to avoid giving larotrectinib, which inhibits CYP3A4, together with a sensitive CYP3A4 substrate. When the combination cannot be prevented, watch for heightened adverse reactions attributable to the sensitive substrate. Using larotrectinib (a CYP3A4 inhibitor) alongside a sensitive CYP3A4 substrate can raise the plasma levels of that sensitive CYP3A4 substrate, potentially leading to a greater frequency or severity of adverse reactions. When larotrectinib 100 mg twice daily was administered with midazolam, a sensitive CYP3A4 substrate, both the AUC(0 to infinity) and Cmax of midazolam rose 1.7-fold relative to midazolam given by itself1.
Why it happens (mechanism)
Inhibition of CYP3A4 substrate metabolism by larotrectinib
How to manage this interaction
What your care team may do:
- Prefer to avoid using these two together when possible.
- If both are needed, watch you more closely for statin side effects, especially muscle pain, tenderness, or weakness.
- Your simvastatin dose may need to be adjusted and individualized by your care team, or they may consider a different cholesterol medicine.
What you can do:
- Keep taking both exactly as prescribed unless your doctor tells you otherwise.
- Tell your pharmacist or prescriber that you take both drugs.
- Report new or worsening muscle aches, weakness, or dark-colored urine promptly.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) When larotrectinib 100 mg twice daily was given together with midazolam, a sensitive CYP3A4 substrate, both the AUC(0 to infinity) and Cmax of midazolam rose by 1.7-fold relative to midazolam given by itself. The AUC(0 to infinity) and Cmax of 1-hydroxymidazolam, the principal metabolite of midazolam, each increased 1.4-fold 1.
Common questions
Can I take Simvastatin and Larotrectinib together?
Larotrectinib can raise simvastatin levels and increase the risk of muscle side effects, so this combination is best avoided; if you take both, stay alert for muscle pain and let your care team adjust things as needed. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Simvastatin and Larotrectinib 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 Larotrectinib interaction managed?
What your care team may do: Prefer to avoid using these two together when possible. If both are needed, watch you more closely for statin side effects, especially muscle pain, tenderness, or weakness. Your simvastatin dose may need to be adjusted and individualized by your care team, or they may consider a different cholesterol medicine. What you can do: Keep taking both exactly as prescribed unle… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
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 Larotrectinib 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: VITRAKVI(R) oral capsules, oral solution, larotrectinib oral capsules, oral solution. Bayer HealthCare Pharmaceuticals Inc (per FDA), Whippany, NJ, 2022. DailyMed
Keep reading about Larotrectinib
Keep reading about Simvastatin
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