Simvastatin and Lonafarnib: 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
Lonafarnib
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.
These two medicines should not be taken together. Lonafarnib (Zokinvy) slows down a liver enzyme called CYP3A. That same enzyme is what your body uses to break down simvastatin (Zocor). So when you take both, simvastatin can build up to much higher levels than intended.
Too much simvastatin can cause serious muscle problems, including muscle pain, weakness, and a rare but dangerous condition called rhabdomyolysis, where muscle tissue breaks down. The good news is that this is very manageable: your care team can choose a safer cholesterol medicine that does not clash with lonafarnib. Talk with your doctor or pharmacist before starting or stopping anything.
Contraindicated combination. Lonafarnib is a strong CYP3A inhibitor; simvastatin is a CYP3A substrate (active drug, not a prodrug requiring CYP3A). Inhibition markedly reduces simvastatin clearance, increasing systemic exposure and dose-dependent risk of myopathy and rhabdomyolysis.
- Magnitude: No direct simvastatin data; a probe study showed midazolam Cmax +180% and AUC +639% with lonafarnib 100 mg BID, implying substantial CYP3A inhibition.
- Evidence: Theoretical/extrapolated, but labeled contraindicated.
- Management: Avoid coadministration. Select a non-CYP3A-dependent statin per lipid guidance. Monitor for muscle symptoms and CK if inadvertent exposure occurs.
What happens
Increased simvastatin exposure and an increased risk of myopathy or rhabdomyolysis
Interaction Deep Dive
Combining lonafarnib, an inhibitor of CYP3A, with simvastatin, a CYP3A substrate, is contraindicated because such use can raise simvastatin exposure, thereby heightening the potential for simvastatin-associated adverse reactions such as myopathy or rhabdomyolysis. Evidence from a clinical study in healthy subjects showed that when a single 3 mg oral dose of midazolam (a CYP3A substrate) was given alongside repeated oral doses of lonafarnib 100 mg twice daily over 5 days, midazolam Cmax rose by 180% and its AUC rose by 639%1.
Why it happens (mechanism)
Inhibition of CYP3A-mediated metabolism of simvastatin
How to manage this interaction
The main step here is avoidance: because this pair is contraindicated, your care team will typically not use them together.
- Do not start, stop, or change either medicine on your own. Keep taking what is prescribed until you speak with your prescriber.
- Your team may switch you to a different cholesterol medicine that is not broken down by the same enzyme, so it can be used safely alongside lonafarnib.
- Tell your doctor or pharmacist right away if you notice unexplained muscle pain, tenderness, weakness, or dark-colored urine.
Make sure every prescriber and pharmacist has your full medication list so this can be caught and managed.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) In a clinical study in which a single oral dose of 3 mg midazolam (a CYP3A substrate) was given together with multiple oral doses of 100 mg lonafarnib twice daily for 5 days in healthy subjects, the Cmax and AUC of midazolam rose by 180% and 639%, respectively 1.
Common questions
Can I take Simvastatin and Lonafarnib together?
Do not take lonafarnib and simvastatin together, as lonafarnib can raise simvastatin levels and increase the risk of serious muscle damage; ask your doctor or pharmacist about a safer cholesterol medicine. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Simvastatin and Lonafarnib 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 Lonafarnib interaction managed?
The main step here is avoidance: because this pair is contraindicated, your care team will typically not use them together. Do not start, stop, or change either medicine on your own. Keep taking what is prescribed until you speak with your prescriber. Your team may switch you to a different cholesterol medicine that is not broken down by the same enzyme, so it can be used safely alongside lonafarn… 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 Lonafarnib 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: ZOKINVY(TM) oral capsules, lonafarnib oral capsules. Eiger BioPharmaceuticals Inc (per FDA), Palo Alto, CA, 2024. DailyMed
Keep reading about Lonafarnib
Keep reading about Simvastatin
These medications also interact with supplements
Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
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