Lefamulin and Fosphenytoin: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Fosphenytoin
Lefamulin
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 happens
Reduced lefamulin exposure, reduced efficacy of lefamulin and an increased risk of QT interval prolongation
Interaction Deep Dive
Avoid concomitant use of lefamulin with fosphenytoin (strong inducers of CYP3A4 and P-gp) unless the benefit outweighs the risks, as it may reduce lefamulin exposure and may also reduce efficacy of lefamulin. Also, avoid lefamulin use in patients receiving drugs that prolong the QT interval including fosphenytoin; monitor ECG during treatment if coadministration cannot be avoided. Oral rifAMPin (a strong CYP3A4 inducer and P-gp inducer) reduced the mean lefamulin AUC and Cmax by 28% and 8%, respectively, when administered concomitantly with IV lefamulin. Additionally, oral rifAMPin reduced the mean lefamulin AUC and Cmax by 72% and 57%, respectively, when administered concomitantly with oral lefamulin1.
Why it happens (mechanism)
Induction of CYP3A4-mediated lefamulin metabolism; induction of P-gp-mediated efflux transport of lefamulin; additive QT interval prolongation
Literature reports
1 report — tap to read
a) Oral rifAMPin (a strong CYP3A4 inducer and P-gp inducer) reduced the mean lefamulin AUC(0 to inf) and Cmax by 28% and 8%, respectively, when administered concomitantly with IV lefamulin. Additionally, oral rifAMPin reduced the mean lefamulin AUC(0 to inf) and Cmax by 72% and 57%, respectively, when administered concomitantly with oral lefamulin 1.
Common questions
Can I take Lefamulin and Fosphenytoin together?
Reduced lefamulin exposure, reduced efficacy of lefamulin and an increased risk of QT interval prolongation Always confirm with your pharmacist or prescriber before making any change.
How serious is the Lefamulin and Fosphenytoin 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 strong is the evidence for this interaction?
The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
Questions for your pharmacist
- Does my dose of Lefamulin or Fosphenytoin 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: XENLETA(R) oral tablets, intravenous injection, lefamulin oral tablets, intravenous injection. Nabriva Therapeutics US Inc (per FDA), King of Prussia, PA, 2021. DailyMed
Keep reading about Fosphenytoin
Keep reading about Lefamulin
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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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