Relugolix and Ensitrelvir: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 2, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Relugolix
Ensitrelvir
No brand names on record
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. Relugolix (Orgovyx) relies on a little pump in your gut called P-gp to help control how much of it gets into your body. Ensitrelvir can slow that pump down. When the pump is slowed, more relugolix can build up in your bloodstream than expected.
Higher levels can mean a stronger effect and a greater chance of side effects. The good news is that this is manageable. Your care team can adjust things and keep a closer eye on you if you need both drugs. Please don't stop or change either medicine on your own, just check in with your pharmacist or doctor.
Mechanism: Relugolix is a P-glycoprotein (P-gp) substrate; ensitrelvir inhibits P-gp-mediated intestinal efflux, reducing efflux and increasing relugolix systemic exposure. Neither is a relevant prodrug here, so the effect is increased relugolix exposure and effect.
- Direction/magnitude: Increased relugolix AUC/Cmax expected. Reference data with digoxin (a probe P-gp substrate) showed Cmax up 2.17-fold and AUC up 1.31-fold with ensitrelvir 500 mg.
- Evidence: Probable. Severity: major. Onset: unspecified.
- Management: Combination may pose severe risk; the relugolix dose may need individualization and closer clinical monitoring. Consult prescribing information for coadministration guidance.
What happens
Increased risk of P-gp substrate exposure
Interaction Deep Dive
When ensitrelvir is given together with P-gp substrates, exposure to those substrates may rise, which carries the potential for severe, life-threatening, or fatal outcomes stemming from the elevated P-gp substrate levels. In a study where a single 500 mg dose of ensitrelvir (a dose that is not recommended for ensitrelvir) was co-administered with a single oral dose of a transporter cocktail that included 0.25 mg digoxin, digoxin Cmax rose 2.17-fold and its AUC(0 to inf) rose 1.31-fold1.
Why it happens (mechanism)
Inhibition of P-gp-mediated efflux transport by ensitrelvir
How to manage this interaction
What your care team may do:
- Individualize and possibly adjust your relugolix dose while you are also taking ensitrelvir.
- Monitor you more closely for stronger relugolix effects or side effects.
- Consider timing or alternative options where appropriate.
What you should do:
- Keep taking both medicines exactly as prescribed unless your team tells you otherwise.
- Tell your pharmacist and prescriber that you take both, and mention any new or worsening symptoms.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) Giving ensitrelvir (a single 500 mg dose, which is not an approved dose of ensitrelvir) together with a single oral dose of a transporter cocktail that contained 0.25 mg digoxin produced a 2.17-fold rise in the Cmax and a 1.31-fold rise in the AUC(0 to inf) of digoxin 1.
Common questions
Can I take Relugolix and Ensitrelvir together?
Ensitrelvir can raise relugolix levels by blocking the P-gp pump, which may increase side effects, so tell your care team you take both so they can adjust your dose and monitor you. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Relugolix and Ensitrelvir 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 Relugolix and Ensitrelvir interaction managed?
What your care team may do: Individualize and possibly adjust your relugolix dose while you are also taking ensitrelvir. Monitor you more closely for stronger relugolix effects or side effects. Consider timing or alternative options where appropriate. What you should do: Keep taking both medicines exactly as prescribed unless your team tells you otherwise. Tell your pharmacist and prescriber that… 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.
Questions for your pharmacist
- Does my dose of Relugolix or Ensitrelvir 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: XOCOVA® oral tablets, ensitrelvir oral tablets. Shionogi Inc. Florham Park, NJ, 2026.
Keep reading about Relugolix
Keep reading about Ensitrelvir
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