Macitentan and Voriconazole: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Voriconazole
Macitentan
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
An increased macitentan exposure and an increased risk of macitentan-related adverse reactions
Interaction Deep Dive
Avoid concomitant use of macitentan with voriconazole2. Coadministration of voriconazole with macitentan (CYP3A4/CYP2C9 substrate) may increase macitentan exposure which may increase risk of macitentan adverse effects. Reduce dosage of macitentan and monitor for adverse reactions 3. Select other treatment options for pulmonary arterial hypertension if required the use of voriconazole 2 for HIV treatment 1.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated metabolism of macitentan; inhibition of CYP2C9-mediated metabolism of macitentan
Literature reports
5 reports — tap to read
a) In an independent published study, concomitant use of voriconazole (400 mg every 12 hours on Day 1, then 200 mg every 12 hours on Day 2) with a single intravenous dose of fentaNYL (CYP3A4 substrate) (5 microgram/kg) resulted in an increase in the mean AUC (0 to inf) of fentaNYL by 1.4-fold (range 0.81- to 2.04-fold) 3.
b) In another independent published study, coadministration of multiple doses of oral voriconazole (400 mg every 12 hours, on Day 1 followed by five doses of 200 mg every 12 hours on Days 2 to 4) with a single 10 mg oral dose of oxyCODONE (CYP3A4 substrate) on Day 3 resulted in an increase in the mean Cmax and AUC (0 to inf) of oxyCODONE by 1.7-fold (range 1.4- to 2.2-fold) and 3.6- fold (range 2.7- to 5.6-fold), respectively. The mean elimination half-life of oxyCODONE was also increased by 2.0-fold (range 1.4- to 2.5-fold) 3.
c) In stable renal transplant recipients receiving chronic cycloSPORINE (CYP3A4 substrate) therapy, concomitant administration of oral voriconazole (200 mg every 12 hours for 8 days) increased cycloSPORINE Cmax and AUC (tau) an average of 1.1 times (90% CI: 0.9, 1.41) and 1.7 times (90% CI: 1.5, 2.0), respectively, as compared to when cycloSPORINE was administered without voriconazole 3.
d) In a 2-period, open-label, crossover, randomized study in 10 healthy subjects, coadministration of ketoconazole with macitentan resulted in an approximately 2-fold increase in AUC (0 to infinity) and a 26% reduction in the formation of its active metabolite (ACT-132577). Subjects received macitentan 10 mg single-dose on day 1 followed by ketoconazole 400 mg daily for 4 days, with concurrent macitentan 10 mg on day 5, and then ketoconazole 400 mg daily for 19 more days. The geometric mean ratio for the AUC (0 to infinity) and Cmax of macitentan given with or without ketoconazole were 2.3 (90% CI, 2.1 to 2.5) and 1.3 (90% CI, 1.2 to 1.4), respectively. The AUC (0 to infinity) of ACT-132577 was 0.74 (90 %CI, 0.66 to 0.84) 4.
e) Coadministration of macitentan with a moderate dual inhibitor of CYP3A4 and CYP2C9 such as fluconazole (400 mg once daily) is predicted to increase macitentan exposure approximately 4-fold without relevant effect on the exposure to its active metabolite in a physiologically based pharmacokinetic (PBPK) modeling and simulations based analysis 2.
Common questions
Can I take Macitentan and Voriconazole together?
An increased macitentan exposure and an increased risk of macitentan-related adverse reactions Always confirm with your pharmacist or prescriber before making any change.
How serious is the Macitentan and Voriconazole 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 Macitentan or Voriconazole 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 (4)
- Product Information: OPSUMIT(R) oral tablets, macitentan oral tablets. Actelion Pharmaceuticals US Inc (per FDA), Titusville, NJ, 2023. DailyMed
- Product Information: OPSYNVI(R) oral tablets, macitentan tadalafil oral tablets. Actelion Pharmaceuticals US, Inc. (Per FDA), Titusville, NJ, 2024. DailyMed
- Product Information: VFEND(R) oral tablets, oral suspension, intravenous injection, voriconazole oral tablets, oral suspension, intravenous injection. Roerig (per FDA), New York, NY, 2025. DailyMed
- Atsmon J, Dingemanse J, Shaikevich D, et al: Investigation of the effects of ketoconazole on the pharmacokinetics of macitentan, a novel dual endothelin receptor antagonist, in healthy subjects. Clin Pharmacokinet 2013; 52(8):685-692. PubMed
Keep reading about Voriconazole
Keep reading about Macitentan
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