Ketoconazole Topical and Macitentan: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Ketoconazole Topical
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
Increased macitentan exposure
Interaction Deep Dive
Avoid coadministration of macitentan with strong CYP3A4 inhibitors. Select other treatment options for pulmonary arterial hypertension if required the use of strong CYP3A4 inhibitors1 for HIV treatment 2. In a pharmacokinetic study, coadministration of ketoconazole (a strong CYP3A4 inhibitor) with macitentan (a CYP3A4 substrate) resulted in approximately double the systemic exposure to macitentan 3. Also, 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 1.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated metabolism of macitentan
Literature reports
2 reports — tap to read
a) 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) 3.
b) 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 1.
Common questions
Can I take Ketoconazole Topical and Macitentan together?
Increased macitentan exposure Always confirm with your pharmacist or prescriber before making any change.
How serious is the Ketoconazole Topical and Macitentan 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 "probable". Good supporting evidence, though not definitively proven.
Questions for your pharmacist
- Does my dose of Ketoconazole Topical or Macitentan 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 (3)
- Product Information: OPSYNVI(R) oral tablets, macitentan tadalafil oral tablets. Actelion Pharmaceuticals US, Inc. (Per FDA), Titusville, NJ, 2024. DailyMed
- Product Information: OPSUMIT(R) oral tablets, macitentan oral tablets. Actelion Pharmaceuticals US Inc (per FDA), Titusville, NJ, 2023. 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 Ketoconazole Topical
Keep reading about Macitentan
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