Rapamycin (Sirolimus) and Apixaban Interaction: What Clinicians and Patients Need to Know

Do sirolimus and apixaban interact?

Sirolimus is a substrate of CYP3A4 and P-glycoprotein, and the Rapamune label says inhibitors of these pathways may increase sirolimus concentrations and inducers may decrease them [1]. Apixaban is also a substrate of CYP3A4 and P-glycoprotein; about 27% of its clearance is renal and its half-life is about 12 hours [2][5].

The Rapamune interaction section does not name apixaban [1]. The one drug the label lists under drugs whose own concentrations could increase when given with Rapamune is verapamil [1].

What the Rapamune label warns about

The Rapamune label covers sirolimus tablets and oral solution (Pfizer; label effective 2026-03-26) [1]. It says to avoid strong CYP3A4 and P-gp inhibitors (ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin) and strong inducers (rifampin, rifabutin), and to use caution with weaker modulators such as diltiazem, verapamil, fluconazole, cimetidine and the HIV or hepatitis C protease inhibitors [1]. Cannabidiol can raise sirolimus blood levels [1].

Grapefruit juice is a separate, explicit rule: because it inhibits the CYP3A4-mediated metabolism of sirolimus, the label says it must not be taken with Rapamune or used to dilute it [1].

What studies show about apixaban with dual P-gp and CYP3A4 drugs

The measured numbers for apixaban come from small pharmacokinetic studies of other drugs, not from sirolimus:

• Ketoconazole 400 mg daily, 18 healthy subjects, apixaban 10 mg: peak apixaban concentration rose 62% (90% CI 47 to 78) and AUC rose 99% (90% CI 81 to 118) [3].
• Diltiazem 360 mg daily, 18 healthy subjects: peak concentration rose 31% (90% CI 16 to 49) and AUC rose 40% (90% CI 23 to 59) [3].
• Rifampin 600 mg daily, 20 healthy participants: oral apixaban AUC fell 54%, and absolute oral bioavailability dropped from 49% to 39% [2].

The Eliquis label says that in patients taking 5 mg or 10 mg twice daily, the dose should be cut by 50% with combined P-gp and strong CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir), and that the combination should be avoided in patients already on 2.5 mg twice daily. It also says to avoid combined P-gp and strong CYP3A4 inducers such as rifampin, carbamazepine, phenytoin and St. John's wort.

Diltiazem appears on both sides: the Rapamune label separately lists it as a drug that can raise sirolimus concentrations [1]. That is diltiazem acting on sirolimus, not sirolimus acting on apixaban. The magnitudes above were measured for other drugs and should not be assumed to apply to sirolimus.

What real-world data show about P-gp/CYP3A4 inhibitors with DOACs

A Belgian nationwide observational cohort followed 193,072 adults with atrial fibrillation on a DOAC between 2013 and 2019. Concomitant use of a P-gp/CYP3A4 inhibitor was associated with more major bleeding (adjusted hazard ratio 1.24, 95% CI 1.18 to 1.30); among apixaban users specifically the adjusted hazard ratio was 1.27 (95% CI 1.16 to 1.39) [6].

The inhibitors that showed a significant increase in major bleeding were amiodarone (1.27), diltiazem (1.28), verapamil (1.36), ticagrelor (1.50) and clarithromycin (1.55) [6]. This is observational data and subject to confounding.

What bleeding looks like for each drug

In ARISTOTLE, which randomized 18,201 people with atrial fibrillation to apixaban 5 mg twice daily or warfarin, major bleeding occurred at 2.13% per year on apixaban versus 3.09% per year on warfarin (hazard ratio 0.69, 95% CI 0.60 to 0.80), and hemorrhagic stroke at 0.24% versus 0.47% [4]. The Eliquis label warns that it can cause serious, potentially fatal bleeding. Its boxed warning covers the increased risk of thrombotic events if an oral anticoagulant is stopped early, and the risk of spinal or epidural hematomas with neuraxial anesthesia or spinal puncture.

On the sirolimus side, thrombocytopenia is a common labeled reaction at transplant doses: in a renal transplant study where everyone also received cyclosporine and corticosteroids, it occurred in 30% of patients on sirolimus 5 mg daily, 14% on 2 mg daily and 9% on placebo [1]. Those are transplant doses, not the intermittent low doses used in longevity research. The 48-week PEARL trial reported adverse and serious adverse events similar across placebo, 5 mg weekly and 10 mg weekly groups [7].

Rapamycin for longevity: off-label, and different doses

The Rapamune label's approved uses are prevention of organ rejection in kidney transplant recipients aged 13 and older, and treatment of lymphangioleiomyomatosis [1]. There is no approval for aging or longevity, so that use is off-label, and compounded rapamycin is not FDA-approved [1][8].

The human longevity data are small and short. The PEARL trial was a 48-week double-blind, placebo-controlled study in healthy adults undergoing normative aging, comparing placebo with 5 mg or 10 mg compounded rapamycin taken once weekly; visceral fat did not change (p=0.942), adverse events were similar across groups, and the authors concluded the drug was relatively safe over 48 weeks without establishing efficacy. There was no lifespan outcome [7]. An earlier pilot randomized 25 adults aged 70 to 95 to rapamycin 1 mg daily or placebo, with 11 and 14 completing at least 8 weeks; reported side effects in the rapamycin group were facial rash (1), stomatitis (1) and gastrointestinal issues (2), and that group had significant decreases in hemoglobin, hematocrit, red cell count, RDW, MCV and MCH [9].