Low-Dose Naltrexone and Rivaroxaban Interaction: What Patients and Prescribers Need to Know

Does Low-Dose Naltrexone Interact With Rivaroxaban?

The naltrexone tablet label says that studies of interactions between naltrexone and drugs other than opioids have not been performed, and that caution is advised if naltrexone is taken with other drugs [1]. Rivaroxaban is not an opioid, disulfiram or thioridazine, so it is not one of the interactions the label names [1].

Low-dose naltrexone has no product label of its own. It is naltrexone at roughly 0.5 to 6 mg a day, most often 4.5 mg, made by compounding pharmacies and used off-label [2][3]. FDA states that compounded drugs are not FDA-approved and that it does not verify their safety, effectiveness or quality before they are marketed [8]. A 2026 review notes that inconsistencies in compounded formulations add uncertainty [2].

What the Naltrexone Label Says About Other Drugs

Opioid-containing medicines. Naltrexone antagonizes opioids, including cough and cold preparations, antidiarrheals and opioid analgesics, so patients may not get their effect [1][9]. The label contraindicates naltrexone in patients receiving opioid analgesics [1].

Disulfiram. The safety and efficacy of combining the two are unknown, and the label says two potentially hepatotoxic medicines are not ordinarily used together unless the probable benefits outweigh the known risks [1].

Thioridazine. Lethargy and somnolence have been reported after doses of naltrexone and thioridazine [1].

Both naltrexone labels were written for the 50 mg tablet and the 380 mg monthly injection, and neither gives guidance on low doses [1][9].

How Rivaroxaban Exposure Can Change

Rivaroxaban is a CYP3A4 and P-glycoprotein substrate, and about one-third of a dose is eliminated through the kidneys [4][5]. A 2008 clinical pharmacology review lists kidney and liver function and interactions with some strong CYP3A4 inhibitors or inducers as the main sources of variability in exposure [5].

The human data in the supplied literature concern St John's wort. In 12 healthy volunteers, two weeks of a Hypericum perforatum extract lowered the rivaroxaban 20 mg AUC ratio to 0.76 (90% CI 0.70 to 0.82), the peak concentration ratio to 0.86 and factor Xa inhibition to 0.80 [6]. A second 12-volunteer study found rivaroxaban AUC and peak concentration about 25% lower after St John's wort, and its authors concluded the combination should be avoided [4]. These studies do not show whether low-dose naltrexone changes rivaroxaban levels.

Bleeding in Context

In ROCKET AF, 14,264 people with non-valvular atrial fibrillation were randomized to rivaroxaban 20 mg daily or dose-adjusted warfarin. Major or clinically relevant non-major bleeding occurred at 14.9% per year with rivaroxaban and 14.5% with warfarin (hazard ratio 1.03). Stroke or systemic embolism occurred at 1.7% versus 2.2% per year in the per-protocol analysis [7].