Xarelto Drug Interactions You Need to Know About

Xarelto (Rivaroxaban) is a powerful blood thinner, and like most anticoagulants, it doesn't play well with certain other medications, supplements, and even some foods. Understanding these interactions can help you avoid dangerous bleeding events or, on the flip side, prevent Xarelto from becoming less effective. Here's what you need to know.

How Drug Interactions Work with Xarelto

Xarelto is processed in your body through two pathways: the CYP3A4 enzyme system in the liver and the P-glycoprotein (P-gp) transport system. Drugs that affect either of these pathways can change how much Xarelto stays in your bloodstream:

• Inhibitors of CYP3A4 and P-gp increase Xarelto levels → higher bleeding risk
• Inducers of CYP3A4 and P-gp decrease Xarelto levels → reduced effectiveness, higher clotting risk

Additionally, any medication that also affects blood clotting can compound Xarelto's anticoagulant effect, raising the risk of bleeding even without changing drug levels.

Major Drug Interactions

These interactions are the most clinically significant and may require avoiding the combination entirely or close medical supervision:

Drugs That Increase Xarelto Levels (Higher Bleeding Risk)

• Ketoconazole (Nizoral) — antifungal
• Itraconazole (Sporanox) — antifungal
• Ritonavir (Norvir) and other HIV protease inhibitors — antivirals
• Clarithromycin (Biaxin) — antibiotic

These are all combined P-gp and strong CYP3A4 inhibitors. Using them with Xarelto can significantly raise Rivaroxaban blood levels, dramatically increasing the risk of major bleeding. Avoid these combinations unless your doctor specifically approves them with close monitoring.

Drugs That Decrease Xarelto Levels (Reduced Effectiveness)

• Rifampin (Rifadin) — antibiotic, commonly used for tuberculosis
• Phenytoin (Dilantin) — seizure medication
• Carbamazepine (Tegretol) — seizure and mood disorder medication
• St. John's Wort — herbal supplement for depression

These are combined P-gp and strong CYP3A4 inducers. They speed up how your body breaks down Xarelto, which means less of the drug stays active in your blood. This can make Xarelto ineffective at preventing clots — a potentially life-threatening problem. Avoid these combinations.

Other Anticoagulants (Double Blood Thinning)

• Warfarin (Coumadin)
• Heparin (injectable)
• Enoxaparin (Lovenox)

Using Xarelto with another anticoagulant dramatically increases bleeding risk. This combination is generally avoided except during carefully supervised transitions (e.g., switching from heparin to Xarelto in the hospital).

Antiplatelet Agents

• Clopidogrel (Plavix)
• Prasugrel (Effient)
• Ticagrelor (Brilinta)

These drugs prevent platelets from clumping together. Combined with Xarelto, they significantly increase bleeding risk. However, some patients (particularly those with coronary artery disease and stents) may need both under careful medical supervision.

Defibrotide

Defibrotide (Defitelio) is contraindicated with Xarelto due to dangerous pharmacodynamic interaction that increases bleeding risk.

Moderate Drug Interactions

These interactions may require dose adjustments or extra monitoring:

NSAIDs (Nonsteroidal Anti-Inflammatory Drugs)

• Ibuprofen (Advil, Motrin)
• Naproxen (Aleve)
• Aspirin

NSAIDs increase the risk of GI bleeding on their own. Combined with Xarelto, the bleeding risk is compounded. If you need pain relief, talk to your doctor about safer alternatives like acetaminophen (Tylenol), which doesn't affect blood clotting.

SSRIs and SNRIs (Antidepressants)

• Fluoxetine (Prozac)
• Venlafaxine (Effexor)
• Duloxetine (Cymbalta)

These antidepressants affect serotonin levels, which can impair platelet function and increase bleeding risk when combined with Xarelto. This doesn't mean you can't take both, but your doctor should be aware so they can monitor you more closely.

Moderate CYP3A4 Inhibitors

• Diltiazem (Cardizem) — blood pressure medication
• Verapamil (Calan) — blood pressure medication
• Erythromycin — antibiotic
• Fluconazole (Diflucan) — antifungal

These moderately increase Xarelto levels. The interaction is less severe than with strong inhibitors, but your doctor may want to monitor you more closely, especially if you also have kidney impairment.

Supplements and Over-the-Counter Products to Watch

• St. John's Wort — Significantly reduces Xarelto effectiveness. Avoid completely.
• Fish oil / Omega-3 supplements — May have mild blood-thinning effects. Discuss with your doctor.
• Vitamin E (high doses) — Can increase bleeding risk.
• Ginkgo biloba — May increase bleeding risk.
• Garlic supplements (high doses) — May have mild anticoagulant properties.
• Aspirin — Even low-dose (81 mg) aspirin increases bleeding risk with Xarelto. Only take if specifically prescribed by your doctor.

Food and Drink Interactions

• Grapefruit juice — May moderately increase Xarelto levels. Occasional consumption is likely fine, but regular or large amounts should be discussed with your doctor.
• Alcohol — Increases bleeding risk and can affect liver function. Moderate alcohol use may be acceptable for some patients, but heavy drinking should be avoided.
• Food and absorption — The 15 mg and 20 mg tablets must be taken with food to ensure proper absorption. Taking them on an empty stomach can result in lower drug levels and reduced effectiveness.

What to Tell Your Doctor

Before starting Xarelto — and at every follow-up — make sure your doctor knows about:

• All prescription medications you take, especially other blood thinners, heart medications, antifungals, antibiotics, HIV medications, and seizure drugs.
• All over-the-counter drugs, including NSAIDs (ibuprofen, naproxen), aspirin, and cold medications.
• All supplements and herbal products, especially St. John's Wort, fish oil, vitamin E, ginkgo, and garlic supplements.
• Any upcoming procedures — dental work, surgery, spinal injections, or epidurals. Xarelto carries a boxed warning about spinal hematoma risk with neuraxial procedures.
• Changes in kidney or liver function, as these affect how your body processes Xarelto.

Keep an updated medication list in your wallet or phone. In an emergency, medical teams need to know you're on a blood thinner — and which one.

Final Thoughts

Xarelto is an effective and convenient blood thinner, but it requires awareness of what you're taking alongside it. The most dangerous interactions involve strong CYP3A4/P-gp inhibitors or inducers, other blood thinners, and common painkillers like ibuprofen. When in doubt, ask your doctor or pharmacist before adding any new medication or supplement to your routine.

Want to learn more about Xarelto? Read our guides on what Xarelto is and how it's used or how Xarelto works. Need to fill your prescription? Visit Medfinder to find Xarelto in stock near you.