Xifaxan Drug Interactions You Need to Know About

Xifaxan (Rifaximin) is a gut-targeted antibiotic with minimal systemic absorption — less than 0.4% enters your bloodstream. That's good news for side effects, but it doesn't mean Xifaxan is completely free of drug interactions. Certain medications can dramatically increase how much Xifaxan your body absorbs, and Xifaxan itself can affect how other drugs work. Here's what you need to know.

How Drug Interactions Work with Xifaxan

Because Xifaxan is barely absorbed, its interaction profile is different from most antibiotics. The biggest concern isn't Xifaxan affecting other drugs — it's other drugs affecting Xifaxan. Specifically, medications that block the body's natural "pumps" and transport proteins (like P-glycoprotein) can prevent your gut from keeping Xifaxan local, causing more of it to enter your bloodstream. When systemic exposure increases, so does the risk of side effects.

Additionally, at higher doses, Xifaxan may activate certain liver enzymes (particularly CYP3A4) that break down other medications faster, potentially reducing their effectiveness.

Medications That Interact with Xifaxan

Major Interactions

• Cyclosporine (Sandimmune, Neoral, Gengraf) — This is the most significant interaction. Cyclosporine is a P-glycoprotein (P-gp) inhibitor that can dramatically increase Rifaximin blood levels. In studies, taking Cyclosporine with Xifaxan increased Rifaximin systemic exposure by up to 83-fold. If you're taking Cyclosporine (commonly prescribed after organ transplants or for autoimmune conditions), your doctor needs to carefully weigh the risks before prescribing Xifaxan.
• Other P-glycoprotein inhibitors — Medications that inhibit P-gp can similarly increase Xifaxan absorption. These include:
  • Verapamil (Calan, Verelan) — a blood pressure and heart medication
  • Ketoconazole (Nizoral) — an antifungal
  • Quinidine — a heart rhythm medication
  • Dronedarone (Multaq) — used for atrial fibrillation
  • Amiodarone (Pacerone) — another heart rhythm drug
• OATP inhibitors — Organic anion transporting polypeptide (OATP) inhibitors may also increase Rifaximin absorption. Some statins and other medications affect these transporters.
• Warfarin (Coumadin, Jantoven) — Rifaximin may alter Warfarin's activity by affecting gut bacteria that produce Vitamin K. If you take Warfarin, your doctor should monitor your INR (blood clotting levels) more frequently when starting or stopping Xifaxan.

Moderate Interactions

• Oral contraceptives (birth control pills) — Rifaximin may induce CYP3A4, the liver enzyme that breaks down many oral contraceptives. This could theoretically reduce the effectiveness of birth control pills. While this interaction is considered moderate and hasn't been widely documented with Xifaxan's typical low absorption, it's worth discussing with your doctor. Consider using a backup method of contraception during your Xifaxan course.
• Other CYP3A4 substrates — Medications metabolized by CYP3A4 could potentially be affected by Rifaximin's enzyme-inducing properties. Common CYP3A4 substrates include:
  • Midazolam (Versed) — a sedative
  • Simvastatin (Zocor) — a cholesterol medication
  • Amlodipine (Norvasc) — a blood pressure medication
  • Sildenafil (Viagra) — for erectile dysfunction

Because Xifaxan is minimally absorbed, these CYP3A4 interactions are generally less of a concern than they would be with a fully systemic medication. But they're worth flagging, especially if you're on medications with a narrow therapeutic window.

Supplements and OTC Medications to Watch

Xifaxan has relatively few interactions with over-the-counter medications and supplements, but keep these in mind:

• Probiotics — Some patients wonder if they should take probiotics while on Xifaxan. Since Xifaxan kills gut bacteria, taking probiotics simultaneously may reduce the effectiveness of either product. Talk to your doctor about timing — some providers recommend starting probiotics after completing your Xifaxan course rather than during it.
• Antacids and acid reducers — Medications like Omeprazole (Prilosec), Pantoprazole (Protonix), and other proton pump inhibitors (PPIs) are commonly taken by patients who also need Xifaxan. While there's no major documented interaction, changes in stomach acid can theoretically affect how any oral medication is absorbed. No dose adjustment is typically needed.
• Herbal supplements — St. John's Wort is a known CYP3A4 and P-gp inducer. While it's more likely to decrease Xifaxan levels (the opposite of the P-gp inhibitor concern), the interaction is unpredictable. Mention it to your doctor.

Food and Drink Interactions

• High-fat meals — Eating a high-fat meal can increase Xifaxan absorption. However, no dose adjustment is recommended. You can take Xifaxan with or without food.
• Alcohol — While there's no direct Xifaxan-alcohol interaction listed in the prescribing information, many patients taking Xifaxan for hepatic encephalopathy should already be avoiding alcohol due to their underlying liver disease. For IBS-D patients, alcohol can worsen diarrhea symptoms. Use common sense and follow your doctor's guidance.

What to Tell Your Doctor

Before starting Xifaxan, make sure your doctor and pharmacist know about:

• All prescription medications — Especially Cyclosporine, Warfarin, heart rhythm medications, and any drugs you take after an organ transplant.
• Over-the-counter medications — Including antacids, pain relievers, and allergy medications.
• Supplements and vitamins — Including probiotics, herbal supplements (especially St. John's Wort), and Vitamin K supplements.
• Your complete medical history — Especially liver disease severity, as patients with severe hepatic impairment (Child-Pugh C) absorb more Rifaximin.
• Allergies — Particularly to rifamycin antibiotics like Rifampin (Rifadin), as cross-reactivity is possible.

Don't stop or change any medications on your own. If your doctor identifies a potential interaction, they'll adjust doses or choose an alternative — like one of the Xifaxan alternatives available.

Final Thoughts

Xifaxan's minimal absorption means it has fewer drug interactions than most antibiotics, but the interactions it does have — particularly with P-glycoprotein inhibitors like Cyclosporine — can be significant. The key takeaway: always give your doctor a complete picture of what you're taking. For more about Xifaxan, read our complete guide to Xifaxan, our side effects overview, or explore ways to save on your prescription.