Xifaxan Side Effects: What You Should Know

Xifaxan (Rifaximin) is a gut-targeted antibiotic used to treat hepatic encephalopathy (HE), irritable bowel syndrome with diarrhea (IBS-D), and travelers' diarrhea. Because it's minimally absorbed into the bloodstream — less than 0.4% — it tends to cause fewer systemic side effects than traditional antibiotics. But like every medication, Xifaxan can cause side effects. Here's what to expect, what's normal, and when you should call your doctor.

What Is Xifaxan?

Xifaxan is a brand-name prescription antibiotic made by Salix Pharmaceuticals (a division of Bausch Health). Its active ingredient, Rifaximin, belongs to the rifamycin class of antibiotics and works locally in your gut to reduce harmful bacteria. For a deeper look at how it works, see our guide to Xifaxan's mechanism of action. For full prescribing details, check our Xifaxan uses and dosage overview.

Common Side Effects

The following side effects were reported in clinical trials and are listed in Xifaxan's FDA-approved labeling. Most are mild to moderate and often resolve on their own:

• Peripheral edema — Swelling in the ankles, feet, or lower legs. This is one of the most commonly reported side effects, particularly in patients taking Xifaxan for hepatic encephalopathy.
• Nausea — A feeling of queasiness that usually improves within the first few days of treatment.
• Fatigue — Feeling unusually tired or lacking energy.
• Dizziness — Lightheadedness, especially when standing up quickly.
• Headache — Mild to moderate headaches that typically respond to over-the-counter pain relievers.
• Constipation — Some patients experience a change in bowel habits while taking Xifaxan.
• Abdominal pain — Stomach discomfort or cramping.
• Muscle spasms — Involuntary muscle contractions, usually mild.
• Increased liver enzymes — Detected through blood tests. Your doctor may monitor liver function periodically.
• Ascites — Fluid accumulation in the abdomen, primarily seen in hepatic encephalopathy patients who already have liver disease.

Most of these side effects affect a small percentage of patients. If any of them persist for more than a few days or become bothersome, let your doctor know.

Serious Side Effects

Serious side effects from Xifaxan are uncommon but require immediate medical attention:

• Clostridioides difficile-associated diarrhea (CDAD) — Like most antibiotics, Xifaxan can disrupt gut flora enough to allow C. difficile bacteria to overgrow. Symptoms include severe watery diarrhea, abdominal pain, and fever. Contact your doctor immediately if you develop persistent diarrhea during or after treatment.
• Severe allergic reactions — Although rare, anaphylaxis and angioedema (severe swelling of the face, lips, tongue, or throat) have been reported. Seek emergency medical care if you experience hives, difficulty breathing, or swelling after taking Xifaxan.
• Drug-resistant bacteria — Prolonged or repeated use of any antibiotic can lead to resistant bacteria. Your doctor will weigh this risk when prescribing Xifaxan, especially for repeat IBS-D courses.

Xifaxan does not carry an FDA boxed warning, which is the most serious type of safety alert. This reflects its relatively favorable safety profile compared to many other medications.

Side Effects in Specific Populations

Patients with Liver Disease

If you have severe hepatic impairment (Child-Pugh Class C), your body may absorb more Rifaximin than usual because the liver can't process it as efficiently. This can increase the risk and severity of systemic side effects. Your doctor may monitor you more closely.

Pregnant or Nursing Women

Xifaxan is classified as Pregnancy Category C, meaning animal studies have shown potential risk but there aren't enough human studies to be certain. Use it during pregnancy only if the potential benefit justifies the risk. Talk to your doctor if you're pregnant, planning to become pregnant, or breastfeeding.

Children and Adolescents

Xifaxan is approved for travelers' diarrhea in patients 12 and older. It has not been established as safe for children under 18 for IBS-D or hepatic encephalopathy.

How to Manage Common Side Effects

Here are practical tips for dealing with the most frequently reported side effects:

• For swelling (peripheral edema): Elevate your legs when resting. Reduce sodium intake. Let your doctor know if swelling worsens or doesn't improve.
• For nausea: Take Xifaxan with a small meal or snack. Ginger tea or over-the-counter remedies like Dramamine may help.
• For fatigue: Get adequate rest and stay hydrated. Fatigue often improves as your body adjusts to the medication.
• For dizziness: Stand up slowly from sitting or lying positions. Avoid driving or operating heavy machinery if dizziness is significant.
• For headache: Over-the-counter pain relievers like Acetaminophen (Tylenol) are generally safe to take with Xifaxan. Ask your pharmacist to confirm.
• For constipation: Increase fiber and fluid intake. A mild stool softener may help.

Be aware that Xifaxan has drug interactions that could affect side effects. For example, P-glycoprotein inhibitors like Cyclosporine can significantly increase how much Rifaximin your body absorbs, which may increase the likelihood of side effects.

When to Call Your Doctor

Contact your healthcare provider if you experience:

• Severe or persistent diarrhea (especially with blood, mucus, or fever)
• Signs of an allergic reaction — hives, rash, swelling, difficulty breathing
• Significant swelling that doesn't improve
• New or worsening symptoms that concern you

Don't stop taking Xifaxan without talking to your doctor first, especially if you're taking it for hepatic encephalopathy. Stopping suddenly could lead to a recurrence of HE symptoms.

Final Thoughts

Xifaxan has a solid safety profile for a prescription antibiotic, largely because it stays in your gut rather than circulating throughout your body. Most side effects are mild, and serious reactions are rare. The key is knowing what to watch for and when to reach out to your healthcare team. If you're just starting Xifaxan and want to learn more about the medication, check out our complete guide to Xifaxan. If cost is a concern, explore savings programs and coupons to keep your prescription affordable.