Epclusa Side Effects: What to Expect and When to Call Your Doctor

Epclusa (sofosbuvir 400 mg/velpatasvir 100 mg) is one of the best-tolerated hepatitis C treatments ever developed. Most patients complete the 12-week course without significant problems. That said, side effects can occur, and there are a few serious warnings you need to know before starting treatment. This guide tells you exactly what to expect.

The Boxed Warning: Hepatitis B Reactivation

Before anything else, you need to know about Epclusa's most serious risk: hepatitis B virus (HBV) reactivation. The FDA has issued a boxed warning — the most serious type of drug warning — because HBV reactivation has been reported in people who had both HCV and HBV infection when they took Epclusa.

HBV reactivation can cause serious liver problems, including liver failure, and in rare cases, death. This is why your doctor will test you for hepatitis B (HBsAg and anti-HBc) before starting Epclusa. If you've ever had hepatitis B — even if it was resolved — your doctor needs to know. Never start Epclusa without HBV screening.

Common Side Effects of Epclusa (Experienced by ≥10% of Patients)

The good news: the most common side effects of Epclusa in adults and children 6 years and older are mild:

• Headache — the most commonly reported side effect, usually mild
• Fatigue (tiredness) — also common and reported by many patients, usually manageable

For children younger than 6 years receiving Epclusa oral pellets, the most common side effects are vomiting and spitting up the medicine. Administering the pellets with food in this age group helps with tolerability.

Other Reported Side Effects (Less Common)

In patients taking Epclusa plus ribavirin (required for decompensated cirrhosis), additional side effects are more common because ribavirin adds to the side effect burden. In clinical trials of this combination, the following were reported in ≥10% of patients with decompensated cirrhosis:

• Fatigue (32%)
• Anemia (26%) — ribavirin is a major contributor to this
• Nausea (15%)
• Headache (11%)
• Insomnia (11%)
• Diarrhea (10%)

Serious Warning: Slow Heart Rate with Amiodarone

If you take amiodarone (Cordarone, Nexterone, Pacerone) for a heart rhythm problem, do NOT take Epclusa without your doctor's specific review. Taking Epclusa with amiodarone can cause a serious, potentially life-threatening slowing of the heart rate (bradycardia). In some cases, this has led to death or the need for a pacemaker.

If you take amiodarone and are prescribed Epclusa, seek emergency care immediately if you experience any of these symptoms after starting treatment:

• Fainting or near-fainting
• Dizziness or lightheadedness
• Shortness of breath or chest pain
• Confusion or memory problems
• Extreme tiredness or weakness

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Side Effects in Special Populations

Some patient groups have additional considerations:

• Patients with diabetes: Curing hepatitis C may significantly improve blood sugar control. Monitor blood glucose closely during and after treatment — some patients require adjustments to diabetes medications.
• Patients on HIV antiretrovirals: Monitor for tenofovir-associated effects (kidney and bone toxicity) if taking tenofovir DF alongside Epclusa.
• Pregnant patients: When used with ribavirin, both Epclusa and ribavirin can cause fetal harm. Two forms of contraception are required during treatment and for 6 months after.

When to Call Your Doctor During Epclusa Treatment

Call your doctor or seek urgent care if you experience any of the following:

• Symptoms of HBV reactivation: jaundice (yellowing of skin/eyes), dark urine, severe fatigue, nausea, or abdominal pain
• Slow heart rate symptoms (especially if on amiodarone): dizziness, fainting, shortness of breath
• Signs of allergic reaction: rash, hives, swelling of the face, lips, tongue, or throat
• Worsening liver symptoms (for patients with cirrhosis)

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The Big Picture on Epclusa Safety

Epclusa has a strong safety profile. For most patients, headache and fatigue are the main issues — and they're generally mild enough that patients complete the full 12 weeks without stopping. The serious risks (HBV reactivation, bradycardia with amiodarone) are manageable with proper screening. For more about Epclusa, read our guides on drug interactions and what Epclusa is and how it's used.