Herpes Antiviral Side Effects: Valacyclovir, Acyclovir & More

DISCLAIMER: I'm no doctor, and none of this is medical advice. Please talk to your doctor before starting, stopping, or changing any medication. What I share below is based on published research and FDA prescribing information, but your doctor knows YOUR body and situation.

If you've just been prescribed valacyclovir (Valtrex), acyclovir (Zovirax), or famciclovir (Famvir) and you're sitting there reading the side effects list with growing dread ... take a breath. I've been there. And I want to walk you through this in a way that's actually helpful, not just a wall of scary medical jargon.

The truth? These medications have been around for decades. Acyclovir was approved by the FDA back in 1982. That's over 40 years of data. The World Health Organization includes acyclovir on its List of Essential Medicines, which is basically the global "this is important and safe enough that every country should have access to it" list. So right off the bat, you're not dealing with some experimental drug here.

But you still want to know what to expect. Of course you do. So let's get into it.

The common side effects (and why most people do just fine)

Let's start with the stuff that actually comes up for people. According to FDA prescribing information for both Valtrex (valacyclovir) and Zovirax (acyclovir), the most commonly reported side effects are:

• Headache (the most common one, reported in about 13-38% of patients in clinical trials, though many placebo groups reported similar rates)
• Nausea (usually mild, tends to settle down after the first few days)
• Stomach pain or discomfort
• Dizziness
• Fatigue

Here's the thing most side effect lists don't tell you: in clinical trials, the people taking a sugar pill (placebo) reported headaches and nausea at almost the same rate as the people taking the actual medication. So some of what gets blamed on the medication is just ... being a human body having a human day.

That said, if you're experiencing nausea, try taking your medication with food and a full glass of water. That alone makes a big difference for most people.

Side effect comparison: valacyclovir vs. acyclovir vs. famciclovir

All three of these medications work in a similar way. They're all antivirals that block the herpes virus from replicating. In fact, valacyclovir actually converts into acyclovir once it's in your body (it's basically a more absorbable version of acyclovir). Famciclovir converts into penciclovir. Same goal, slightly different paths.

Here's a comparison to help you see them side by side:

The side effect profiles are quite similar across all three. The biggest practical difference? Valacyclovir only needs to be taken once a day for suppressive therapy, while acyclovir and famciclovir require twice daily dosing. That convenience factor is a big reason valacyclovir is the most commonly prescribed option these days.

The rare but serious stuff (let's be honest about it)

I believe in giving you the full picture, not just the comfortable parts. So here's what you should be aware of, even though these are genuinely rare:

• Kidney issues: Both acyclovir and valacyclovir are processed through your kidneys. In rare cases (especially at high doses or in people with pre-existing kidney problems), they can cause kidney injury. This is why your doctor will tell you to stay hydrated. Drinking plenty of water while on these medications isn't optional advice. It actually matters. If you have kidney disease or are on other medications that affect your kidneys, make sure your doctor knows.
• Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS): This sounds terrifying, and it can be serious. But it has primarily been reported in people who are immunocompromised (like those with advanced HIV or organ transplant recipients) taking very high doses. For healthy people taking standard herpes suppressive doses, this is extremely rare.
• Central nervous system effects: Confusion, agitation, tremors, or hallucinations have been reported in rare cases, mostly in elderly patients or those with kidney impairment where the drug accumulates to higher levels than intended.

I'm not sharing this to scare you. I'm sharing it because you deserve complete information so you can have an informed conversation with your doctor. For the vast majority of people taking standard doses for herpes, these serious side effects are not part of the picture.

Is valacyclovir safe long term? (The big question)

This is the one I hear the most. "Am I going to be on this medication forever? Is that even safe?"

The research is actually really reassuring on this one. A landmark study by Tyring et al. (2012) looked at the long-term safety of acyclovir and valacyclovir and found no significant safety concerns with prolonged use. People have been taking daily suppressive therapy for years (some for decades) without issues.

The FDA prescribing information for Valtrex notes that it has been studied in suppressive therapy for up to one year in clinical trials, and post-marketing surveillance data covers a much longer period. No new or worsening side effects emerged over time.

Here's something that might put your mind at ease: these medications only target cells where the herpes virus is actively replicating. They don't affect your healthy cells. That's a big part of why the safety profile is so good. Your body processes the medication and clears it. It doesn't build up in some harmful way.

That said, my personal philosophy (which I share in my article about herpes medication) is: don't take it if you don't have to. If your body has built up its own immunity and your outbreaks are minimal or nonexistent, talk to your doctor about whether you still need daily medication. But if you DO need it, whether to keep outbreaks at bay or to protect a partner, please don't stress about taking it long-term. The data supports that it's safe.

What about pregnancy?

If you're pregnant or planning to become pregnant, this is absolutely a conversation for you and your OB/GYN. Here's what the research currently shows: acyclovir and valacyclovir are classified as generally considered safe during pregnancy, particularly in the third trimester when suppressive therapy is often recommended to reduce the risk of an outbreak during delivery. Both have extensive pregnancy registry data and have not been associated with an increased risk of birth defects.

Famciclovir has less pregnancy data, so it's not typically the first choice for pregnant patients.

Again, this is your doctor's call. But if your doctor recommends suppressive therapy in your third trimester, the research supports that decision.

Drug interactions to know about

These antivirals are generally well-tolerated alongside other medications, but there are a few things to flag for your doctor:

• Other kidney-affecting drugs: NSAIDs (like ibuprofen) at high doses, certain antibiotics, or other nephrotoxic medications can compound kidney stress when combined with antivirals. Occasional ibuprofen for a headache is different from daily high-dose use.
• Cimetidine and probenecid: These can increase blood levels of acyclovir/valacyclovir because they reduce how quickly your kidneys clear the drug.
• Immunosuppressive drugs: If you're taking medications that suppress your immune system, your doctor needs to monitor you more closely on antivirals.

The bottom line: bring a list of everything you're taking (including supplements) to your doctor and let them sort it out. That's literally their job, and they're good at it.

The bigger picture

Here's what I want you to take away from all of this. Herpes antivirals are among the most well-studied, well-tolerated medications out there. Millions of people take them daily. The common side effects are mild and usually temporary. The serious stuff is rare and mostly limited to people with other health conditions.

If you're newly prescribed and feeling nervous, that's completely normal. Give your body a week or two to adjust. Most people find that any initial side effects (a little nausea, a headache) fade quickly. And if they don't, or if something feels off, talk to your doctor. There are three different medications to choose from, and switching is always an option.

You're not "broken" for needing medication. You're not "damaged" for having a skin condition that sometimes needs medical management. You're a person making a smart, informed choice about your health. And the fact that you're researching side effects before you take something? That tells me you care about your body. Good. Keep caring about it.

You've got this.

Sources

• FDA Prescribing Information: Valtrex (valacyclovir hydrochloride)
• FDA Prescribing Information: Zovirax (acyclovir)
• Tyring SK, et al. (2012). Long-term safety and efficacy of acyclovir/valacyclovir for HSV suppressive therapy.
• WHO Model List of Essential Medicines (acyclovir)