Antifungals: Liver Safety and Drug Interaction Risks You Can't Ignore

Dec, 2 2025

When you take an antifungal for a stubborn nail infection or a systemic yeast problem, you’re not just fighting fungus-you’re putting your liver on the line. Most people assume these drugs are safe because they’re common, over-the-counter, or prescribed by a doctor. But the truth is, some antifungals carry a real risk of serious liver damage, and the warning signs often show up too late.

Why Your Liver Is at Risk

Antifungals don’t just target fungi. They mess with your liver’s ability to process chemicals, and that’s where things go wrong. The liver breaks down these drugs, but some antifungals are so harsh on liver cells that they cause inflammation, cell death, or even complete failure. It’s not rare. Between 2004 and 2021, the FDA recorded over 4,000 reports of liver injury linked to antifungal use. The real number is likely higher-many cases go unreported because symptoms like fatigue or nausea are easy to ignore.

The Worst Offenders: Ketoconazole, Itraconazole, Voriconazole

Not all antifungals are created equal. Some are far more dangerous to your liver than others.

Ketoconazole used to be the go-to oral antifungal. Now, it’s a last-resort drug. The FDA slapped it with a boxed warning in 2013-its strongest alert-after linking it to over 1,800 cases of liver injury. One patient in a Reddit thread saw their ALT levels spike to 1,200 U/L (normal is under 56). That’s liver failure territory. Doctors in Europe stopped prescribing it entirely in 2013. In the U.S., it’s only used when nothing else works, and even then, only if your liver is already healthy.

Itraconazole and voriconazole are next in line. A 2009 meta-analysis found these two caused liver injury more often than fluconazole. Voriconazole is especially tricky because it’s used in cancer and transplant patients-people already at higher risk. Studies show that if you have a certain gene variation (CYP2C19), your risk of liver damage from voriconazole jumps nearly fourfold. That’s why some hospitals now test for this before prescribing it.

The Misunderstood Safe Ones: Terbinafine and Echinocandins

Many assume terbinafine (used for athlete’s foot and nail fungus) is harmless because it’s available over the counter. But it carries a black box warning from the FDA for rare but deadly liver failure. The risk is low-about 1 in 1,000-but it strikes fast. Most cases happen within the first six weeks. A 2023 Healthline user reported jaundice at week five. They stopped the drug and recovered, but not everyone is that lucky.

Then there are the echinocandins-caspofungin, micafungin, and anidulafungin. These are given intravenously in hospitals for serious infections like candidemia. You’d think they’d be safer since they’re not processed by the liver the same way. But data from the FDA shows anidulafungin had the highest death rate among DILI cases-50%. That sounds terrifying, but here’s the catch: these drugs are usually given to people who are already critically ill, often with pre-existing liver damage. So the risk isn’t necessarily from the drug itself-it’s from the patient’s condition. Micafungin has the best safety profile among this group.

How to Spot Trouble Before It’s Too Late

Liver damage doesn’t always show up on a blood test right away. Early signs are vague: fatigue, nausea, loss of appetite, dark urine, or yellowing of the skin. By the time you feel sick, your liver might already be badly hurt.

The good news? You can catch it early with simple blood tests. Here’s what experts recommend:

• Baseline test: Get liver function tests (ALT, AST, bilirubin) before starting any systemic antifungal.
• Weekly monitoring: For ketoconazole, itraconazole, and voriconazole, check every week for the first month.
• Biweekly after that: Keep checking every two weeks if you’re on long-term therapy.
• Terbinafine: Test at 4-6 weeks, then again if you’re on it longer than 8 weeks.

Stop the drug if:

• ALT or AST is more than 3 times the normal level AND you have symptoms like nausea or jaundice.
• ALT or AST is more than 5 times normal-even if you feel fine.

That’s not a suggestion. That’s the standard of care.

Drug Interactions: The Hidden Danger

Antifungals don’t just hurt your liver-they make other drugs more dangerous. Many antifungals block liver enzymes (CYP3A4, CYP2C19) that break down other medications. This causes those drugs to build up in your system.

Here are common and dangerous combos:

• Voriconazole + statins: Can cause muscle breakdown (rhabdomyolysis), which can lead to kidney failure.
• Itraconazole + blood thinners (warfarin): Increases bleeding risk dramatically.
• Fluconazole + diabetes drugs: Can cause dangerous drops in blood sugar.
• Any azole + alcohol: Increases liver stress and risk of injury.

Always tell your doctor every medication, supplement, or herb you take-even CBD or St. John’s Wort. Many people don’t realize these can interact too.

Who’s Most at Risk?

You’re not equally at risk. Certain people need extra caution:

• People over 65: Liver function slows with age. Risk of injury is over 7 times higher than in younger adults.
• Those with existing liver disease: Hepatitis, fatty liver, or cirrhosis? Avoid ketoconazole entirely. Even terbinafine needs careful monitoring.
• People on multiple medications: The more drugs you take, the higher the chance of a bad interaction.
• Those with genetic differences: If you’re a slow metabolizer of CYP2C19, voriconazole is riskier. Genetic testing is now available and worth considering.

What’s Changing in 2025?

The field is evolving fast. Ketoconazole use has dropped by over 90% since 2013. Hospitals now use echinocandins as first-line for invasive candidiasis-not because they’re perfectly safe, but because they’re safer than azoles for most patients.

New antifungals like olorofim and ibrexafungerp are in development. Early trials show they cause 78% fewer liver enzyme spikes than older azoles. That’s huge. The FDA is also using AI to scan adverse event reports in real time, hoping to catch liver risks before they become widespread.

And for the first time, pre-treatment genetic testing for CYP2C19 is being recommended in some major hospitals. It’s not routine yet-but it might be soon.

What You Should Do Now

If you’re on or thinking about starting an antifungal:

• Ask your doctor: “Which one are you prescribing, and why?”
• Request a baseline liver test before you start.
• Ask if you need weekly blood work-and stick to it.
• Never take antifungals with alcohol or other liver-stressing drugs without checking.
• If you feel unusually tired, nauseous, or notice yellowing skin, stop the drug and get tested immediately.

Don’t assume your doctor knows all the risks. Many primary care providers don’t monitor LFTs for terbinafine, even though the guidelines say they should. A 2020 study found only 37% of them did it right. Be your own advocate.

Antifungals save lives. But they can also end them-quietly, and without warning. The difference between safety and disaster often comes down to one simple thing: paying attention to your liver.