Annual Boxed Warnings Summary: What Changed and Why It Matters

The most serious safety alerts on prescription drugs don’t appear in ads or on pill bottles. They’re hidden in the fine print-enclosed in a thick black border, bold and unmistakable. These are boxed warnings, the FDA’s highest-level alert for drugs that can cause serious, even deadly, side effects. In 2025, over 400 medications in the U.S. carry one. And each year, more get added, updated, or removed. If you’re a patient, caregiver, or clinician, ignoring these changes isn’t an option-it could mean the difference between safety and tragedy.

What Exactly Is a Boxed Warning?

A boxed warning, sometimes called a black box warning, is the strongest safety alert the U.S. Food and Drug Administration (FDA) can require. It’s not a suggestion. It’s a legal requirement. These warnings appear at the very top of a drug’s prescribing information, surrounded by a heavy black border, and they spell out risks so severe that the FDA says: “This drug can kill you if used incorrectly.”

They’re not for minor side effects like headaches or nausea. Boxed warnings are reserved for outcomes like liver failure, sudden heart rhythm changes, fatal breathing problems, or birth defects. For example, isotretinoin (Accutane) carries a warning about severe birth defects, which is why it’s only available through a strict pregnancy prevention program called iPledge. Fentanyl patches warn that they can stop breathing in patients who’ve never taken opioids before. Valproic acid can cause fatal liver damage in children under two.

The FDA first started requiring these warnings in the 1970s. Since then, they’ve become the gold standard for communicating life-threatening risks. According to the FDA’s Center for Drug Evaluation and Research (CDER), they’re triggered by real-world data-usually from the Adverse Event Reporting System (FAERS)-not just lab studies. If enough patients die or suffer serious harm after taking a drug, the FDA steps in.

What Changed in the Latest Annual Summary?

In 2025, the FDA issued 47 new or revised boxed warnings-the highest number in five years. That’s up from 42 in 2024 and 38 in 2023. The biggest changes? Three major categories.

• Immunomodulators: 11 new or updated warnings for drugs used in autoimmune diseases and cancer. These include checkpoint inhibitors like pembrolizumab (Keytruda) and nivolumab (Opdivo), which now carry clearer warnings about myocarditis and colitis risks in patients under 40.
• GLP-1 agonists: Drugs like semaglutide (Wegovy, Ozempic) received new warnings about delayed gastric emptying and its link to increased risk of aspiration pneumonia, especially in older adults or those with swallowing disorders.
• Antibiotics: Moxifloxacin and levofloxacin now have updated warnings about QT prolongation and sudden cardiac death, with specific thresholds: “Avoid in patients with QTc >450 ms (men) or >470 ms (women).”

What’s new isn’t just the number-it’s the detail. Starting in January 2024, the FDA mandated that all boxed warnings include quantified risk data. No more vague phrases like “monitor for liver damage.” Now you’ll see: “Hepatotoxicity occurred in 1.8% of patients within the first 3 months of therapy, with 0.3% requiring hospitalization.”

For example, the warning for methotrexate (used for rheumatoid arthritis and psoriasis) used to say: “Risk of fatal bone marrow suppression.” Now it says: “Fatal bone marrow suppression occurred in 0.7% of patients taking weekly doses; 89% of those cases involved patients who accidentally took daily doses. Always confirm dosing schedule with patient.”

Why These Changes Matter

These aren’t just bureaucratic updates. They directly affect how doctors prescribe, how pharmacists dispense, and how patients survive.

Take clozapine, an antipsychotic with a decades-old boxed warning for agranulocytosis-a drop in white blood cells that can lead to fatal infections. For years, doctors had to order weekly blood tests. In 2024, the FDA updated the warning to specify: “Discontinue monitoring after 6 months if ANC remains >1,500 cells/μL and no prior episodes.” That change saved patients from unnecessary finger pricks and clinic visits, while still keeping them safe.

On the flip side, a 2025 update to the warning for valproic acid now requires liver enzyme tests every month for the first six months-down from every three months. Why? New data from the FDA’s Sentinel Initiative showed that 62% of fatal liver injuries occurred between weeks 4 and 16. That’s a narrow window. Missing one test could be deadly.

And then there’s the economic impact. A 2023 study in JAMA Internal Medicine found that drugs receiving new boxed warnings saw an average 22% drop in prescriptions within a year. But some drugs, like warfarin, barely budged. Why? Because there’s no good alternative. Patients need it. So doctors manage the risk instead of avoiding the drug.

That’s the core truth: Boxed warnings aren’t meant to stop use. They’re meant to make use safer.

How Clinicians Are Adapting

Health systems are scrambling to keep up. Hospitals now require triple-check systems for high-alert drugs. At Henry Mayo Newhall Hospital, pharmacists must verify opioid tolerance before dispensing fentanyl patches. Electronic health records (EHRs) now pop up mandatory alerts that require prescribers to click “I acknowledge the risk” before signing the prescription.

But it’s not perfect. A 2024 Medscape survey found that 44% of doctors still override these alerts in emergencies-especially when treating sepsis or heart failure. One ER physician in Atlanta told Medscape: “I gave moxifloxacin to a 78-year-old with pneumonia. The alert screamed ‘QT prolongation risk.’ But she was crashing. We didn’t have time. She lived.”

Pharmacists are also seeing system flaws. On Reddit’s r/Pharmacy, a user posted: “I had a patient on warfarin. The EHR said ‘INR not available.’ I called the clinic. The nurse said, ‘We didn’t draw it because she’s stable.’ But the warning requires it. We held the script.”

Training is improving, too. The American Society of Health-System Pharmacists reports that clinicians need 3-5 patient encounters to fully internalize new boxed warning protocols. For methotrexate, training now includes a 2.7-hour simulation module that walks staff through what happens when a patient takes it daily instead of weekly.

What Patients Need to Know

If you’re taking a medication with a boxed warning, here’s what you should do:

• Ask: “Is there a boxed warning on this drug? What’s the biggest risk?”
• Know your monitoring schedule. If you’re on valproic acid, know when your next liver test is due.
• Don’t ignore EHR alerts. If your doctor skips a warning, ask why.
• Keep a list of all your medications and their warnings. Share it with every provider.

Patients who understand their warnings are more likely to follow instructions. A 2021 FDA patient forum found that 78% of those who received clear, verbal explanations of boxed warnings (like for isotretinoin) reported better adherence and fewer side effects.

The Bigger Picture: Where This Is Headed

The FDA isn’t slowing down. Its 2023-2027 strategic plan calls for a 25% increase in boxed warnings by 2027-mostly based on real-world data from 200 million patient records tracked through the Sentinel Initiative.

One pilot program is testing “dynamic” warnings: alerts that change severity based on your age, kidney function, or other factors. For example, a 65-year-old with chronic kidney disease might get a red alert for a certain drug, while a healthy 30-year-old gets a yellow one. Early results show a 37% drop in alert fatigue.

But challenges remain. A 2024 GAO report found that 31% of warnings still lack clear guidance. What does “monitor for hepatotoxicity” even mean? Without specific tests, timelines, or thresholds, it’s useless.

The future? More precision. More data. Fewer vague warnings. And more accountability-for manufacturers, prescribers, and patients alike.

What You Can Do Today

Don’t wait for your doctor to bring it up. Take control:

• Go to FDA’s Drug Database (search by drug name) and check the “Boxed Warning” section.
• Keep a printed copy of your drug’s warning in your wallet or phone.
• Ask your pharmacist to walk you through the warning during your next refill.
• If you’re on multiple high-risk drugs, consider a medication therapy management (MTM) session with a clinical pharmacist.

Boxed warnings aren’t scare tactics. They’re lifelines. And in a world where drugs are faster, more powerful, and more complex than ever, understanding them isn’t optional-it’s essential.