What is a Boxed Warning?

By Sarabeth Lowe, MPH

Ms. Lowe is a Communication Specialist at the University of Delaware Disaster Research Center.

Welcome to the fifth edition of Health Literacy Highlights, a column that explores topics related to finding, understanding, and utilizing health information. In this issue, I will discuss boxed warnings, the highest safety warning the United States (US) Food and Drug Administration (FDA) can assign to prescription medications.

In November 2025, the US Department of Health and Human Services made a shocking announcement: the FDA decided to remove the boxed warning from hormone replacement therapy (HRT), used to treat menopausal symptoms.^1–3 These warnings, formerly known as “black box” warnings, are the FDA’s highest and most stringent safety warnings for prescription drugs that alert clinicians and consumers to serious, harmful, and potentially life-threatening adverse reactions.^4–6 These communications might sound scary, but they are a crucial tool for public health messaging and conveying medications’ risks.^7,8 Here’s what you need to know about boxed warnings.

What Boxed Warnings Are—And Are Not

A boxed warning is the written, printed, or visual material on a medication’s packaging that alerts prescribers, pharmacists, and consumers to major, life-threatening, or permanently disabling risks associated with the drug’s use.⁵ Since 1979, the FDA has required pharmaceutical companies to assign these labels to prescription drugs that may pose these risks in the event of an adverse reaction.^4,5,7,9,10

These labels take their names from the prominent, bold, black-bordered box surrounding the warning content, which is organized in bullet points with a header written in bold uppercase letters.^11,12 These notices appear at the top of a drug’s label or inside its informational package insert. They are also attached to bulk containers of drugs so that pharmacists have the most up-to-date official information available.¹⁰ 

In addition to being posted and maintained on the FDA and drug manufacturers’ websites, boxed warnings are recorded in the Prescriber’s Digital Reference, an annually updated online drug information resource containing FDA-approved prescribing details for prescription drugs.^7,13,14

Boxed warnings include important information for healthcare professionals and consumers, including:^5,12,14

Severe adverse effects. These side effects are risks that could result in severe harm, hospitalization, or death, such as severe asthma attacks, stroke, addiction, and suicidal thoughts.

Cautions for consumers. Boxed warnings may advise consumers to avoid certain activities, such as driving or operating large machinery, while using the drug.

Medication guidelines. This information includes when to take the medication, foods or drinks to avoid, dosage, and potential harmful drug interactions.

Notably, boxed warnings indicate that there is reasonable evidence of a significant safety risk or serious hazard when taking the medicine; a definitive causal relationship between the drug and its potential risk(s) does not need be proven.^10,14 Boxed warnings are not intended to prevent doctors from prescribing these drugs or to dissuade patients from taking them. They are designed to raise awareness of a medication’s potential serious adverse effects so that providers can discuss potential harms with their patients and effectively weigh the risks and benefits.^5,9

Safety and Approval Process—Assessing Risks

Healthcare providers are expected to exercise clinical judgment when deciding whether to prescribe medications with boxed warnings.⁴ However, the safety of these medications has been effectively and thoroughly studied by the time they reach this point. All medications must pass the FDA’s rigorous approval process, which can take years depending on the kind of drug, before hitting the market.^15,16 Why, then, are boxed warnings issued after this approval process?

Issuing these warnings is a complex, evidence-based process that requires postmarketing surveillance and ongoing drug safety monitoring. Boxed warnings are added only when substantial clinical data show the drug can cause severe harm, hospitalization, or death, and researchers and clinicians usually don’t discover all of medicine’s adverse effects until it “can be used in larger, broader populations for longer durations” and “prescribed for unapproved or off-label purposes.”¹⁰ 

The FDA’s MedWatch program is designed to gather this kind of data. This online platform allows clinicians, hospitals, and patients to report adverse events associated with certain drugs or medical products.^10,17 The FDA tracks and evaluates these reports, looking to find any concerning patterns.^14,16–18 Potential safety issues can also be identified through clinical trial data. Based on its findings from these and other epidemiological data sources, the FDA can begin the process of issuing a boxed warning to a medication label.

This evaluation process is what makes these notices living documents. Boxed warnings can also be rescinded, a change that requires new, robust scientific evidence showing that the risks are overstated or don’t apply to current patient populations.⁵ There are several reasons boxed warnings can be removed:⁵

Outdated or flawed original studies. Upon review, the FDA might decide that the original study that led to the boxed warning had design flaws, differences in patient demographics, or older drug formulations that no longer reflect current use.

Evolving science. With innovative technologies and approaches, subsequent, better-designed research can lead to new data, evidence, and findings. This can create a clearer, broader picture of a medication’s potential adverse reactions, sometimes showing that benefits outweigh risks for certain groups when used as prescribed.

Distorted risk perception. Boxed warnings list the most serious potential harms, even if those adverse effects are incredibly rare. This can scare eligible patients, leading to fear and misinformation, and prevent them from accessing necessary, targeted treatments.

Expert review and advocacy. Calls to action from expert panels, medical organizations, and advocacy groups have led the FDA to reconsider and remove boxed warnings.

What Drugs Have Boxed Warnings?

According to a 2022 study, more than 400 medications currently carry boxed warnings.¹⁰ These warnings typically apply to entire classes of medications instead of a single drug. This is because medications in the same class share similar chemical structures, therapeutic uses, and mechanisms of action (ie, how the drug causes specific biochemical changes in the body).^4,9,19,20 

Examples of medications with boxed warnings include:

Antidepressants. While selective serotonin reuptake inhibitors can lessen the severity of depression symptoms, research shows that patients, particularly children and young adults, have an increased risk of suicide in the first few weeks of taking them.^{5–7,11,20–22} 

Opioids. Opioid painkillers, such as fentanyl and oxycodone, pose serious risks, including addiction, misuse, abuse, overdose, and death.^5,11,20,23 

Loop diuretics. These drugs, which help manage fluid overload conditions such as heart failure and hypertension, are highly potent and pose a significant risk for diuresis, dehydration, and electrolyte depletion.^20,24

Isotretinoin. Isotretinoin increases the risk of severe birth defects and psychiatric issues, including depression, psychosis, aggression, and suicidal thoughts.^5,20,25,26 The FDA created iPLEDGE, a mandatory federal safety program specifically designed to prevent fetal exposure to isotretinoin, in 2006.²⁷

Angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors, a common blood pressure medication, can cause serious harm or death to an unborn baby during pregnancy.^5,28

Boxed warnings do not exist in a vacuum. They affect multiple facets of personal and public health, including clinicians’ prescribing decisions, health policy, medical malpractice law, insurance coverage, and access to the most effective care.^{5–7,11,20,29,30}

What to Do If Your Medication Has a Boxed Warning 

Before starting any new medication, always check the label and follow all directions. If it contains a boxed warning, speak with your provider if you are concerned or have any questions. Pharmacists are also a wealth of information and can provide valuable insight. Both providers will allow you to:

Make sure you understand the risks, benefits, and potential tradeoffs of a medication.

Ask if alternative treatments are available.

Discuss risk management and the likelihood of potential side effects.

With this information in mind, you can be confident that your treatment plan is safe and appropriate for your needs.

Looking Forward

According to a 2026 Pew Research Center survey, 77% of US adults have at least a “fair amount of confidence” in scientists’ ability to act in the public’s best interests.³² Still, it remains lower than it was before the COVID-19 pandemic.^32,33 A common reason for this skepticism is the fact that even well-established theories and findings have been overturned. Look no further than the shifting prevention advice during the pandemic. This lack of consistency has eroded many people’s trust in science and the scientific community. 

However, changes in such conclusions and shifts in perspective can be interpreted as a strength rather than a weakness. Science does not progress linearly toward the truth; it is always evolving as new research and analyses emerge.^34,35 Thus, shifts in advice or guidance can also be seen as a promising sign of a vibrant and healthy scientific community.^36–38 Boxed warnings are an exemplary testament to this sentiment. 

The FDA issued a boxed warning to HRT in 2003 after data from the Women’s Health Initiative linked the treatment to increased risks of breast and endometrial cancers, stroke, blood clots, heart attacks, and dementia.^5,37 After the boxed warning was issued, the use of HRT treatments among postmenopausal women fell from nearly 30% to about 5% from 1999 to 2020.³⁸ Upon review, the FDA determined that these findings were applied too broadly and that the risks of HRT are lower—and the benefits greater—in certain groups.^2,3,5,38

Changes like these show that, just as in scientific research, seemingly established conclusions around the risks and benefits of a medicine are not static. Boxed warnings profoundly impact public health, and, thanks to more transparent research and growing trust in the scientific community, their issuance can protect millions of people from harm and improve health outcomes.

Sources

1. FDA removes black-box warnings on hormone replacement therapy. Society of Gynecologic Oncology 20 Nov 2025. Accessed 11 Jan 2026. https://www.sgo.org/news/fda-removes-black-box-warnings-on-hormone-replacement-therapy/
2. HHS advances women’s health, removes misleading FDA warnings on hormone replacement therapy. US Food and Drug Administration. 10 Nov 2025. Accessed 11 Jan 2026. https://www.fda.gov/news-events/press-announcements/hhs-advances-womens-health-removes-misleading-fda-warnings-hormone-replacement-therapy
3. FACT SHEET: FDA initiates removal of “black box” warnings from menopausal hormone replacement therapy products. US Department of Health and Human Services. 10 Nov 2025. Accessed 20 Jan 2026. https://www.hhs.gov/press-room/fact-sheet-fda-initiates-removal-of-black-box-warnings-from-menopausal-hormone-replacement-therapy-products.html
4. Delong C, Preuss CV. Box warning. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Updated 17 Jun 2023. Accessed 28 Jan 2026. https://www.ncbi.nlm.nih.gov/books/NBK538521/
5. Coulson M. What is a black box warning? Johns Hopkins University Bloomberg School of Public Health. 19 Dec 2025. Accessed 11 Jan 2026. https://publichealth.jhu.edu/2025/what-is-a-black-box-warning
6. Balon R. Black-box warnings: their consequences and how we should approach them. Ann Clin Psychiatry. 2022;34(4):217–219. 
7. White CM. What’s a ’black box’ warning? A pharmacologist explains how these labels protect patients. The Conversation.13 Nov 2025. Accessed 11 Jan 2026. https://theconversation.com/whats-a-black-box-warning-a-pharmacologist-explains-how-these-labels-protect-patients-269470
8. Ingersoll RN, Bui ET, Coleman B, et al. Prescriber perceptions of boxed warnings: a qualitative study. Pharmacoepidemiol Drug Saf. 2024;33(3):e5766.
9. What is a ’boxed warning’ on medications? Cleveland Clinic. 17 Jan 2025. Accessed 11 Jan 2026. https://health.clevelandclinic.org/what-does-it-mean-if-my-medication-has-a-black-box-warning
10. Greiwe J, Honsinger R, Hvisdas C, et al. Boxed warnings and off-label use of allergy medications: risks, benefits, and shared decision making. J Allergy Clin Immunol Pract. 2022;10(12):3057–3063.
11. Rajendran Y, Kondampati N, Eerike M, et al. A longitudinal analysis of black box warnings: trends and implications for drug safety. Cureus. 2024;16(4):e57597.
12. Guidance for industry: warnings and precautions, contraindications, and boxed warning sections of labeling for human prescription drug and biological products — content and format. US Food and Drug Administration. Oct 2011. Accessed 20 Jan 2026. https://www.fda.gov/media/71866/download
13. About us. Prescribers’ Digital Reference. Accessed 20 Jan 2026. https://www.pdr.net/about-us
14. Schuchardt EE. What are boxed warnings on medications? UPMC HealthBeat. 26 May 2025. Accessed 11 Jan 2026. https://share.upmc.com/2025/05/medication-boxed-warning/
15. The FDA’s drug review process: ensuring drugs are safe and effective. US Food and Drug Administration. Updated 24 Nov 2017. Accessed 25 Jan 2026. https://www.fda.gov/drugs/information-consumers-and-patients-drugs/fdas-drug-review-process-ensuring-drugs-are-safe-and-effective
16. FDA’s drug review process: continued. US Food and Drug Administration. Updated 8 Aug 2015. Accessed 25 Jan 2026. https://www.fda.gov/drugs/information-consumers-and-patients-drugs/fdas-drug-review-process-continued
17. Information about reporting adverse events to FDAs MedWatch program. US Food and Drug Administration. Updated 21 Feb 2018. Accessed 23 Jan 2026. https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-program/information-about-reporting-adverse-events-fdas-medwatch-program
18. Craigle V. MedWatch: the FDA safety information and adverse event reporting program. J Med Libr Assoc. 2007;95(2):224–225.
19. Bihari M. Decoding drug classes and why they’re important. Verywell Health. Updated 26 Oct 2025. Accessed 23 Jan 2026. https://www.verywellhealth.com/drug-classes-1123991
20. O’Connor NR. FDA boxed warnings: how to prescribe drugs safely. Am Fam Physician. 2010;81(3):298–303.
21. Friedman RA. Antidepressants’ black-box warning – 10 years later. N Engl J Med. 2014;371(18):1666–1668.
22. Suicidality in children and adolescents being treated with antidepressant medications. US Food and Drug Administration. Updated 5 Feb 2018. Accessed 25 Jan 2026. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/suicidality-children-and-adolescents-being-treated-antidepressant-medications
23. FDA announces enhanced warnings for immediate-release opioid pain medications related to risks of misuse, abuse, addiction, overdose and death. US Food and Drug Administration. 22 Mar 2016. Accessed 25 Jan 2026. https://www.fda.gov/news-events/press-announcements/fda-announces-enhanced-warnings-immediate-release-opioid-pain-medications-related-risks-misuse-abuse
24. Huxel C, Raja A, Ollivierre-Lawrence MD. Loop diuretics. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Updated 22 May 2023. Accessed 28 Jan 2026. https://www.ncbi.nlm.nih.gov/books/NBK546656/ 
25. Pile HD, Patel P. Isotretinoin. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Updated 13 Dec 2025. Accessed 28 Jan 2026.  https://www.ncbi.nlm.nih.gov/books/NBK525949/
26. Isotretinoin capsule information. US Food and Drug Administration. Updated 12 Oct 2021. Accessed 25 Jan 2026. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/isotretinoin-capsule-information
27. Safety notice – what is the iPLEDGE® REMS (Risk Evaluation and Mitigation Strategy)? iPLEDGE. Accessed 25 Jan 2026. https://ipledgeprogram.com/#Main
28. Sica DA. Angiotensin‐converting enzyme inhibitors’ side effects—physiologic and non‐physiologic considerations. J Clin Hypertens (Greenwich). 2007;7(Suppl 8):17–23.
29. Popova L, Massey ZB, Giordano NA. Warning labels as a public health intervention: effects and challenges for tobacco, cannabis, and opioid medications. Annu Rev Public Health. 2024;45(1):425–442.
30. Dhruva SS, Karaca-Mandic P, Shah ND, et al. Association between FDA black box warnings and Medicare formulary coverage changes. Am J Manag Care. 2017;23(9):e310–e315.
31. The FDA boxed warning: regulatory strategy & negotiation. IntuitionLabs. Accessed 25 Jan 2026. https://intuitionlabs.ai/articles/fda-boxed-warning-negotiation
32. Kennedy B, Kikuchi E. Americans’ confidence in scientists. Pew Research Center. 15 Jan 2026. Accessed 19 Jan 2026. https://www.pewresearch.org/science/2026/01/15/americans-confidence-in-scientists/
33. Kennedy B, Tyson A. Public trust in scientists and views on their role in policymaking. Pew Research Center. 14 Nov 2024. Accessed 19 Jan 2026. https://www.pewresearch.org/science/2024/11/14/public-trust-in-scientists-and-views-on-their-role-in-policymaking/
34. Alpert JS. Advances in science are not linear; they are zigzag. Am J Med. 2022;135(5):543–544.
35. Shech E. Science keeps changing. So why should we trust it? New York Times. 5 Jan 2026. Accessed 19 Jan 2026. https://www.nytimes.com/2026/01/05/opinion/science-trust.html
36. Steier J. Science changes. That’s the point. Unbiased Science. 5 Jan 2026. Accessed 19 Jan 2026. https://theunbiasedscipod.substack.com/p/science-changes-thats-the-point. 
37. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321–333.
38. FDA expert panel on menopause and hormone replacement therapy for women. US Food and Drug Administration. Updated 28 Jul 2025. Accessed 19 Jan 2025. https://www.fda.gov/patients/fda-expert-panels/fda-expert-panel-menopause-and-hormone-replacement-therapy-women-07172025