What Is a Black Box Warning?

A black box warning (BBW)—officially called a boxed warning—is the most stringent safety warning the FDA can require from a drug manufacturer. As the name implies, a box warning is a bold, black-bordered notice at the top of a drug's label or informational package insert. This prominent warning is designed to alert health care providers and patients to serious, life-threatening, or permanently disabling risks associated with the drug's use, should an adverse reaction occur. 

“It's reserved for risks that are deemed particularly serious,” says Caleb Alexander, MD, MS, professor in Epidemiology and co-director of the Center for Drug Safety and Effectiveness. “The FDA is saying, ‘This is important, and we think as a prescriber, you should know about it.’” 

How they are deemed necessary, and what it takes to place, remove, or update one, is a complicated process that the FDA navigates, involving clinical data and monitoring after a drug is on the market.

“The FDA has a lot of tools that it can use to communicate information about drug risks to prescribers and patients, and a black box warning is one of them,” Alexander says.  
“It's not appropriate for every drug or every risk, but for select risks and drugs, it's the right tool to use.”

Warnings Can Be Added, Modified, or Removed  

Black box warnings are added only when substantial clinical data shows the drug can cause severe harm, hospitalization, or death. The FDA continuously gathers data from clinical trials and post-marketing surveillance (like MedWatch).

If data shows severe adverse effects (e.g., increased cancer risk, severe asthma attacks, suicidal thoughts) or situations where benefits might not outweigh risks, a BBW is considered.

“When and how to communicate risks to the public about prescription drugs is an art, as well as a science, and the FDA has to undertake this carefully and based on a variety of inputs,” Alexander says. “Risk mitigation is a dynamic process because it really should be iterative and reflect not only emerging evidence about the product's safety and use, but also what has been and is being learned in an ongoing fashion from historic and current risk mitigation efforts.”

Removing these warnings requires new, robust scientific evidence that shows the risks are overstated or don't apply to current patient populations. Some reasons for BBW removal include: 

• Outdated or flawed original studies: The original reason for a black box warning might stem from large studies with design flaws, different patient demographics, or older drug formulations not reflective of current use.
• Evolving science: Subsequent, better-designed research provides a clearer picture, often showing that benefits outweigh risks for specific groups when used as prescribed.
• Distorted risk perception: Broad warnings can scare eligible patients, preventing them from getting needed treatments, leading to significant public health consequences.
• Expert review and advocacy: The FDA often acts after expert panels review evidence and medical organizations advocate for changes, recognizing the harm the warning causes.  

For example, hormone replacement therapy (HRT) drugs, which are commonly used to treat menopause symptoms, have had a black box warning since 2003. The warning is based on the 2002 Women's Health Initiative (WHI) study, which linked combination HRT (estrogen and progestin) to increased risks of breast and endometrial cancers, stroke, blood clots, heart attacks, and dementia. Following the implementation of the label, the use of these treatments among postmenopausal women fell from nearly 30% to about 5% from 1999 to 2020. 

The WHI findings were broadly applied to all women, but the study's participants were older (average age of 63), postmenopausal, and using older oral hormone types. Later re-analysis found that for women under age 60 who are within 10 years of menopause, the risks of using HRT are lower—and benefits greater. And newer, lower doses and different delivery methods (like transdermal patches) have different risk profiles than the older oral pills used in the WHI study. 

In November 2025, the FDA initiated removal of these warnings, recognizing that risks and benefits depend heavily on age and timing of initiation, with benefits often outweighing risks for appropriate candidates, while noting that doctor-patient consultation remains crucial. 

“Ultimately, whether to use a drug or not depends upon the risk and the benefit,” says Alexander. “That's a tradeoff that clinicians and patients have to navigate together.” 

But, Alexander says, it’s important to keep in mind that, “this change hasn't been driven by a wealth of recent new evidence suggesting that these [HRT] products are safer than we thought. Rather, the changes are being driven by judgments as to whether the risks warrant black box warnings at all.” 

Varenicline, a smoking cessation aid, had its black box warning removed in 2016 after a large clinical trial showed the risk of serious psychiatric side effects (like depression and suicidal thoughts) was lower than previously thought, comparable to use of a nicotine replacement or placebo, and the benefits of quitting smoking outweighed the risks. 

Box Warnings Aren’t on All Drugs 

More than 400 drugs have this warning, but the risks aren’t the same for every demographic and can be physiological or psychological. More often than not, Alexander says, a black box warning will be instituted across all the members of a drug class, “because typically, the sort of risks that we're talking about are risks that are shared across different members of a therapeutic class.” 

Examples of medications with black box warnings: 

• Antidepressants (SSRIs): Increase risk of worsening depression, agitation, and suicidal thinking and behavior in children, adolescents, and young adults (up to age 24), especially early in treatment.
• Fluoroquinolone antibiotics: Increase risk of tendinitis and/or tendon rupture, particularly in older adults, transplant recipients, and people taking steroids.
• Isotretinoin (Accutane) for acne: Elevates risk of severe birth defects, potential depression, psychosis, aggression, and suicidal thoughts or actions. Patients must enroll in strict pregnancy prevention programs (like iPLEDGE in the U.S.), and prescribers monitor for psychiatric symptoms, advising immediate discontinuation if severe mood changes occur.
• ACE inhibitors: Can cause serious harm or death to an unborn baby during pregnancy.
• Atypical antipsychotics: Increase the risk of death in elderly patients with dementia-related psychosis.
• Opioid painkillers: Pose serious risks like addiction, abuse, misuse, overdose, and death, especially when combined with benzodiazepines or other central nervous system depressants or used in pregnancy.
• Methadone: High risk for severe respiratory depression (slowed breathing) and QT prolongation (heart rhythm issue), requiring careful dosing and monitoring for addiction treatment.
• Rosiglitazone (used for type 2 diabetes): Increased risk of heart failure or myocardial infarction if the patient has current heart disease.

What a Black Box Warning Isn’t 

A BBW is not a definitive declaration of causation. The warnings use words like "associated," "increased risk," or "reported," because post-marketing observational data struggles to prove a drug directly causes an effect; it just shows it happens more often with the drug. A black box warning also doesn’t indicate how often a bad reaction happens; it warns about the reaction’s severity. 

“All medicines have risks, and most medicines have rare but serious risks,” Alexander says. “It's important that people are only taking medicines that have a favorable risk-benefit balance.”  

Physicians often prescribe drugs with black box warnings “off-label”—meaning for a use, dosage, or patient population that has not necessarily been approved by the FDA—based on clinical judgement, Alexander says.  

What to Do If Your Medication Has a Black Box Warning 

“As long as you and your prescriber agree that it's the right drug for you, you should not be worried,” says Alexander. “What's important is that clinicians and patients are reaching sound judgments together about medicines and how they're used.” 

If you have concerns about your medications: 

• Talk to your doctor about potential risks and benefits.
• If you’re uncomfortable taking the drug, ask if there are alternative treatments available.
• Discuss risk management strategies and potential side effects.
• Do not be afraid to ask questions and take time to understand the information.  

“Keep in mind that the risks and the benefits of a medicine are not static features of the drug itself any more so than it's fair to say that a razor blade or hammer is good or bad,” Alexander says. “It depends upon how it's used—and the same is true with prescription drugs.”