What is an FDA Black Box Warning?

What is a Black Box Warning?  

A “Black Box Warning” or “Boxed WARNING” is the U.S. Food and Drug Administration’s (FDA) most serious type of warning for over-the-counter and prescription medications and medical devices on the market. This type of warning appears at the top of the package insert for a particular medication. It is formatted in a box with a black border to make it more noticeable and emphasize its importance.

The Food and Drug Administration requires pharmaceutical companies to place boxed warning sections on drug labels of certain medications to inform healthcare providers and patients about a significant risk of serious harm, injury, or death. The FDA identifies medication safety concerns using clinical trial data and post-marketing reports of adverse events.

After a drug's approval, the FDA can issue a boxed warning at any time. The agency may even recall a medication if the adverse effect is serious enough. 

How Serious Is a Black Box Warning?  

Boxed warnings are the highest safety-related warnings assigned to medications by the U.S. Food and Drug Administration and bring the attention of the prescribing doctor, dispensing pharmacist, and patient to a potentially severe adverse reaction. A common misunderstanding is that medications with boxed warnings should be avoided. In reality, your doctor will discuss the risks and benefits of the medication with you before prescribing it. 

That said, black box warnings also provide an opportunity for patient education by prescribers. They help patients understand the potential for adverse drug reactions.

How Do Medications Get Box Warnings?

A medication may require a Boxed warning if it meets any of the following criteria:

No Causal Relationship Necessary

A boxed warning is issued when there is reasonable evidence that a serious adverse effect is associated with a drug. A definite causal relationship does not need to be established between a drug and a side effect. A boxed warning means that the adverse reaction may occur and could lead to serious harm or death.

Specific Populations

Sometimes, drug labeling includes boxed warnings to warn prescribers of risks in a particular group of people, for example, young children, elderly patients, or pregnant women. It is important to note that drug classifications based on pregnancy risk are distinct from black box warnings. The advisory may also contraindicate a particular drug in people with a specific medical condition, such as myasthenia gravis or QT prolongation (issues with the heart’s electrical system).

Combinations of Medications

The FDA can also require boxed warnings and patient-focused medication guides for combinations of products. For example, combining benzodiazepines and opioid pain relievers or cough medications carries a boxed warning for serious risks of extreme drowsiness, respiratory depression, coma, and death. 

Instructions on Safe Use

Boxed warnings may also include advisories or important instructions on the safe use of a particular medication, for example, its:

• Dosage

• Interactions with other medications

• Guidelines for activities, such as not driving or operating heavy machinery while on the medication

Regulatory and Monitoring Processes  

FDA’s Role and Processes Involved 

All drugs marketed in the United States are required to undergo testing for effectiveness and safety risks before they receive approval from the FDA. During this process, side effects of a drug may be discovered that require a black box warning to be included in the package insert. The FDA uses clinical trial data, as well as post-market surveillance and reports from healthcare professionals and patients, to determine when a black box warning is necessary. 

Postmarket Safety Findings and Updates  

Sometimes, side effects are not discovered during clinical trials on new drugs which are done on a limited number of patients. After a drug is brought to market, the Food and Drug Administration relies on reporting of serious adverse events by clinicians and patients. MedWatch is the FDA’s online program that helps to track adverse events associated with medications based on reports from clinicians and patients. 

What Medication Requires a Black Box Warning?

Boxed warnings are typically issued for entire classes of medications rather than a specific drug. Medication classes are groups of drugs that share a similar chemical structure, have the same mechanism of action, and treat the same medical conditions. Boxed warnings usually apply to all drugs in a class because the severe risk is frequently associated with the mechanism of action of the drug, which is common to all the medications within a class.

Notably, not all drugs within a class are equally impacted by an FDA black box warning. For example, an FDA-mandated boxed warning led to a decrease in prescriptions of the diabetes medication rosiglitazone by 70% due to media reports and scientific publications. However, pioglitazone, a medication from the same class, was not similarly affected. 

List of Medications With Black Box Warnings

More than 400 drugs carry boxed warnings. Some black box warning drugs are listed below:

What Should I Do if My Medication Has a Black Box Warning?

Physician Decision-Making and Patient Education  

When prescribing medicines with black box warnings, clinicians should use their clinical judgment to decide whether or not to prescribe a particular medication to a patient. In addition, they should have a discussion with the patient and bring their attention to the increased risks associated with the drug.

Patients should use this opportunity to ask questions about adverse drug reactions. In addition, patients should provide their health care provider with a complete list of their medications to prevent drug interactions.

Incorporating Warnings Into Treatment Plans

Black box warnings are designed to warn the public and alert healthcare professionals about serious and potentially life-threatening side effects. If a drug receives a black box warning, the manufacturer is required to create a medication guide describing how patients can safely use the drug. These guides come with the medication when it is picked up at the pharmacy and are also available on the FDA website.

Addressing Common Concerns  

Can A Black Box Warning Be Removed?

Yes, a Black Box Warning can be removed by the FDA if further clinical trial data shows that the safety concerns associated with black box medications are less severe than previously believed. Similarly, a black box warning can be added after the drug has been on the market for some time and after the medicine has been used by a large number of patients if more serious side effects are identified after the drug approval.

For example, in 2009, the FDA added a boxed warning to varenicline (Chantix), a prescription medication that helps people quit smoking. The warning alerted patients to a potential risk of neuropsychiatric side effects, including depression and suicidal thoughts. However, after reviewing clinical data from the EAGLES study, the boxed warning was removed in 2016.

Does Ibuprofen Have A Black Box Warning?

Yes, ibuprofen has a black box warning. Ibuprofen and other nonsteroidal anti-inflammatory drugs (NSAIDs) ,such as naproxen, diclofenac, and celecoxib, carry serious cardiovascular and gastrointestinal risks of heart attack, stroke, and GI bleeding, ulceration, or perforation.