Black Box Warning

A boxed warning (“black box warning”) is a warning that appears on the package insert for some prescription drugs that is mandated to be placed there by the Food and Drug Administration (FDA) in the USA. They specify that the warning be formatted with a border around the text, hence the name, ‘box warning’ or ‘black box warning’. This is the strongest warning that the FDA requires to signify that the drug can carry a high significant risk of serious adverse effects. This black box warning was introduced in 1979. The warning is not supposed to be a contraindication for the use of the medication, but to bring the risk of the adverse affects to the attention of the clinician and patient. The warning will appear at the top of the medication’s package insert.

A box warning can affect the marketing of a drug that will have financial consequences for the drug company in terms of sales and possible negative publicity in the news media.

The FDA documentation states that:

A boxed warning is ordinarily used to highlight for prescribers one of the following situations:
• There is an adverse reaction so serious in proportion to the potential benefit from the drug (e.g., a fatal, life-threatening or permanently disabling adverse reaction) that it is essential that it be considered in assessing the risks and benefits of using the drug
OR
• There is a serious adverse reaction that can be prevented or reduced in frequency or severity by appropriate use of the drug (e.g., patient selection, careful monitoring, avoiding certain concomitant therapy, addition of another drug or managing patients in a specific manner, avoiding use in a specific clinical situation).
OR
• FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted (e.g under 21 CFR 314.520 and 601.42 “Approval with restrictions to assure safe use” or under 505-1(f)(3) of the Federal Food, Drug, and Cosmetic Act (FDCA) “Risk Evaluation and Mitigation Strategies” Elements to assure safe use).

Examples:
In 2004, the FDA mandated a black box warning for all antidepressants due to the increased risk of suicidal thinking and behaviors in younger individuals.

In 2006 a boxed warning was added to warfarin due to the risk of bleeding to death.

Celecoxib carries a high risk for cardiovascular events:

In 2008 the FDA mandated a warning be applied to Fluoroquinolones as they increase the risk of tendon injury:

In 2007, the FDA required a boxed warning for Avandia (rosiglitazone) due to the increased risk of heart failure or heart attack in those with underlying heart disease.

in 2017, The FDA mandated that there be a box warning for canagliflozin due to what appeared to be an increased risk for amputation compared to the benefit of the drug. Later studies have shown the benefits of the drug and that the increased risk for amputation was not as high as originally reported, so the box warning was removed in 2020. The amputation risk is still described in the ‘Warnings and Precautions’ section of the prescribing information.

Criticisms:
There appears to be wide variability among clinicians in how much weight they give to the boxed warning and it is inconsistent with a low overall compliance with the warning.
The box warning may discourage people who would benefit from the medication from using it or being prescribed it.

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