Boxed Warning

Key facts

Regulation

21 CFR 201.57(c)(1)

Location

Before section 1 of the Full Prescribing Information, summarized in Highlights

FDA authority to require

Safety labeling changes under FD&C Act Section 505(o)(4)

Advertising effect

Reminder advertisements are not permitted (21 CFR 202.1)

What is a Boxed Warning?

A Boxed Warning, often called a black box warning, appears inside a border at the beginning of a prescription drug label, ahead of the indications. The Highlights section at the top of the label repeats a short version, so the risk is among the first things a prescriber reads.

The Food and Drug Administration (FDA) reserves the box for a limited set of situations. A box does not remove a drug from the market. It identifies a specific serious risk that prescribers are expected to weigh against the benefit, or to manage through how the drug is prescribed and monitored.

When FDA requires a Boxed Warning

FDA guidance on the warnings sections of labeling describes three general situations in which a box is appropriate:

Boxes can be added at approval or years later as postmarketing evidence accumulates. Well-known examples include the 2004 warning about suicidality in children and adolescents taking antidepressants, later extended to young adults, and the 2008 warning about tendon rupture with fluoroquinolone antibiotics. FDA can also remove a box when new evidence supports it, as it did for the smoking cessation drug varenicline in 2016.

• An adverse reaction is so serious in proportion to the potential benefit that it is essential to consider it when assessing risks and benefits.
• A serious adverse reaction can be prevented, or made less frequent or less severe, by appropriate use, such as patient selection, monitoring or avoiding certain concomitant therapy.
• FDA approved the drug with restrictions to assure safe use, for example under a Risk Evaluation and Mitigation Strategy (REMS).

Why Boxed Warnings matter

A box has practical effects beyond the label itself:

• Utilization management: payers may add prior authorization, step therapy or monitoring requirements for drugs with boxed risks.
• Competitive positioning: a box on one product in a class but not on its rivals is a frequent point of differentiation.
• Promotion: reminder advertisements, which name a drug without discussing its uses and risks, are not permitted for drugs with a Boxed Warning.
• Life cycle monitoring: a new or expanded box is a dated, public safety signal that often follows an FDA Drug Safety Communication.

Boxed Warning vs Warnings and Precautions

Section 5 of the label, Warnings and Precautions, lists clinically significant risks that do not reach the boxed threshold. A risk can move from section 5 into a box when evidence strengthens, and the reverse can also happen.

Contraindications in section 4 are different again. They describe situations in which the label states the drug should not be used because the risk clearly outweighs any possible benefit.