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FDA Black Box Warnings

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FDA Drug Warnings

The Food and Drug Administration (FDA) is charged with the responsibility of regulating most medicines used by the public in order to ensure that pharmaceutical products are safe. One of its most straightforward ways of doing this is by issuing black-box warnings.

The agency can require a pharmaceutical company to include a bold warning on the packaging and the patient instruction sheet if serious or life-threatening risks are associated with the drug. Black-box warnings take their name from the black border around the information and are the FDA’s most stringent warning a drug can carry before it is pulled from the shelves.

Once a drug receives a black-box warning, its manufacturer must also create a medication guide that describes how patients can safely use the drug. The guides are given out by pharmacists when prescriptions are filled and also are available online from the drug company and the FDA.

Although black-box warnings are one of the strongest tools used by the FDA to promote pharmaceutical safety, there is concern by many that they are not being used effectively and, therefore, are not protecting consumers.

Increased Use of Black-box Warnings

Although black-box warnings have been used for decades, in the last 10 years, there has been an explosion in the number issued.

Here’s how many black-box warnings are created: Before a drug is made available to the public, limited clinical trials are performed. After the release and widespread patient use, however, the FDA typically has more of an understanding of the drug and its potential adverse effects and may decide to add black-box warnings.

Between 2005 and 2008, about 14 percent of safety-labeling changes have been related to black-box warning additions or revisions, according to an editorial in Hospital Pharmacy.

Still, black-box warnings are not just for relatively new drugs. For example, Darvon/Darvocet, a widely used pain reliever for more than 50 years, was issued a black-box warning in July 2009 when it was linked to fatal overdoses. Yet it wasn’t until November 2010 that it was taken off the market because it was found to dangerously alter the electrical activity of the heart.

Public Scrutiny

Recently, the watchdog group Public Citizen petitioned the FDA to include more substantial warnings on two high-profile and popular drugs: injectable botulinum toxins, such as Botox, and proton pump inhibitors, such as Nexium, used to treat acid reflux disease.

In January 2008, Public Citizen, which represents 100,000 consumers, requested regulatory action in the form of “Dear Doctor letters” and black-box warnings for injectable botulinum toxins. The petition explains:

“Botulinum toxin acts by blocking the transmission of nerve impulses to muscles, causing those muscles to relax and resulting in a loss of muscle control. … Subsequent paralysis of respiratory muscles can lead to death. In the case of injected therapeutic or cosmetic use of botulinum toxin, if the product spreads from the injection site to another area of the body, this loss of muscle control can be similarly harmful.”

Public Citizen also cited the series of warnings the European Union posted regarding the spread of toxins and subsequent studies of adverse effects and fatalities linked to the drugs.

The FDA granted the petition in April 2009, clearing the way for black-box warnings on botulinum toxins (Botox, Myobloc, Dysport).

In August 2011, Public Citizen pursued the addition of black-box warnings for prescription and over-the-counter proton pump inhibitors, which are used to treat acid reflux disease, gastric ulcers and erosive esophagitis, and upper-gastrointestinal bleeding from nonsteroidal anti-inflammatory drug (NSAID) use.

The petition asserts: “Compounding the problem of massive inappropriate use, recent evidence has documented several serious new safety problems with long-term PPI use. For some of these risks, current FDA-approved PPI labels do not mention the adverse effect at all, including the potential for developing dependence on the drugs, which results in rebound hypersecretion of stomach acid and recurrence of symptoms after stopping PPI use.”

The FDA has yet to rule on Public Citizen’s most recent petition.

Confusing Use of Black-box Warnings

In at least one instance that the FDA has aggressively issued a black-box warning and then an expanded black-box warning, it has been roundly criticized, including in the New England Journal of Medicine.

Since October 2004, antidepressants have been required to have a black-box warning indicating that they are associated with an increased risk of suicide in children and adolescents. In May 2007, however, the FDA changed the warning to specify the risk was for young adults between ages 18 and 24, and it stated that the disease itself — depression — carries a risk of suicide. That was the first time a black-box warning implied there was a risk to not using the drug that might outweigh the drug warning itself.

“Whether the new warning will do more good than harm is not clear. There are already some signs that the warning will discourage depressed patients and their families from seeking treatment and frighten physicians away from prescribing antidepressants,” wrote doctors Richard A. Friedman and Andrew C. Leon.

These are just a few examples of how the FDA’s black-box warnings are applied. Although the warnings are designed to protect consumers, it’s easy to see from these few case studies that black-box warnings aren’t always applied in a non-arbitrary way or a consistently effective manner.

Last modified: March 25, 2014

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