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FDA Black Box Warnings

An FDA boxed warning, or “black box warning”, is an advisory to consumers that an approved prescription medication can have serious and potentially fatal side effects. It is the strongest warning required by FDA regulations. A black box warning consists of a prominent label notice, literally contained within a black square, with the header capitalized and the entire text printed in bold lettering.

Although intended for both patients and physicians, data suggests that health care providers do not always read, or even notice black box warnings. Additionally, black box warnings are usually added after a prescription medication has been on the market for a period of time, usually as the result of post-market studies and observations demonstrating that it poses major risks. Therefore, the first patients who have taken the new medication have been literal “guinea pigs,” and are the most likely to have suffered from taking it.

In rare instances, the FDA may require a pharmaceutical company to include a boxed warning before a new drug reaches the market. When this happens, the new drug's initial sales are likely to be very limited – and the new product may not even continue to be offered.

One example of this occurred in 2014 with the introduction of an inhalable form of insulin known as Afrezza. An earlier product, Exubera, was approved in 2006 and marketed by Pfizer, but was withdrawn a year later after post-marketing studies showed it to be no more effective than insulin injections. Biopharmaceutical company MannKind submitted a New Drug Application (NDA) for Afrezza in 2009, but the product was initially rejected by the FDA.

After additional clinical studies, Afrezza obtained FDA approval. However, a boxed warning instructed physicians to take a detailed medical history and perform a full physical examination because of the dangers to patients with respiratory disorders (including asthma, COPD, and lung cancer). Because there are numerous alternatives that are less expensive, less restrictive, and equally or more effective, sales of Afrezza have been limited.

The history of the boxed warning dates back to the mid-1970s. The FDA requires a boxed warning on a medication's package labeling when:

  1. the product is approved for a limited population
  2. post-marketing studies have demonstrated that serious adverse events can result to the point that the risks outweigh the benefits
  3. Adverse events can be prevented or made less severe or more infrequent by prescribing the drug in very limited circumstances, such as avoiding taking the medication with alcohol or certain other drugs or foods, or not giving it to patients with certain conditions or co-morbidities
  4. People of a certain age (for example, very old or very young) or expectant mothers would be more adversely affected by taking the drug

Because of “fast tracking” via the 510(k) process (driven in part by the well-intentioned, but ultimately misguided "21st Century Cures Act"), the number of new drugs that end up requiring boxed warnings is higher than ever. The unfortunate result is that more patients are being exposed to these dangerous drugs than ever before.