What Do the FDA Black Box Medication Warnings Mean?

Dr. Larry Chiaramonte
If you had a headache and I advised you to take a certain small white pill, the rules of informed consent would require to that I warn you that it might cause severe reaction as wheezing or hives, irritate your stomach, and inhibit your blood from clotting normally if you got a cut.
Would you take the medication or not?
I bet you already know what it is–I just described aspirin.
If we listed all the things that could have harmed you today, you would have stayed in bed.
I was thinking about this because someone recently drew my attention to a commercial for Symbicort, a common, effective asthma-control medication. Symbicort “contains a drug” formoterol whose side effects were so drastic, including possible death, that he wondered why anyone would take it. Should we believe those smiling, confident, paid actors more than the scary words they ae saying?
There is no question that stated in isolation, side effects sound terrible, but sometimes the words don’t tell the whole story either.
Consider the following warnings about Symbicort, which are basically the same as those for of the competing drug Advair.
“Updated Important Safety Information:
“WARNING: Long-acting beta2-adrenergic agonists (LABA), such as formoterol, one of the active ingredients in SYMBICORT, increase the risk of asthma-related death. A placebo-controlled study with another LABA (salmeterol) showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including formoterol. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients
“When treating patients with asthma, prescribe SYMBICORT only for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (eg, discontinue SYMBICORT) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use SYMBICORT for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids
“SYMBICORT is NOT a rescue medication and does NOT replace fast-acting inhalers to treat acute symptoms.”
This language is misleading as well as alarming. Symbicort itself contains an ICS and is basically an asthma control medication, yet the wording suggests that they are somehow separate.
So what is the source of the red-alert tone?
It is based on the Salmeterol Multicenter Asthma Research Trial [or so- called SMART study], which covered a total of 26,000 Asthmatics over 12 years of age, who had not previously taken a long-acting beta agonist. Each subject received a 7-month supply of either salmeterol or placebo, which they were to take in addition to whatever asthma medication they were already. Each month a researcher would call to inquire if they were still taking the medicine, had any adverse events, and or changed their medication. An interim analysis done at 7 months revealed an excess of either deaths from asthma and severe asthma attacks, and therefore it was determined to stop the study.
There were 15 more severe asthma attacks in the salmeterol group compared with placebo and an excess of 10 deaths in the salmeterol group. These were not evenly distributed throughout the study population. The study population was 17% African-American and 70% white and yet very clearly almost all of the excess events occurred in the African American participants, although there was an excess of deaths in the white participants as well. (As my TV-watching friend points out, vis-á-vis this last point, the talking head in the commercial who talks about death as a side effect is an African American man.)
SMART was conceived before the appreciation of the inappropriateness of LABA monotherapy—i.e. LABA without ICS–was fully developed. There was no requirement that the patients in SMART be on inhaled corticosteroids (ICS), and in fact only 48% listed ICS as one of the drugs they were taking at the time of randomization. Even in those 48%, it is not certain how regularly ICS was used (and as you know from reading Asthma Allergies Children: a parent’s guide, many asthma patients and their parents are fearful of steroids). Even with these limitations, in the SMART study the deaths and severe reactions largely occurred in patients who were definitely not taking ICS. Nine of the ten excess deaths occurred in this non-corticosteroid-treated group of the subjects. Furthermore, the data suggests that the additional problems among African Americans were due to socioeconomic factors that made it less likely they would also use ICS and receive appropriate medical follow up; all the data shows that health care for whites and blacks is not equal, so this makes perfect sense.
But the warning was written without regard for these shortcomings, which were well-known to SMART’s authors. One of those, Dr. Harold Nelson, recently a contributing author to this website, told reporters in 2003 that the warning implied a broader problem that didn’t exist.
Moreover, the assertion in the current black box warning that “Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA” is wrong now and it was then.
The problems with monotherapy, or using only LABA, have long been recognized by clinical allergists like Dr. Ehrlich and me. Asthma is a dual problem—the airways are both inflamed and constricted. ICS treats the first and LABA the other. (For a full explanation of why treating just bronchoconstriction is dangerous, read chapter 3 Asthma Allergies Children: a parent’s guide.)
The FDA in its required black box warnings for asthma medications does not credit ICS use mitigating the increased risk of asthma-related deaths from beta2-adrenergic agonists. So we are stuck with a warning that Symbicort contains a drug that may do all these terrible things, even though it is paired with another medication for an unassailable combination.
I am not saying it is wrong to have warnings. It’s just that regulatory language often lags behind current events and knowledge. This mismatch isn’t confined to medicine. It was recently reported that some railroad workers were arrested for insider trading after deducing that their company was going to be taken over from repeated visits by men in blue suits and investing in “puts”. Somehow I don’t think that’s what the laws were written to prevent.
We are already miles ahead of the methodology and conclusions of SMART. A new study by English researchers found: “Formoterol use in children and adolescents (4-17 years) with asthma in this large study where the majority are prescribed concomitant ICS is not associated with any increased risk of asthma-related hospitalizations. The results are not influenced by dose or ethnicity.”
One of these days, this new data might find its way onto TV and pharmaceutical packaging. However, it will happen quietly, and thus not make up for the shock value of: WARNING.