“Boxed warnings” or “black boxes” are the strictest FDA label warnings. They appear on cigarettes, fluoroquinolones (for tendon rupture), Lamictal (for SJS and TEN), Accutane (birth defects), and other products with well-known risks.

The industry obviously dislikes black boxes since they reduce sales (though their lobbyists charge the boxes “confuse” and “unnecessarily alarm” patients).

So it was no surprise that when the FDA held a Joint Meeting of the Pediatric and Drug Safety and Risk Management Advisory Committees on September 27, 2019, to address growing reports of neuropsychiatric events from montelukast in pediatric patients there was a lot of talk about black boxes.

Montelukast, marketed as Singulair, is a leukotriene receptor antagonist used in asthma and allergy.

Singulair was Merck’s biggest seller when on patent, bringing in $3.3 billion in 2011 and named one of Kiplinger’s 15 all-time best-selling prescription drugs. Merck used Scholastic, the educational publishing group, and the American Academy of Pediatrics to help market it.

Testifying at the hearings were parents whose children had taken their own lives on the drug or experienced other severe harm.

The parents, from groups like Parents United for Pharmaceutical Safety and Accountability and the Montelukast Side Effects Support and Discussion Group, asserted that a black box warning would prevent future tragedies. The current montelukast label only warns against “neuropsychiatric events.”

Many safety signals

Fox 5 first reported neuropsychiatric events in late 2010 — parents seeing aggressive behavior, hostility, hallucinations, night-terrors, tremors, irritability, anxiety, depression, and even suicide in their children taking montelukast.

But red flags existed much earlier, especially regarding montelukast’s effect on children. In the late 1990s, FDA reviewers note in montelukast’s new drug approval documents note that infant monkey had to be euthanized and “may be more sensitive to the toxicity.”

In 1998, Peter Honig and John Jenkins of the FDA repeated the warning cautioning in the New England Journal of Medicine that adult studies of the montelukast “may not be predictive of the response,” in children.

In 2016, a Vigibase report found that suicidal behavior “and completed suicide appear to be more frequently reported than previously thought in practice.” In 2018, research in the Springer journal Drug Safety reported that “ten pharmacovigilance studies using different global databases detected the signals” of neuropsychiatric events.

Even the briefing documents released by the FDA for montelukast September hearings were something of a red flag. They acknowledge, for the first time, the drug’s action on the brain as a competitive antagonist of GPR17, not merely acting on the CysLT1 receptor as prescribing information portrays. The new information is relevant to the neuropsychiatric events under investigation, said parents at the hearings.

To add a black box to montelukast or not?

Steven Meisel, PharmD, CPPS, Director of Medication Safety Fairview Health Services, and a FDA committee member agreed that a black box is necessary. The “FAERS data shows that between six and 800 neuropsychiatric events have been reported every year,” he said, and the 35 million montelukast prescriptions written a year tell “me that this drug is being prescribed in a cavalier manner.”

Christy Turer, an internist and a pediatrician on the committee, also recommended a black box. “In thinking about risk-benefit, I think the black box would send a message and would decrease prescribing,” she said. “We as a country, our physicians, our prescribers, we over-prescribe.”

But others on the FDA committee disagreed. Jim Tracy, an allergist and associate professor at the University of Nebraska, said black boxes would create “obstacles to care,” and that patients could “all of a sudden get terrified. And they, without supervision, they just stop their drug.”

Committee member James McGough, a child psychiatrist at UCLA, concurred, recalling the FDA’s 2004 addition of black box warnings for child and adolescent suicide on SSRIs and which, in his opinion, backfired. “There’s a clear association between declining antidepressant use and increased suicide among youth,” he said.

It is noteworthy that while industry fought and continues to fight SSRI black boxes, both their use and the suicide rate have never been higher. U.S. suicide is 33 percent higher than it was two decades ago, and one in eight Americans is on antidepressants. Declining prescriptions of antidepressants clearly aren’t causal.

Patient safety or profit safety?

Sadly, when warnings could affect drug sales, there is often a battle. When the huge Salmeterol Multi-center Asthma Research Trial, or SMART trial was terminated in 2003 after 16 deaths, 44 intubations, and 369 hospitalizations, mostly in African-Americans, black boxes were added to Advair and Serevent which contain salmeterol and to Symbicort, Dulera and Foradil which contain the similar, formoterol fumarate. The drugs are known as long-acting beta-agonists or LABAs.

The industry assailed the warnings as it did SSRI black boxes, citing the National Asthma Education and Prevention Program Expert Panel Report 3 as proof of LABA safety though it was written almost exclusively by industry-funded physicians. For example, William W. Busse, MD, who chaired the expert panel, listed 21 relationships with drug makers.

But there were other safety signals, especially concerning Glaxo’s Advair. According to ProPublica, in 2011, the Justice Department said Glaxo’s Advair promotion had exposed patients to “significant safety risks,” and there were “scores of lawsuits” from people “whose relatives have died while taking Advair.”

Nevertheless, the FDA asked Glaxo and other LABA makers, AstraZeneca, Novartis, and Merck in 2011 to conduct studies on LABA safety despite objectivity questions and the cloud over Glaxo. In 2017 the FDA repealed the LABA black boxes on the basis of the industry studies. William Busse led the analysis.

Is montelukast so safe it needs no black box? Are LABAs so safe their black box can be removed? Unfortunately, black boxes are too frequently regarded by the influential drug industry as profit warnings, not health warnings.

Martha Rosenberg is an investigative reporter whose work has appeared in the British Medical Journal (BMJ), Consumer Reports, Public Citizen, the Center for Health Journalism at USC Annenberg, the Nieman Foundation for Journalism at Harvard University, and other outlets. She studied at Rush Medical School and writes on health care, food, medicine, and public policy.

Rosenberg’s reporting has been cited by Memorial Sloan Kettering Cancer Center, Mayo Clinic Proceedings, Public Library of Science Biology, ScienceDirect, the Journal of Pain & Palliative Care Pharmacotherapy, the Journal of Trauma & Dissociation, Britannica, National Geographic, Hastings Law Journal, and Wikipedia. She is the author of several books, including Multidisciplinary Management of Chronic Pain: A Practical Guide for Clinicians, Born With a Junk Food Deficiency, Big Food, Big Pharma, Big Lies, and Food, Clothes, Men, Gas and Other Problems. She publishes on Substack, OpEdNews, and her Amazon author page.

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