Dozens of these buttons flooded the United States Food and Drug Administration’s (FDA) headquarters at a meeting for the widely prescribed asthma/allergy medication, montelukast (brand name, Singulair). The message was simple:
“The benefits did not outweigh the risks.”
As each button approached the podium, the panel of experts heard gut-wrenching testimonials about the unimaginable psychiatric symptoms induced by this medication. Each button also clung to the presentations made by neuroscientists, researchers, and representatives from patient advocacy groups that have been in the ring for over a decade.1
Five months later, the FDA issued a Drug Safety Communication2 reflecting the button’s message:
“The benefits of Singulair may not outweigh the risks of mental health side effects in some patients.”
As a result, the FDA required a boxed warning – the strongest, most prominent warning available – for the neuropsychiatric effects in addition to advising health care professionals to avoid prescribing Singulair for mild conditions that can be adequately treated with other medicines.
A momentous decision prompted by…. a button. If only it were that simple!
Not So “Minimal” Change
While the black box warning captivated the spotlight, the most significant change was lost in the shadows. Without explanation or inclusion with the other “recent major changes,” one word was discretely removed from Singulair’s Prescribing Information. A word used to describe Singulair’s distribution across the blood-brain barrier. Minimal.
Prior to the FDA investigation, Singulair’s Prescribing Information3 indicated:
“Studies in rats with radiolabeled montelukast indicate minimal distribution across the blood-brain barrier.”
After the FDA investigation, Singulair’s Prescribing Information4 was modified to indicate:
“Orally administered montelukast distributes into the brain in rats.”
The removal of the “minimal” description without emphasis would lead one to think the word must not have carried much weight. If only it were that simple!
For more than twenty years, the word “minimal” has provided assurance that Singulair’s distribution to the brain was inconsequential or too little to induce structural or functional effects to the brain. As a result, Singulair was marketed and prescribed to millions of asthma/allergy consumers as a medication that acts only on the airways. This perception has led to catastrophic implications.
To start, the medication was granted FDA approval with absolutely no requirement to study its effects to the brain either through additional animal studies or subsequent clinical trials in humans. This inadequacy has been acknowledged by the FDA and advisors, specifically at a 2014 meeting in which an advisory committee voted overwhelmingly against moving Singulair from prescription to over-the-counter status5:
- “The clinical trials were not designed specifically to examine neuropsychiatric events and many of the trials were of short duration.”
- “What we’ve learned about clinical trials in agents has changed substantially, particularly in trying to ascertain neuropsychiatric side effects. We would never construct a trial nowadays the way this was constructed in 1998.”
This inadequacy of the clinical trials can also be captured in Merck’s own words in a 2009 review6:
- “These studies of montelukast were generally designed as clinical trials of asthma and allergic rhinitis and were not designed to determine the incidence of behavior-related adverse experiences with montelukast treatment.”
- “These trials were designed without specific prompting to report such adverse events and without providing criteria to investigators for reporting behavior-related adverse experiences as psychiatric diagnoses.”
- “Patients who do not connect the study drug with an experience might not report that experience, or patients who are embarrassed or ashamed of a certain symptom might not offer information unless questioned specifically. Thus, we cannot conclude definitively that all adverse events were reported, and we cannot exclude definitively that all adverse events were more frequent in one of the treatment groups.”
Another implication of the word “minimal” is that it prevented the medical community from accepting the possibility that stopping montelukast treatment could induce new or worsening neuropsychiatric symptoms, similar to the withdrawal syndrome associated with drugs that are centrally acting like antidepressants and benzodiazepines. Without understanding that montelukast does act on the central nervous system, not only the airways, these post-discontinuation symptoms are typically considered anecdotal and are misdiagnosed and mistreated. Its important to note that although the FDA did not use the term Montelukast Withdrawal Syndrome, the reports that “mental health side effects developed or continued after stopping montelukast” were acknowledged in the FDA Drug Safety Communication.2
These significant implications of the word “minimal” beg the question: why would this word discretely be removed after twenty years? A reasonable explanation would be that its removal was prompted by a new, scientific discovery. If only it were that simple!
Evidence for “minimal” removal
Originally, the word “minimal” was selected to describe Singulair’s distribution into the brain based on the pre-clinical trial data showing only a “trace” amount was detected in the rat brain hours after administration.7 However, this same pre-clinical data was re-analyzed by a research group interested in evaluating montelukast’s impact on inflammation associated with Alzheimer’s disease and a very different conclusion was reached.8 Most notably, rather than note the distribution to the brain in terms of absolute volume, these researchers expressed it as a brain/plasma ratio which increased from 10% at 1 hour post administration to 971% after 24 hours. They concluded that a substantial amount of montelukast crosses the blood brain barrier and after 24 hours after drug administration, the levels in the brain were even higher than the amount in plasma. This was not new science at all – but original data that yielded conflicting conclusions and carried catastrophic consequences.
In addition to the distribution to the brain, this research uncovered that montelukast does have structural and functional effects to the central nervous system that “can be either beneficial or unfavorable, depending on physiological conditions” which are mediated through the GPR17 receptor, a recognized regulator of central nervous system cells.8,9 The FDA acknowledged this evidence in its Briefing Document10 as well as the Drug Safety Communication2:
“We also reviewed evidence from animal studies, which suggest montelukast could act directly on cells in the brain. Orally administered montelukast was detectable in brain tissue and cerebrospinal fluid in rats, providing evidence of its ability to cross the blood-brain barrier.”2
One would expect this acknowledgment to immediately prompt a call for additional studies. If only it were that simple!
Left with “minimal” hope
Although the FDA does have the authority to require Merck to perform additional studies to address the safety concerns, an FDA expert shared her opinion into why this is not likely to happen:
“I think we have to be realistic here about the situation. I honestly don’t know how Merck — if they would conduct a study or not. It’s a generic product. The branded product has very little market distribution. So I think while recommendations for studies that they should conduct we definitely want to hear about, but I don’t know if we went to them and said, “You need to do these studies,” if they would actually happen.” She continued, “you could imagine a company who no longer makes a lot of money off of this product, looking at a very expensive trial to do, may make a business decision that we no longer want to have an NDA for this product.”1
Distressingly, without additional studies or emphasis on the evidence prompting the modification to the distribution section, it leaves an airway medication being prescribed to millions of children, some as young as 6 months old, with an acknowledged direct action to the brain. It leaves a strong twenty-year perception intact that this airway drug’s distribution to the brain is too “minimal” to induce pharmacological effects. It leaves many viewing the FDA action as nothing new and a mere duplication of adverse events already contained in the Prescribing Information. It leaves the thousands of injured consumers clinging to the hope that others will find the “minimal” change, beyond the black box.
Laura Marotta has spent three years researching the neuropsychiatric adverse events induced by the commonly prescribed asthma/allergy medication, Singulair (montelukast). Her son’s intense onset of unimaginable psychiatric symptoms after discontinuation of treatment with montelukast (montelukast withdrawal syndrome) led her to advocate for drug labeling changes, further research, and awareness about this airway drug’s direct action on the brain.
Laura’s post on the difficulties her son and other children have had – Montelukast Withdrawal Syndrome – featured on RxISK nearly a year ago, shortly before the FDA meeting that led to the Black Box Warning. It drew a huge number of comments,
- S. Food and Drug Administration. Transcript of the Joint Meeting of the Pediatric Advisory Committee and Drug Safety and Risk Management Advisory Committee (September 27, 2019). Available from: https://www.fda.gov/media/132560/download
- S. Food and Drug Administration. Drug Safety Communication. “FDA requires Boxed Warning about serious mental health side effects for asthma and allergy drug montelukast (Singulair); advises restricting use for allergic rhinitis.” (March 4, 2020) Available from: https://www.fda.gov/media/135840/download
- Merck’s Prescribing Information (August 2019) Available from: https://www.fda.gov/media/131036/download
- Merck’s Prescribing Information (April 2020) Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020829s073,020830s075,021409s051lbl.pdf?utm_campaign=FDA%20Approves%20Label%20Changes%20for%20Montelukast%20%28Singulair%29%20Regarding%20the%20Potential&utm_medium=email&utm_source=Eloqua
- S. Food and Drug Administration. Transcript of Nonprescription Drugs Advisory Committee Meeting (2014). Available from: http://wayback.archive- it.org/7993/20170113035319/http://www.fda.gov/downloads/AdvisoryCommittees/Co mmitteesMeetingMaterials/Drugs/NonprescriptionDrugsAdvisoryCommittee/UCM4023 52.pdf.
- Philip G et al. Analysis of behavior-related adverse experiences in clinical trials of montelukast. J Allergy Clin Immunol Volume 124, Number 4. 2009
- FDA Pharmacology Review of Merck’s New Drug Application NDA No. 20-829 (10mg) and 20-830 (5mg)
- Marschallinger, J et al. Structural and functional rejuvenation of the brain in old rats by an approved anti-asthmatic drug. Nat Commun. 6:8466 doi: 10.1038/ncomms9466 (2015)
- Erikkson et al. The anti-asthmatic drug, montelukast, modifies the neurogenic potential in the young healthy and irradiated brain. Cell Death and Disease (2018)9:775 doi 10.1038/s41419-018-0783-7
- FDA Briefing Document “Neuropsychiatric events with the use of montelukast in pediatric patients” (September 27, 2019) Available from:https://www.fda.gov/media/131035/download