In early 2020, the Food and Drug Administration responded to decades of escalating concerns about a commonly prescribed drug for asthma and allergies by deploying one of its most potent tools: a stark warning on the drug’s label that it could cause aggression, agitation and even suicidal thoughts.
The agency’s label, which was primarily aimed at doctors, was supposed to sound an alert about the 25-year-old medication, Singulair, also known by its generic name, montelukast. But it barely dented use: The drug was still prescribed to 12 million people in the United States in 2022.
Children face the greatest risks of the drug’s ill effects, and while usage by minors did decline, it was still taken by 1.6 million of them — including Nicole Sims’s son. Ms. Sims had no idea why, at 6, her son started having nightmares and hallucinations of a woman in the window. When he told her that he wanted to die, Ms. Sims went online, desperate for answers.
Only then did she learn about the F.D.A. warning. She also found a Facebook support group with 20,000 members for people who had experienced side effects of the drug. Members of the group recounted a haunting toll that they linked to the drug with the help of peers, not their doctors.
“It’s a mental health crisis that nobody is recognizing,” said Anna Maria Rosenberg, an administrator of the group.
The F.D.A.’s handling of Singulair illustrates systemic gaps in the agency’s approach to addressing troubling side effects from medicines approved long ago — and to warning the public and doctors when serious issues arise. The agency had flagged the 2020 warning label, known as a “boxed warning,” to physicians’ groups, but it had not required that doctors be educated about the drug’s side effects.
Federal regulators in 1998 initially dismissed evidence that emerged during the approval process about the drug’s potential to affect the brain and did not revise their assessment until two decades later. The F.D.A. was slow to alert the public as reports of psychiatric problems surfaced, highlighting deficiencies of a drug-monitoring system that puts the onus on drugmakers to report problems.
Federal regulators themselves can be blind to the full scale of a problem: The F.D.A. discovered nearly a decade ago that Merck, the maker of Singulair, received thousands more reports of side effects from the drug than the agency or its global counterpart. And after a teenager’s high-profile suicide in 2007, the F.D.A. stopped short of forcing Merck to conduct more rigorous and expensive studies that could have made clear how common bad reactions were.
Prescribing of the drug has remained at high levels, raising questions about whether the alert reached enough doctors and patients, who often don’t read the fine print on the drug’s tightly folded label, tucked into a bag at the pharmacy. (Prescribing data was provided to The New York Times by Komodo Health.)
Many doctors support the drug’s availability and see existing cautions as sufficient. But researchers have grown increasingly alarmed about its effects, especially on children, and about what they see as the F.D.A.’s failure to determine how many have been harmed or to get the word out to doctors.
“What are the great studies that tell us how often it happens? There aren’t any,” said Thomas Moore, of the Johns Hopkins Center for Drug Safety and Effectiveness, who has long tracked reports of montelukast’s psychiatric effects. “This is a structural problem.”
Dr. Reshma Ramachandran, a Yale University assistant professor and family doctor, said that the warning had not broken through to channels that doctors notice and that the agency “needs to do much more in terms of direct communication to clinicians and through more active channels.”
‘Searching for answers’
In issuing the warning in March 2020, the F.D.A. required pharmacists to hand out a medication guide and added the warning, with a thin black line as a border, to the drug label. The agency also sent a safety alert to email subscribers, flagged the warning to dozens of professional and patient groups, and published an article in a medical journal on its reasoning.
But it did not use its authority to require monitoring of side effects or the education of doctors. Rarely are approved drugs with known side effects fully barred from sale.
While researchers see evidence that points to a link between the drug and psychiatric side effects, studies vary significantly on how frequently they appear — or, in some cases, whether they appear at all. Reports include a wide range of psychiatric effects, making it challenging to pinpoint the cause.
The agency’s risk-benefit calculus for montelukast has weighed its psychiatric risks against its wide use in treating many patients for asthma, which can be deadly.
F.D.A. officials said they had taken appropriate action. In an interview, officials said that a number of compelling reports of psychiatric problems seemed drug-related and that the boxed warning was meant to raise awareness.
The agency is continuing to study notes in electronic health records for clues about side effects, and officials said it “continues to monitor and investigate this important issue.” But pinpointing the risks may not be feasible: It would take a large study to capture events such as suicides that remain rare, said Dr. Sally Seymour, director of the F.D.A.’s pulmonary drugs division.
With concerns lingering, researchers, including some at the F.D.A., have returned to basic animal studies to examine possible effects of montelukast in the brain, a quest that could take a decade to complete.
Merck, which reaped billions of dollars in revenue from the drug, spun it off in 2021 to the company Organon. Merck referred comment to Organon, but in an April 2023 court filing denied “a significant link between Singulair and neuropsychiatric events.”
Organon said in a statement that the company had communicated appropriate information to patients and health providers about the drug’s risks and benefits. “Nothing is more important to Organon than the safety of our medicines and the people who use them,” the company said. Other generic companies also sell the drug.
The warning was added before Ms. Sims’s son began talking about hearing scary voices and seeing walls that appeared to be melting. If she had known, she said, she would have stopped the drug right away.
Ashley Bracken also wishes her family’s allergy practice in Utah had alerted her to the boxed warning.
Ms. Bracken’s daughter, Genevieve, had been on the medication since age 7 and grew increasingly depressed after a doctor increased her dose to the adult level in April 2021, when she was 13. Her mother initially attributed her daughter’s obsessive hand washing to the pandemic. She wrote off her daughter’s moodiness to teenage angst.
Ms. Bracken said she first saw a list of the drug’s side effects, which include obsessive compulsive disorder, in a screenshot on Genevieve’s phone from October 2021.
She and her husband had been scouring the device for any clue to why the girl, then 14, had killed herself days before Christmas that year. The F.D.A.’s warning included suicide, though the agency has said no studies have definitively assessed the risk. The family’s medical practice declined an interview request.
“It sickened us,” Ms. Bracken said. “In the moment, we were searching for answers, because what she did didn’t make sense.”
Rising sales, growing concerns
Approved in 1998, Singulair soon became a top-selling drug. With a market of 25 million people battling asthma and more with allergies, sales representatives blanketed doctors’ offices. They promoted the drug as a once-a-day alternative to inhaled corticosteroids, which are considered more effective but also more cumbersome. Singulair came in a chewable, cherry-flavored pill for children.
Concerns surfaced within Merck: A whistle-blower claimed in a 2008 lawsuit that the company improperly paid doctors to prescribe drugs, including Singulair, and that the drug “leads to aggressiveness and attention deficit problems” in children. Merck settled the claims, largely related to other drugs, and admitted no wrongdoing.
Merck promoted the medication to parents, in 2009 partnering with the TV personality Jo Frost, known as “Supernanny” on reality television. Merck, which also made an inhaler for asthma, funded the American Academy of Pediatrics to train doctors about asthma diagnosis and prescribing, a Fox affiliate reported in 2010. (An NBC affiliate has also reported on problems with the drug.)
A worldwide success, the drug would earn Merck an estimated $50 billion in revenue, according to a recent Reuters analysis of the drug’s troubled history.
In 2007, its possible drawbacks drew wider attention when Elizabeth Little, a New York state senator, contacted the F.D.A. about a 15-year-old on Singulair who became hopeless and anxious, agency records show. The teenager killed himself 17 days after starting the drug.
Rather than mandating fresh studies of Singulair, the F.D.A. allowed Merck to review its existing trials. The company concluded in 2009 that those trials were not devised to identify psychiatric problems or suicides, and few had been noted. An F.D.A. examination of reports of side effects prompted Merck the same year to add warnings about hallucinations, hostility, anxiety and suicide to the label.
As of 2019, the F.D.A. had documented 82 suicides of people on montelukast. More than 500 suicide attempts have also been linked to the drug in unverified reports to the agency.
Problems drew notice worldwide. Researchers examining side effect reports sent to the World Health Organization in 2015 discovered outsize rates of anxiety and suicidal behavior among children on montelukast, a finding researchers deemed “striking” in young children.
A 2022 revi