It took the US Food & Drug Administration (FDA) 12 years after launching a safety review of the allergy-and-asthma drug Singulair before it required a black-box warning about serious neuropsychiatric side effects, including suicidal thinking, in 2020.
Responding to decades of escalating concerns about the commonly prescribed drug, it deployed one of its most potent tools: a warning on the drug’s label that it could cause aggression, agitation and even suicidal thoughts – but it came too late for many children.
By then, it had received more than 80 reports of people killing themselves while taking the medicine, including 31 children and teenagers.
The Washington Post reports that the label, aimed mainly at doctors, was supposed to sound an alert about the 25-year-old medication, Singulair (generic name: montelukast). Yet the drug was still prescribed to 12m Americans in 2022. It is also available in South Africa.
Children face the greatest risks of the drug’s ill effects, and while use by minors did decline, it was still taken by 1.6m of them, including Nicole Sims’ son (6), who started having nightmares and hallucinations of a woman at the window. When he told her he wanted to die, his mother went online, desperate for answers.
Only then did she learn about the FDA warning. She also found a Facebook support group with 20 000 members for people who had experienced the drug’s side effects. Members recounted a haunting toll that they linked to the drug with the help of peers, not their doctors.
The FDA’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 had not required doctors be educated about side effects.
Federal regulators in 1998 initially dismissed evidence that emerged during the approval process about the drug’s potential to affect the brain, or revise their assessment until two decades later. The FDA was slow to alert the public as reports of psychiatric problems surfaced, highlighting deficiencies of a drug-monitoring system that puts the onus on manufacturers to report problems.
Federal regulators themselves can be blind to the full scale of a problem: The FDA 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 FDA stopped short of forcing Merck to conduct more rigorous studies that could have revealed 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.
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 the perceived failure by the FDA to determine how many have been harmed or to alert doctors.
“Where are the great studies telling us how often it happens? There aren’t any,” said Thomas Moore, of the Johns Hopkins Centre for Drug Safety and Effectiveness, who has long tracked reports of montelukast’s psychiatric effects.
The FDA added a boxed warning to Singulair in March 2020, requiring 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.
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 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.
FDA officials said they had taken appropriate action. Officials said a number of reports of psychiatric problems seemed drug-related and 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 like suicides that remain rare, said Dr Sally Seymour, director of the FDA’s pulmonary drugs division.
With concerns lingering, researchers, including some at the FDA, have returned to basic animal studies to examine possible effects of montelukast in the brain, which 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 the company had communicated appropriate information to patients and health providers about the drug’s risks and benefits.
The warning was added before Sims’ 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 had alerted her to the boxed warning.
Her daughter, Genevieve, had been on the medication since she was seven and grew increasingly depressed after her dose was increased 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 the moodiness to teenage angst.
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 FDA’s warning included suicide, though the agency has said no studies have definitively assessed the risk.
Rising sales, growing concerns
Approved in 1998, Singulair soon became a top-selling drug. With a market of 25m people battling asthma and more with allergies, sales representatives blanketed doctors’ offices, promoting the drug as a once-a-day alternative to inhaled corticosteroids, considered more effective but also more cumbersome. Singulair came in a chewable, cherry-flavoured 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.
People taking the drug have 30 times the odds of reporting abnormal behaviour or aggression compared with those taking other drugs.
It would earn the company about $50bn in revenue.
In 2007, Elizabeth Little, a New York state senator, contacted the FDA about a 15-year-old on Singulair who became hopeless and anxious. He killed himself 17 days after starting the drug.
Rather than mandating fresh studies of Singulair, the FDA 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 FDA examination of reports of side effects prompted Merck that year to add warnings to the label about hallucinations, hostility, anxiety and suicide.
By 2019, the FDA had documented 82 suicides of people on montelukast. More than 500 suicide attempts have also been linked to the drug in unverified reports.
Problems drew notice worldwide. Researchers examining side effect reports sent to the WHO in 2015 discovered outsize rates of anxiety and suicidal behaviour among children on montelukast.
A 2022 review of similar reports found high rates of aggression and agitation. Nightmares were reported 25 times as frequently as expected and suicidal thinking 18 times as frequently.
Such studies based on voluntary reports can identify problems, but not pinpoint how often they appear. Research trying to do so using more detailed health records is mixed. Studies of older adults and of US veterans and an FDA study on depression and suicide found few problems.
Some doctors cite those studies in arguing the FDA’s warning in 2020 was sufficient. They said montelukast remained popular because it addressed asthma and allergies simultaneously, with no side effects for some people. The drug eases breathing by suppressing inflammation in the airways.
Yet a 2021 study of Korean health data found older adults who had asthma and then developed psychiatric problems were 70% more likely to have taken montelukast-type drugs than those who had not.
Younger adults in Denmark on the drug were 38% more likely to soon need psychiatric or ADHD medications, another study found.
Even such “observational” reports can be biased by the unique features of people taking a drug, Moore, of Johns Hopkins, said.
Still, he said other evidence suggested the drug was causing the problems: They crop up in children with no psychiatric history. They go away when the drug is stopped. They tend to return if it’s restarted.
Drugs targeted at airway enter the brain
FDA scrutiny of montelukast has uncovered new information and shed fresh light on older data. In records approving the drug in 1998, the agency said only a “trace” amount crossed into the brain, though data showed lingering levels in a rat’s brain 24 hours after dosage.
That remained its stance for decades.
The agency reversed that conclusion in 2020. It cited a 2015 study saying it showed “significant” penetration of the blood-brain barrier in rats. The agency concluded anew that “montelukast could act directly on cells in the brain” in rats, and updated the drug label in 2020.
The FDA has also struggled to determine how many patients experienced harm.
In 2014, as Merck unsuccessfully sought approval to sell Singulair over the counter, FDA records for an oversight meeting showed Merck had data on about 46 500 cases with adverse events. US officials and the WHO knew of only 14 000.
The breadth of problems remained urgent for the Facebook group, which in 2017 urged the FDA to consider a boxed warning.
At an emotional hearing in 2019, one mother testified that when her 12-year-old daughter’s dose was raised, she started hearing voices telling her to harm herself; she dreamed about people being tortured and decapitated.
Another mother said her son (11) dreamed about his family being murdered.
Months later, the FDA announced the boxed warning and began studies of the drug’s interactions with the brain.
‘Leave this drug to adults’
Other scientists, too, have been examining the drug’s effect on the central nervous system and its potential to accumulate in the brain.
One Swedish study found that mice taking the drug for two weeks had impaired cell growth in the hippocampus, a brain region critical for memory and learning. A 2022 study in Portugal found altered levels of dopamine and serotonin in rats, and lowered defences against stress, said Dr Gonçalo Justino, a biochemistry researcher at the University of Lisbon.
Justino said he was haunted by numerous case studies of distressed children. Given the degree of harm to some children, he said, doctors should “leave this drug to adults”.
• Another warning in the packaging alerts consumers that “during worldwide marketing experience, congenital limb defects have been reported in the offspring of women being treated with Singulair during pregnancy”. “A causal relationship between these events and SINGULAIR has not been established.”
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