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 that "infants may be more sensitive to the toxicity, since one infant monkey required euthanasia at an oral dose of 150 mg/kg, whereas in the 3-monthstudy in adult monkeys, euthanasia was performed on two monkeys at an oral dose of 450 mg/kg." (Page 29)
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 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 the montelukast September hearings were a red flag. They acknowledge for the first time new 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 Boxed Warning to Montelukast or Not?
At the hearings, experts testified both for and against a boxed warning.
Steve Meisel, PharmD, CPPS, Director of Medication Safety Fairview Health Services and a FDA committee member agreed a boxed warning 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 at the University of Texas Southwestern Medical Center on the FDA committee, also recommended a boxed warning. "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."
(Note: You can view every article as one long page if you sign up as an Advocate Member, or higher).
