FDA Initiates Acetaminophen Label Change, Leucovorin Approval for Cerebral Folate Deficiency

The US Food and Drug Administration (FDA) has initiated the process for a label change for acetaminophen (Tylenol and similar products) to reflect evidence suggesting use of acetaminophen by pregnant women may be associated with an increased risk of neurological conditions such as autism and ADHD in children.1

Additionally, the Agency has initiated the approval of GSK’s leucovorin calcium tablets (Wellcovorin) for patients with cerebral folate deficiency (CFD), a neurological condition affecting folate transport into the brain and leads to developmental delays with autistic features, seizures, and problems with movement and coordination. The FDA requested GSK submit a supplemental New Drug Application (sNDA) as part of the Agency’s initiative to investigate opportunities to repurpose older medications for the treatment of chronic diseases.2,3

“The FDA is taking action to make parents and doctors aware of a considerable body of evidence about potential risks associated with acetaminophen,” FDA Commissioner Marty Makary, MD, MPH, said in a statement.1 “Even with this body of evidence, the choice still belongs with parents. The precautionary principle may lead many to avoid using acetaminophen during pregnancy, especially since most low-grade fevers don’t require treatment. It remains reasonable, however, for pregnant women to use acetaminophen in certain scenarios.”

As described by the Agency, evidence in recent years points to a correlation between acetaminophen use during pregnancy and subsequent diagnosis of conditions like autism and ADHD, including the Nurses’ Health Study II and the Boston Birth Cohort. Of note, some studies have described that the risk may be most pronounced when acetaminophen is taken chronically throughout pregnancy.1

While an association between acetaminophen and neurological conditions has been described in many studies, a causal relationship has not been established. Additionally, acetaminophen is the only over-the-counter drug approved for use to treat fevers during pregnancy, and high fevers in pregnant women can pose a risk to their children. Aspirin and ibuprofen have well-documented adverse impacts on the fetus.1

Regarding the initiation of the approval of leucovorin calcium tablets for patients with CFD, the Agency conducted a systematic analysis of literature published between 2009-2024, including published case reports with patient-level information, as well as mechanistic data, and has determined that the information supports a finding that leucovorin calcium can help individuals suffering from CFD.2

"We have witnessed a tragic four-fold increase in autism over two decades,” Makary said.2 “Children are suffering and deserve access to potential treatments that have shown promise. We are using gold standard science and common sense to deliver for the American people.”

The FDA is working with GSK, the innovator of leucovorin calcium, on a process to include the essential scientific information needed for the safe and effective use of these drug products for adults and pediatric patients with CFD. As the New Drug Application (NDA) holder for this medicine, GSK has preliminarily agreed to work with the FDA on this relabeling effort and is supporting this initiative by adding data from case reports identified by the FDA of genetically confirmed CFD into the US prescribing information.2,3

“The FDA is collaborating with GSK to broaden the existing Wellcovorin label," said George Tidmarsh, MD, PhD, director of the FDA’s Center for Drug Evaluation and Research.2 “This effort reflects the FDA’s commitment to identify opportunities to repurpose drugs to treat chronic diseases. The FDA remains committed to finding and treating the root causes of autism.”

CFD has also been reported in a broader patient population with neuropsychiatric symptoms, including autistic features, and detectable serum autoantibodies to the folate receptor alpha; however, there are limitations on the available data for the use of leucovorin in this population and additional studies are needed to assess safety and efficacy.2

References

1. US Food and Drug Administration. FDA Responds to Evidence of Possible Association Between Autism and Acetaminophen Use During Pregnancy. September 22, 2025. Accessed September 22, 2025. https://www.fda.gov/news-events/press-announcements/fda-responds-evidence-possible-association-between-autism-and-acetaminophen-use-during-pregnancy

2. US Food and Drug Administration. FDA Takes Action to Make a Treatment Available for Autism Symptoms. September 22, 2025. Accessed September 22, 2025. https://www.fda.gov/news-events/press-announcements/fda-takes-action-make-treatment-available-autism-symptoms

3. GSK. GSK to submit label update for Wellcovorin (leucovorin) at US FDA’s request. September 22, 2025. Accessed September 22, 2025. https://www.gsk.com/en-gb/media/press-releases/gsk-to-submit-label-update-for-wellcovorin-leucovorin-at-us-fda-s-request/