As experts express concern about new British guidelines that restrict the use of valproate in women and men under 55 due to safety risks, questions are being raised about whether the United States should consider updating its own guidelines accordingly.
On 31 January, the UK Medicines and Healthcare products Regulatory Agency (MHRA) issued new guidelines banning the use of valproate in new female patients under the age of 55 unless two independent experts agree that there are no other effective or acceptable treatments. The same level of consent is required for existing female patients to continue their current valproate treatment.
These requirements were put in place after a large body of research showed that mothers who use the drug during pregnancy are at increased risk of serious congenital malformations in their offspring. The restrictions also apply to men, because fathers who take the drug within the first three months of pregnancy may be at increased risk of neurodevelopmental disorders in their offspring.
but, editorial Published in February of The Lancet Neurology They say the guidance goes too far and omits important information.
“As a drastic measure that no other country has yet taken, [MHRA] “The government has introduced strict new guidelines on the use of valproate,” the editorialists wrote. “The move will bring many challenges for healthcare professionals and patients. Epilepsy”
Asked to comment on the UK initiative, the American Epilepsy Society (AES) said: Medscape Medical News “The teratogenic risk of valproic acid is well established. [UK] The regulatory changes are not based on new evidence.”
Therefore, the organization “does not recommend any changes to current prescribing regulations for valproate in the United States,” the AES said. Current Position Statement Last updated in 2021.
Why now?
Valproic acid is primarily used to treat epilepsy, but it is also approved to treat: Bipolar disorder.
of The Lancet Neurology The editorial points out that recent data shows a significant fall in the number of pregnant women prescribed the drug in the UK between 2018 and 2022.
So why has the MHRA decided to update its guidelines? What prompted the MHRA to go ahead with what the editorial describes as a “controversial decision”?
In a written response Medscape Medical NewsThe agency explained that despite a 38% decline in valproate use among women of childbearing age since 2018, approximately two to three babies continue to be born each month having been exposed to the drug in the womb.
“Evidence from patient advocacy groups shows that some women taking valproate still [adequately] People should be informed of the risks by their healthcare professional,” the MHRA said.
“The new measures will increase oversight over the prescribing of valproate and ensure that valproate is administered only when there are no other effective or acceptable treatment options,” the agency added. Based on sufficient research, “there is no safe dose of valproate during pregnancy.”
In response to concerns raised The Lancet Neurology The editorial explained that the MHRA had had extensive discussions with the Human Medicines Committee, epilepsy and bipolar disorder experts, experienced GPs and patients about the lack of recommendations on alternative medications and the potential burden of needing two independent specialists, which could put strain on already busy neurology clinics.
“The UK Medicines Commission recognised that successful implementation of the new measures will require significant changes to clinical practice,” the MHRA said. “We have listened to the commission’s feedback and agreed to a phased introduction to reduce disruption to ongoing patient care. We have also introduced new materials to support patients. The patient voice must remain our main focus.”
Moreover, the MHRA noted that the guidelines “allow for some flexibility for implementation at local level”, including the use of multidisciplinary teams to discuss prescribing decisions.
Regarding alternative medicines, the agency noted that other treatment options are already covered in clinical guidelines from the UK National Institute for Health and Care Excellence and the Scottish Intercollegiate Guidelines Network, but these guidelines will need to be updated to reflect new regulatory requirements.
US Considerations
Commenting on the UK’s decision, Kimford J. Meader, MD, professor of neurology and neuroscience at the Stanford University School of Medicine in Palo Alto, California, said: Medscape Medical News He’s not inclined to think the U.S. needs such updated guidelines for female patients, especially when it comes to blanket statements that apply to everyone.
“I don’t think the government can regulate what every single person should do,” Meader said. “I think they’ve spent money on research to find out whether women who are taking the drugs feel like they’re being properly supervised and properly informed. That’s more interesting to me than adding more regulation.”
“It takes away the right to choose between the doctor and the woman, but I don’t think the decision should be made there,” Meader said.
Both he and Alison M. Pack, M.D., professor of neurology at Columbia University Irving Medical Center in New York City, said valproate should not be used as a first- or second-line drug for women who are considering becoming pregnant.
“This is a drug that can be used in certain patients, but we can only try it if we’ve exhausted other medications and it’s the only drug that the patient responds to, and even then, we would use it at the lowest possible dose,” said Pack, who is also head of Columbia University’s epilepsy and sleep division. Medscape Medical News
Meader added that there is “sufficient evidence” that valproate should not be a first-line drug for younger women.
In the early 1980s, the U.S. Centers for Disease Control and Prevention Neural tube defects Side effects from valproate have been reported in infants whose mothers took the drug during pregnancy, but the warnings have had limited impact and valproate use continues to increase, he said.
In 2004, Meader was part of a research team that found preliminary data suggesting a link between valproate use and neurocognitive disorders. Published in of New England Journal of Medicine In 2009, we investigated these findings further.
Meader noted that subsequent population studies have “fairly consistently” shown an association between valproate use and major congenital malformations, reduced IQ and a range of other neurodevelopmental disorders. “So there’s no question that valproate use is an issue in the context of fetal exposure,” he said.
He noted that use of valproate among women in the United States dropped significantly following publication of the study, with rates of use stabilizing at about 1.5 percent across all indications since 2017. “It’s still being used, but it’s not widely used,” Meader said.
He also noted that because many pregnancies are unplanned, it would be unrealistic to stop taking valproate until a woman decided to become pregnant, and the issue needed to be addressed at an earlier stage.
“The drug is still being used in the United States, so hopefully all of these women have given their informed consent and are aware of the risks,” Meader said.
Women’s Independence
of The Lancet Neurology The editorial also points out that “the independence of women who do not intend to have children must also be taken into consideration.”
Pack agreed, noting that if a woman is taking medication that effectively suppresses seizures, she may not want to be seen as a potential mother simply because she is. “What we need to do is mentor individuals,” she said.
Responding to this concern, the MHRA stated that all patients have the right to be involved in discussions about their own treatment.
“However, our role as the UK medicines regulator is first and foremost to protect the health of patients and if we find that the potential risks of a medicine outweigh the benefits for many people, we will take steps to address this,” it said. It also stressed that “it is important not to stop taking valproate without the advice of a medical professional.”
In his practice, Meader treats physical and mental health conditions, Sexual orientation.
“I think all of that needs to be taken into consideration, but to me I think the most important thing is to get as much information as possible and provide it to women so they can make an informed choice,” he said.
Why include men?
The MHRA said there was “growing evidence of harm to men”, including ongoing investigations. Registry Data ReviewThere is evidence suggesting an increased risk of neurodevelopmental disorders in offspring of fathers who took valproic acid in the 3 months prior to conception.
This follows a recommendation in January by the European Medicines Agency’s (EMA) Medicinal Products Risk Assessment Committee (PRAC) to strictly restrict the use of valproate in men to treat epilepsy, bipolar disorder or depression. Migraine.
However, the EMA noted that the recommendation was based mainly on data from ongoing retrospective observational studies, which did not confirm any increased risk of neurodevelopmental disorders in children with the use of valproate.
Meader said the organization also looked at animal studies, but noted that none of the data from the human studies is available for clinicians to review. “So we can’t say whether the studies were properly conducted and properly designed,” he said.
He added that the PRAC’s warning but then saying it could not verify its findings “seems to be a mixed message. I think the ‘men’s issue’ remains very opaque.”
Pack agreed: “I think a lot of us who work in this field feel like it’s a little premature,” she said.
But the MHRA is standing by its decision to include men in the update, and not just because of a possible increased risk of neurodevelopmental disorders.
“The potential effects of valproic acid on adult male fertility have been described in the product information since 2011, but many patients are currently unaware of this risk,” the group noted. They added that research is also currently being conducted to understand the potential adverse effects of valproic acid on the testes in young and adult animals.
“For the vast majority of patients, both male and female, there are other effective treatment options available. Our goal is to ensure that patients in the UK have access to the safest and most effective treatment options,” the MHRA said.
Pack said he believes “very much” in shared decision-making, a central theme of U.S. clinician practice, but is not opposed to stronger warnings for valproate.
“We need a balanced statement. This [drug] “It should be avoided at all costs, but we should also recognise that there are subgroups of people for whom it works as the only medicine,” she said.
“The question is how far do we want to take this in terms of regulation? I’m worried about the message at a national level and to underserved areas where they might not have access to neurologists or epileptologists. That’s where regulation may step in,” Pack said.
Meader reports receiving research support from the National Institutes of Health, the Department of Veterans Affairs, Eisai Co., Ltd., and Suno Medtronic Navigation Co., Ltd. Additionally, the Epilepsy Research Consortium has paid Meader’s university for research on the Human Epilepsy Project and for consulting time with Eisai, UCB Pharma, and Xenon. Pack reports no relevant financial disclosures.
Follow Deborah Brauser on Twitter: Translator
