UK Restrictions on Valproate: Should the US Follow Suit?

As experts voice concerns over new UK guidelines that restrict valproate use in women and men younger than 55 years owing to safety risks, the question arises: Should the US consider updating its own guidelines in response?

On January 31, the UK Medicines and Healthcare products Regulatory Agency (MHRA) has issued new guidance, banning the use of valproate in new female patients under 55 unless two independent specialists agree that no other effective or tolerated treatment is available. This same level of agreement is also required for existing female patients to continue current valproate treatment.

These requirements were introduced due to substantial research showing an increased risk of major congenital malformations in offspring when mothers use the drug during pregnancy. The restrictions also apply to men, because there is a potential increased risk for neurodevelopmental disorders in offspring if fathers take the medication within 3 months of conception.

However, an editorial published in February in The Lancet Neurology says the guidance goes too far and omits key information.

“In a drastic move that no other country has taken yet, the [MHRA] has introduced new stringent guidelines for valproate use,” the editorialists write. “The move…will create multiple challenges for healthcare providers and people with epilepsy.” 

Contacted for comment on the UK initiative, the American Epilepsy Society (AES) told Medscape Medical News in a statement that the “teratogenic risks of valproate are well established, and this [UK] regulatory change is not based upon new evidence.” 

Therefore, the organization “is not recommending any changes to current valproate prescribing regulations in the United States,” the AES said. Its current position statement was last updated in 2src21. 

Why Now?

Although valproate is primarily used to manage epilepsy, it is also approved for the treatment of bipolar disorder. 

The Lancet Neurology editorial notes that recent data show that from 2src18 to 2src22, there was a significant reduction in the number of pregnant women prescribed the drug in the UK.

So why did the MHRA take the decision to update its guidelines? What prompted the agency to proceed with what the editorial describes as a “controversial decision”?

In a written response to Medscape Medical News, the agency explained that despite a 38% reduction in valproate use among women of childbearing age since 2src18, approximately two to three babies a month continue to be born with in utero exposure to the medication.

“Evidence from patient support groups makes it clear that some women on valproate are still not being [adequately] informed about the risks by their healthcare professionals,” the MHRA noted.

“The new measures will provide additional scrutiny on the prescribing of valproate, which should ensure that valproate is only initiated when there are no other effective or tolerated treatment options,” the agency added. On the basis of substantial research, “there is no safe dose of valproate in pregnancy.”

In response to concerns raised in the Lancet Neurology editorial — including the lack of recommendations on alternative medications and the potential burden of requiring two independent specialists, which could strain already busy neurology clinics — the MHRA explained that it had engaged in extensive discussions with the Commission on Human Medicines, specialists in epilepsy and bipolar disorder, experienced general practitioners, and patients.

The Commission on Human Medicines “recognized that successful implementation of the new measures would require a significant change in clinical practice,” the MHRA said. “Listening to their feedback, we have agreed to a phased rollout to mitigate disruption to ongoing patient care. And we have introduced new materials to support patients, whose voices must remain our main focus.”

In addition, the guidance “allows some flexibility in implementation at a local level,” including the use of multidisciplinary teams, to discuss prescribing decisions, the MHRA noted. 

Regarding alternative medications, the agency noted that clinical guidance from the National Institute for Health and Care Excellence and the Scottish Intercollegiate Guidelines Network already address other treatment options. However, these guidelines will need to be updated to reflect the new regulatory requirements. 

US Considerations

Commenting on the UK’s decision, Kimford J. Meador, MD, professor of neurology and neurological sciences at Stanford University School of Medicine, Palo Alto, California, told Medscape Medical News that he isn’t leaning toward the US needing updated guidelines like this for female patients, especially when it comes to one-size-fits-all blanket statements.

“I don’t think the government can regulate what should be done in every individual person,” Meador said. “I think I would have spent my money doing surveys finding out if women who are taking the drug felt they were appropriately managed and appropriately informed. That would be more interesting to me than adding more regulations,” he noted.

“They’re taking away the choice between the doctor and the woman, and I don’t think that’s where the decision should be made,” Meador said.

Both he and Alison M. Pack, MD, a professor of neurology at Columbia University Irving Medical Center in New York City, pointed out that valproate should not be used as a first- or even second-line treatment for any woman considering pregnancy.

“It’s a medication that for certain individuals we may use, but only as something we try after we’ve exhausted other medications and it’s the only one that the individual responds to. And even in that case, we’d use it at as low a dose as possible,” Pack, who is also chief of the Epilepsy and Sleep Division at Columbia, told Medscape Medical News 

Meador added that there is “plenty of evidence” that valproate should not be the first-line option in young women.

In the early 198srcs, the US Centers for Disease Control and Prevention warned of data indicating an increased risk for neural tube defects in babies born to mothers who took valproate during pregnancy. However, this warning had limited impact, and the use of valproate continued to rise, he said.

In 2srcsrc4, Meador was part of a research team that uncovered preliminary data suggesting a link between valproate use and adverse neurocognitive outcomes. That study, published in The New England Journal of Medicine in 2srcsrc9, further explored these findings.

Meador noted that subsequent population studies have been “pretty consistent” in demonstrating a link between valproate use and major congenital malformations, reduced IQ, and a variety of other neurodevelopmental disorders. “So, there’s no doubt that valproate use is a problem in this setting of fetal exposure,” Meador said.

He noted that following the release of this research, there was a significant decrease in valproate use among women in the US, with use stabilizing at around 1.5% across all indications since 2src17. “It’s still used, but not widely,” said Meador.

He also pointed out that it’s impractical for a woman to wait until she decides to get pregnant to switch off valproate because many pregnancies are unplanned, and so this needs to be addressed much earlier.

He also noted that other patient populations use the medication off-label for other conditions, including diabetic peripheral neuropathy. “Its use is still there in the US, so I hope all these women are getting informed consent and know the risk,” Meador said. 

Women’s Autonomy

The Lancet Neurology editorial also notes that “consideration must be given to the autonomy of women who do not intend to have children.”

Pack agreed, noting that if a woman is on a medication that effectively controls her seizures, she may not want to be seen solely as a potential mother. “What we need to do is guide the individual,” she said.

In response to this concern, the MHRA stated that all patients have the right to be involved in discussions about their own care.

“However, our role as the UK’s medicines regulator is first and foremost to protect patients’ health and if we find that the potential risks of a medicine outweigh the benefits for a number of people, we will take action to address this,” the agency noted. It also emphasized that “it is vital that no one stops taking valproate without advice from their healthcare professional.”

Meador noted that in his practice, he encounters patients who are unlikely to become pregnant owing to various factors, including physical and mental health conditions or sexual orientation.

“I think you have to take all of that into consideration. But for me, I think it’s most important to get as much information as you can and give it to women to help them make an informed choice,” he said.

Why Include Men? 

The MHRA noted that “a growing body of evidence of harms in males,” including an ongoing review of registry data, suggest an increased risk for neurodevelopmental disorders in offspring of fathers who took valproate in the 3 months before conception. 

This follows recommendations in January from the European Medicines Agency’s (EMA’s) Pharmacovigilance Risk Assessment Committee (PRAC) for tighter valproate measures in men for the management of epilepsy, bipolar disorder, or migraine.

However, because the recommendations were based largely on data from an ongoing retrospective observational study, the EMA noted that increased risk for neurodevelopmental disorders in children due to valproate use was unable to be confirmed. 

Meador noted that the organization also considered animal studies — and he pointed out that none of the data from the human study are available for clinicians to examine. “So, I can’t assess whether I think this study is well done and well formulated,” he said.

He added that PRAC putting out a warning but also saying they can’t confirm the findings “seems like a muddled message. I think the ‘men issue’ is still very much up in the air.”

Pack agreed. “I think many of us who work in this area find it to be a little bit premature,” she said. 

But the MHRA stands by its decision to include men in their update — and not just for the possible increased risk for neurodevelopmental disorders.

“The potential effects of valproate on adult male fertility have been in the product information since 2src11, but many patients are not currently aware of this risk,” they note. The organization added that research is also currently being done to understand the potential adverse effects of valproate on the testes of juvenile and adult animals.

“For the majority of patients, male and female, other effective treatment options are available. Our aim is to ensure that UK patients have the safest effective treatment option for them,” the MHRA said. 

Pack said she “very much” believes in shared decision-making, which is a central theme in how US clinicians practice, but she isn’t opposed to a stronger warning for valproate 

“We need to have a balanced statement. We need to have a strong statement that this [drug] should be avoided at all costs — but also recognize that there is a subgroup of individuals where that’s the only medicine that they respond to,” she said. 

“The question is: How far do we want to take that in a regulatory sense? I worry about the message on a national level and in under-served communities where they may not have access to neurologists or epilepsy specialists. Maybe that’s where a regulatory piece could come in,” Pack said. 

Meador reports having received research support from the National Institutes of Health; Veterans Administration; Eisai, Inc; and Suno Medtronic Navigation, Inc. In addition, the Epilepsy Study Consortium pays Meador’s university for his research on the Human Epilepsy Project and consultant time related to Eisai, UCB Pharma, and Xenon. Pack reports having no relevant financial disclosures. 

Follow Deborah Brauser on Twitter: @MedWriterDeb