Consumer advocacy organization Public Citizen is sounding the alarm about potential risks for birth defects associated with modafinil (Provigil) and armodafinil (Nuvigil), two stimulants commonly prescribed during pregnancy.
The group argued that animal toxicity studies and post-marketing observational studies have turned up sufficient evidence to justify additional precautions for pregnant patients.
Public Citizen submitted a citizen petition to the FDA asking the agency to contraindicate the use of the drugs during pregnancy, and by females of reproductive potential who are not using effective nonhormonal contraception. The petition also called for boxed warnings about the potential for embryofetal toxicity.
Modafinil and armodafinil are FDA-approved for shift work disorders, obstructive sleep apnea, and narcolepsy but are often taken off-label for many conditions ranging from attention deficit-hyperactivity disorder (ADHD) to multiple sclerosis.
"Fetal developmental toxicity and death due to modafinil and armodafinil exposure during pregnancy occurred at clinically relevant doses in animal studies," Azza AbuDagga, MHA, PhD, health services researcher at Public Citizen's Health Research Group, said in a press release. AbuDagga also noted that other countries including Australia, Canada, Ireland, and the U.K. have already contraindicated the use of these drugs in pregnancy.
The citizen petition cites three pre-marketing studies and one post-marketing study of animal embryofetal development involving modafinil. In one study, pregnant rats were given oral modafinil (50, 100, or 200 mg/kg daily), which resulted in embryotoxicity during organogenesis with more problems found at the 200 mg/kg per day dosage. Another rat study at 480 mg/kg per day did not show embryofetal developmental effects, although FDA reviewers flagged potential issues with that study.
A study on pregnant rabbits given 100 mg/kg per day modafinil throughout organogenesis found no impact on development, although the doses may have been too low for adequate assessment. Another rabbit study conducted to fulfill an FDA post-marketing requirement involved giving pregnant rabbits 45, 90, or 180 mg/kg modafinil from gestation day 6 to 18. The high-dose group had increased incidences of resorption or alterations of fetuses.
For armodafinil, a single pre-marketing study on rats given 60, 200, or 600 mg/kg from gestational day 7 through 17 found a slight but statistically significant increase in resorption and reduced fetal body weight in the high-dose group.
FDA toxicology reviewers had concluded back in 2006 that both modafinil and armodafinil should be labeled as developmental toxicants, according to the petition.
Additionally, the petition noted that various reports on data from the FDA-mandated Nuvigil and Provigil Pregnancy Registry have found increased prevalence of major congenital malformations among babies of modafinil and armodafinil users.
David Hackney, MD, a maternal-fetal medicine physician at Case Western Reserve University in Cleveland, said that while the research cited in the citizen petition is alarming, research on the topic overall seems to be mixed. He pointed to a large observational Scandinavian study published in JAMA in 2020 that found no link between modafinil during pregnancy and birth defects.
"Overall, I would say these medications are best avoided in pregnancy and, at a minimum, pregnant patients or reproductive-capable people taking these medications need to be advised about the existent concerns and possible association with congenital anomalies," he said, adding that "enhanced warnings and provider and public education are reasonable."
However, he said absolute contraindications are more complicated, because many medications in pregnancy require balancing risks and benefits.
"Sometimes patients do take medications with known risks if they don't otherwise have safe options. Say a pregnant patient with narcolepsy would crash their car into a tree if unmedicated, or a nurse with ADHD would make a patient medication error," he noted.
Nikki Zite, MD, MPH, an ob/gyn at the University of Tennessee Graduate School of Medicine in Knoxville, agreed that more education on the topic is not unreasonable. However, she countered that working to decrease the use of these medications without prescriptions, and "educating the public about potential drug interactions" might be more worthwhile.
These stimulants increase the enzyme that metabolizes some forms of birth control, she noted. But because the drugs are stimulants, there is potential for abuse and for people to use them without prescriptions, which means those groups likely wouldn't see boxed warnings, Zite said.
"People need to be aware there are many drugs that decrease contraceptive effectiveness and [that] there is a potential for birth defects with medications taken without a doctor's prescription -- that is a bad combination," she said.
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