Narcolepsy Drugs Linked to Fetal Malformations

The narcolepsy drugs modafinil (Provigil) and armodafinil (Nuvigil) were both associated with major congenital malformations, a post-marketing report showed.

Of 102 prospective live births in the U.S. Provigil/Nuvigil Pregnancy Registry, 13% had major congenital malformations, considerably above the prevalence of about 3% in the general population, according to Sigal Kaplan, PhD, of Teva Pharmaceutical Industries in Netanya, Israel, and co-authors.

“Although the available data are inconclusive for causality, the potential increased risk of major congenital malformations provides an impetus for health care professionals to enhance the benefit-risk monitoring of modafinil and/or armodafinil use in pregnant individuals and individuals who may become pregnant,” Kaplan and colleagues wrote in JAMA Internal Medicine.

Four of the newborns with malformations were diagnosed with congenital torticollis; two were diagnosed with hypospadias, and three with congenital heart defects, making the cardiac malformation prevalence 3%, compared with about 1% in the general population.

These data are important to manage care for individuals who could become pregnant who may be prescribed modafinil or armodafinil, noted Neda Ghaffari, MD, and Patricia Robertson, MD, both of the University of California San Francisco, in an accompanying commentary.

“Raising the awareness of the medical community and educating individuals who could become pregnant on the high rate of unintended pregnancy — up to 45% in 2011 in the United States — are crucial when considering teratogens, especially in those disparately affected: women 18 to 24 years of age, unmarried/cohabiting, of low income, with an incomplete high school education, and/or of an ethnic or racial minority group.”

In the United States, modafinil and armodafinil (the latter is the R-enantiomer of racemic modafinil) are indicated to improve wakefulness in adults with excessive sleepiness associated with obstructive sleep apnea, narcolepsy, or shift work disorder. Modafinil also is used to treat fatigue in multiple sclerosis and other diseases.

FDA-approved labels for the drugs put them in pregnancy category C, citing reports of “intrauterine growth restrictions and spontaneous abortions,” as well as animal studies showing fetal structural abnormalities. Both agents “should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus,” the labels state.

Modafinil’s popularity has grown in the U.S. with a steep rise in off-label uses as the drug became touted as a brain booster. Military personnel, truck drivers, students, entrepreneurs, and Wall Street traders reported using the drug to sleep less and produce more. In 2008, Cephalon, which developed and manufactured modafinil, paid $425 million to settle charges of off-label marketing of modafinil and two other drugs. (The company since has been acquired by Teva.)

Studies about modafinil’s cognitive effects have produced mixed results: while some demonstrated the drug didn’t help with simple tasks, others showed complex and difficult functions could be performed more accurately after taking modafinil than placebo. A double-blind fMRI study published earlier this year suggested modafinil had the potential to enhance some cognitive functions in healthy men.

Two European reports in 2020 produced seemingly conflicting findings about modafinil and major congenital malformations. In January, a Danish study reported a 12% risk of major malformations among 49 infants who had been exposed to the drug in utero. In September, pooled data from birth registries in Norway and Sweden showed that among infants born to 133 women with first-trimester exposure to modafinil, prevalence of major malformations was 2.6%, similar to that of unexposed pregnancies.

“In our dataset, we have included all the live births in Norway and Sweden, nearly 2 million births,” said study author Kari Furi, MScPharm, MPH, PhD, of the Norwegian Institute of Public Health in Oslo. The study was “population-based and nationwide, and we had no selection of the births we studied,” she told MedPage Today.

The U.S. Provigil/Nuvigil Pregnancy Registry is a post-marketing requirement with data reported annually to the FDA. Enrollment is ongoing and open on a voluntary basis to any individual exposed to modafinil or armodafinil within 6 weeks before conception or during pregnancy. In the registry, pregnancy is classified as prospective if a patient enrolled before pregnancy outcome was known or congenital malformation was detected in a prenatal test, and as retrospective if enrollment occurred after that.

From February 2010 to February 2019, 148 individuals enrolled in the registry: 122 pregnancies were classified as prospective and 26 as retrospective. In total, 81 women received modafinil during pregnancy, 66 received armodafinil, and one received both drugs. Narcolepsy was the main indication (70%).

The prevalence of major malformations in 97 prospective live births exposed during the first trimester was 13%. Pooled data from both prospective and retrospective live births resulted in the same prevalence of 13%.

The study’s limitations included selection bias because enrollment was voluntary, possible incorrect or incomplete data reporting, lack of an internal comparison group, and small sample size, Kaplan and colleagues noted.

“Given the risks of these medications and the high rate of unintended pregnancy, we recommend that pregnancy be considered a possibility in all individuals of reproductive age who may be prescribed a potential teratogen,” Ghaffari and Robertson wrote. “To avoid major congenital malformations associated with modafinil and armodafinil, these medications should be avoided or offered along with a reliable contraceptive to individuals who could become pregnant.”

In 2019, Health Canada issued a safety alert that modafinil use was contraindicated in women who are pregnant or may become pregnant due to the drug’s association with major fetal congenital malformations, including congenital cardiac abnormalities.