Public Citizen Petitions the FDA To Contraindicate Use of Two Wakefulness-Promoting Drugs During Pregnancy

In May 2025 Public Citizen filed a petition with the Food and Drug Administration (FDA) to request contraindicating the use of the widely used oral wakefulness-promoting drugs modafinil (PROVIGIL and generics)[1] and armodafinil (NUVIGIL and generics)[2] during pregnancy due to their potential to cause major congenital malformations in exposed babies.[3] Similarly, we asked the agency to require contraindicating the use of modafinil and armodafinil in females who can become pregnant and are not using effective contraceptives. We also asked the FDA to mandate boxed warnings (the most prominent warnings the agency can require) to highlight the risk of embryofetal toxicity in the labels of both drugs.

The current U.S. modafinil label indicates that it “should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus,” and the armodafinil label states that “[i]t is not known if [the drug] will harm [the] unborn baby.” Yet, there is sufficient evidence from animal studies and post-marketing observational studies — including interim results from an FDA-mandated registry — that supports the precautionary pregnancy contraindication warnings requested in our petition.

About modafinil and armodafinil

In 1998 and 2007 the FDA approved the centrally acting, structurally similar drugs modafinil and armodafinil, respectively, to improve wakefulness in adults with excessive sleepiness associated with narcolepsy. Narcolepsy is a rare chronic sleep disorder characterized by excessive daytime sleepiness and brief involuntary sleep episodes as well as certain other symptoms, including sleep paralysis and sleep-related hallucinations.

Subsequently, the FDA extended the approved wakefulness-promoting indications of modafinil and armodafinil to include adults with obstructive sleep apnea (repeated blocking of the upper airway during sleep) and shift work disorder (excessive sleepiness or insomnia in people who work shifts or irregular schedules during the typical sleep period).

Both drugs also are commonly used for unapproved (off-label) uses, such as treating symptoms of attention-deficit hyperactivity disorder (ADHD), chronic fatigue, jet lag, multiple sclerosis and Parkinson’s disease.

Fetal harm in animal studies

A preapproval study that examined the use of modafinil in pregnant rats showed that the drug was toxic to the fetus throughout the period of organogenesis (organ formation). Specifically, modafinil exposure caused increased rates of resorption (disintegration), hydronephrosis (swelling of kidneys due to a buildup of urine), and abnormal structural differences in the internal organs (viscera) and skeleton of the developing fetus.

Two other preapproval animal studies did not find harmful effects of modafinil on embryofetal development. One of these studies, however, involved modafinil doses that were “too low to adequately assess the effects of modafinil on embryofetal development.” The other study had questionable conduct, according to FDA reviewers.

A post-marketing trial of modafinil in rabbits that was required by the FDA showed increased rates of resorption that resulted in a reduced number of live fetuses and fetal alterations (including skeletal malformations and abnormal variations) as well as decreased fetal body weight due to exposure to the drug. Therefore, in 2006 an FDA reviewer recommended that modafinil should be identified as a developmental toxicant.

Similarly, a preapproval animal study for armodafinil, which was conducted in rats, found a slight statistically significant increase in fetal resorption and reduced body weight due to exposure to the drug. Also, there were abnormal alterations, such as dilation of the kidney and certain reduced bone ossification, in exposed fetuses. An FDA reviewer concluded that armodafinil “should be labeled as a developmental toxicant.”

Fetal harm in interim analyses of a U.S. registry

FDA reviewers recommended the establishment of a pregnancy registry for modafinil and armodafinil because the fetal harm in animal studies of both drugs occurred at clinically relevant doses.[4],[5] The FDA also became aware of a signal for growth restriction in the offspring of females who used these drugs during pregnancy.

Therefore, the agency required the manufacturer of both drugs to establish a U.S. pregnancy registry, which is called the Nuvigil and Provigil Pregnancy Registry. The purpose of the registry is to compare pregnancy, fetal and infant outcomes associated with exposure to modafinil and armodafinil during pregnancy with those of an unexposed control population in the Metropolitan Atlanta Congenital Defects Program.

Various interim results from this registry showed higher prevalence of major congenital malformations among infants who were exposed to modafinil or armodafinil in utero. For example, a 2018 interim report of registry data that had been submitted to the U.K.’s Medicines and Healthcare products Regulatory Agency indicated that the estimated rate of major congenital malformations among live babies born to mothers who used either modafinil or armodafinil during pregnancy was approximately 15%, compared with just 3% among the general U.S. population.[6] Also, the estimated rate of heart anomalies among live births exposed to either modafinil or armodafinil during pregnancy was approximately 5%, compared with just 1% in the general U.S. population.

Likewise, a 2021 industry-funded analysis of data from the same registry found that 13% and 3% of 102 prospective live births with prenatal exposure to these drugs had major congenital malformations and heart malformations, respectively.[7] Examples of the congenital malformations include torticollis (a condition with contracted neck muscles, twisting the head to one side) and hypospadias (a congenital condition in which the urethra does not develop completely in males, resulting in an abnormal location of its opening).

Other observational studies

An analysis of Danish national health registries data from 2004 to 2017 found that 12% of the babies exposed to modafinil during pregnancy had congenital malformations, compared with 4.5% in babies exposed to the ADHD drug methylphenidate and 3.9% of those with no exposure to either drug.[8] Overall, the adjusted odds ratio of congenital malformations due to modafinil exposure was three times higher than that for methylphenidate exposure.

A 2024 analysis by international researchers that used data from 12 countries involving a sample of 153 live births with modafinil exposure during pregnancy found that the percentiles of neonatal head circumference and birth weights for these newborns were lower than those in reference standards.[9] Despite this inhibited fetal-growth effect of modafinil exposure, there was no increased risk of major birth defects. However, the researchers concluded that “[U]ntil safety concerns… are more extensively investigated, patients should avoid modafinil intake during pregnancy.”

Action by international regulators

For several years, regulators in many countries — including Australia[10],[11], Canada[12], Ireland[13] and the United Kingdom[14] — have required contraindicating the use of modafinil and armodafinil during pregnancy and in females who can become pregnant and are not using effective contraceptives. In contrast, the FDA has not yet taken a similar action. The FDA cannot afford any further delay in following the precautionary principle of public health by warning patients and clinicians about the potential congenital malformation risks of modafinil and armodafinil.

We urged the FDA to act quickly on our petition due to the severity of the congenital malformations associated with use of modafinil and armodafinil so far, the extensive off-label use of these drugs, and the fact that nearly half of U.S. pregnancies are unplanned.[15]

What You Can Do

Do not use either modafinil or armodafinil if you are currently pregnant, planning to become pregnant or if you are using a hormonal contraceptive as your only contraceptive method, because modafinil and armodafinil decrease the effectiveness of hormonal contraceptives.

If you can become pregnant and need treatment with modafinil or armodafinil, consult your clinician to rule out pregnancy before you initiate treatment with these drugs and use effective contraceptive(s) during treatment and for two months after discontinuing these drugs.

Because of the serious skin adverse effects, risk of abuse, and other risks, we do not recommend the use of modafinil or armodafinil for any reason except managing narcolepsy symptoms, as advised by the European Medicines Agency since 2010.[16]
 

References

[1] Teva Pharmaceuticals. U.S. label: modafinil (PROVIGIL). December 2022. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=e16c26ad-7bc2-d155-3a5d-da83ad6492c8&type=display. Accessed July 5, 2025.

[2] Teva Pharmaceuticals. U.S. label: armodafinil (NUVIGIL). December 2022. https://www.nuvigil.com/globalassets/nuvigil-consumer/prescribinginformation.pdf. Accessed July 5, 2025.

[3] Public Citizen. FDA Petition to require contraindicating use of modafinil (PROVIGIL and generics) and armodafinil (NUVIGIL) during pregnancy. May 28, 2025. https://www.citizen.org/article/fda-petition-to-require-contraindicating-use-of-modafinil-provigil-and-generics-and-armodafinil-nuvigil-during-pregnancy/. Accessed July 5, 2025.

[4] Food and Drug Administration. Medical review, Part 1, NDA 21-875, armodafinil (Nuvigil). June 2, 2007. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021875s000_MedR_P1.pdf. Accessed July 5, 2025.

[5] Food and Drug Administration. Review and evaluation of pharmacology and toxicology (by J. Edward Fisher, Ph.D. et al.), armodafinil (Nuvigil), NDA: 21-875. April 28, 2006. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021875s000_PharmR.pdf. Accessed July 5, 2025.

[6] U.K.’s Medicines and Healthcare products Regulatory Agency. Modafinil (Provigil): increased risk of congenital malformations if used during pregnancy. November 16, 2020. https://www.gov.uk/drug-safety-update/modafinil-provigil-increased-risk-of-congenital-malformations-if-used-during-pregnancy. Accessed July 5, 2025.

[7] Kaplan S, Braverman DL, Frishman I, Bartov N. Pregnancy and fetal outcomes following exposure to modafinil and armodafinil during pregnancy. JAMA Intern Med. 2021;181(2):275-277.

[8] Damkier P, Broe A. First-trimester pregnancy exposure to modafinil and risk of congenital malformations. JAMA. 2020;323(4):374-376.

[9] Onken M, Lohse L, Coulm B, et al. Effects of maternal modafinil treatment on fetal development and neonatal growth parameters — a multicenter case series of the European Network of Teratology Information Services (ENITS). Acta Psychiatr Scand. 2024;150(5):372-384.

[10] Arrotex Pharmaceuticals Pty Ltd. Australian label: Modafinil (APO-MODAFINIL). June 2023. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2023-PI-01696-1. Accessed July 5, 2025.

[11] Arrotex Pharmaceuticals Pty Ltd. Australian label: armodafinil (NUVIGIL). November 2024. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2015-PI-02888-1. Accessed July 5, 2025.

[12] Teva Canada. Canadian label: Modafinil (ALERTEC). July 2023. https://pdf.hres.ca/dpd_pm/00071543.PDF. Accessed July 5, 2025.

[13] Bluefish Pharmaceuticals. Irish label: modafinil September 2022. https://assets.hpra.ie/products/Human/19717/Licence_PA1436-031-002_08092022120619.pdf. Accessed July 5, 2025.

[14] Teva Pharma B.V. U.K. label: modafinil (PROVIGIL). June 2021. https://www.medicines.org.uk/emc/product/5412/smpc/print. Accessed July 5, 2025.

[15] Rossen LM, Hamilton BE, Abma JC, et al. Updated methodology to estimate overall and unintended pregnancy rates in the United States. National Center for Health Statistics. Vital Health Stat 2(201). 2023. https://www.cdc.gov/nchs/data/series/sr_02/sr02-201.pdf. Accessed July 5, 2025.

[16] European Medicines Agency. European Medicines Agency recommends restricting the use of modafinil. July 22, 2010. https://www.ema.europa.eu/en/news/european-medicines-agency-recommends-restricting-use-modafinil. Accessed July 5, 2025.