May 28, 2025

FDA Petition To Require Contraindicating Use of Modafinil (PROVIGIL and Generics) and Armodafinil (NUVIGIL) During Pregnancy

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Citizen Petition

Date: May 28, 2025
Martin A. Makary, M.D., M.P.H.
Commissioner, Food and Drug Administration
Department of Health and Human Services
WO 2200
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002

Division of Dockets Management
Food and Drug Administration
Department of Health and Human Services
5630 Fishers Lane, Room 1061
Rockville, MD 20852

RE: FDA Petition To Require Contraindicating Use of Modafinil (PROVIGIL and Generics) and Armodafinil (NUVIGIL) During Pregnancy and in Females of Reproductive Potential Who Are Not Using Effective Nonhormonal Contraceptives and To Add Boxed Warnings Regarding the Potential Embryofetal Toxicity of Both Drugs

Dear Commissioner Makary,

Public Citizen, a consumer nonprofit advocacy organization with more than 500,000 members and supporters nationwide, and Public Citizen’s Health Research Group submit this petition under the Federal Food, Drug, and Cosmetic Act (FDCA), 21 U.S.C. sections 352 and 505(o)(4), as well as the Food and Drug Administration (FDA) regulations at 21 C.F.R. sections 10.30, 201.56, 201.57(c)(1), and 201.57(c)(5) to request that the commissioner of the FDA require contraindicating the use of the oral wakefulness-promoting drugs modafinil (PROVIGIL and generics)[1] and armodafinil (NUVIGIL and generics) [2] during pregnancy and in females of reproductive potential who are not using effective nonhormonal contraceptives, and add a boxed warning on the labeling of both drugs regarding their potential risk of major fetal congenital malformations.

There is sufficient evidence from animal toxicity studies and post-marketing observational studies — including interim results from an FDA-mandated registry — that supports precautionary labeling changes against the use of the two related drugs modafinil and armodafinil in females who are pregnant and those of reproductive potential who are not using effective nonhormonal contraceptives, due to the potential risk of major fetal congenital malformations associated with both drugs. Since 2019 this evidence has led regulators in several countries — including Australia, Canada, Ireland, and the United Kingdom — to require contraindicating these drugs during pregnancy and in females of reproductive potential who are not using effective nonhormonal contraceptives and to add this contraindication in the labeling of both drugs. In contrast, the FDA has not yet taken a similar action to warn U.S. clinicians and patients. Implementing these actions is in the best interest of the public because it can be instrumental in curbing inappropriate prescribing of modafinil and armodafinil in pregnant women and those who may become pregnant, helping to prevent potential serious fetal harm.

A. ACTIONS REQUESTED

Promptly require the following actions:
(1) Contraindicate the use of modafinil and armodafinil during pregnancy and in females of reproductive potential who are not using effective nonhormonal contraceptives, and
(2) Add boxed warnings in the labeling of these drugs due to their potential embryofetal toxicity.

Public Citizen proposes the following boxed warnings:

Embryofetal Toxicity WARNINGs

Modafinil and armodafinil are contraindicated for use during pregnancy and in females of reproductive potential who are not using effective nonhormonal contraceptives because of their potential to cause serious fetal harm. Developmental toxicity and embryolethality due to exposure to modafinil and armodafinil during pregnancy occurred at clinically relevant exposures in animal studies. Interim results from a U.S. pregnancy registry and other post-marketing evidence suggest that modafinil and armodafinil are suspected to cause congenital malformations when used during pregnancy.

Rule out pregnancy before the start of treatment with modafinil or armodafinil in females of reproductive potential. Advise females of reproductive potential to use effective contraception during treatment with modafinil or armodafinil and for two months after discontinuing these drugs. Because modafinil and armodafinil may reduce the effectiveness of hormonal contraceptives, additional or alternative contraceptive methods are required. Stop modafinil and armodafinil if pregnancy occurs.

Corresponding changes should be made in the “Contraindications and Warnings,” “Precautions,” and “Limitations of Use” sections in the labeling of these drugs.

B. STATEMENT OF GROUNDS

1. Legal Standards

The legal standards applicable to our requested actions regarding modafinil and armodafinil labeling are described below along with recent legislation for expeditious finalization of safety warnings.

1.1. Standard for a drug contraindication

According to an FDA guidance, a drug should be contraindicated for a certain clinical situation only when the risk associated with its use clearly outweighs any likely therapeutic benefit. Only known hazards, not theoretical possibilities, can be the basis for a contraindication.[3]

The guidance indicates that for observed adverse drug reactions (including “a congenital anomaly or birth defect”), the following would be reasons to contraindicate a drug:

(1) “The risk of adverse reaction in the clinical situation to which the contraindication applies, based on both likelihood and severity of the adverse reaction, outweighs any potential benefit to any patient” and

(2) “The causal relationship between exposure to the drug and the adverse reaction is well established.”

For an anticipated adverse reaction, a drug can be contraindicated based on the likely severity of such adverse reaction and the likelihood that it outweighs any potential benefit of the drug in any patient in the clinical situation to which the contraindication will apply, and either

(1) “Based on what is known about the pharmacology, chemistry, or class of the drug it appears highly likely that the adverse reaction is caused by the drug” or

(2) “Animal data raise substantial concern about the potential for occurrence of the adverse reaction in humans (e.g., animal data demonstrating that a drug has teratogenic effects).”

1.2. Standard for boxed warnings

The FDA has the authority to require manufacturers of approved drugs to fully describe drug risks on the labeling of their products. Specifically, the agency can require a boxed warning on the labeling of prescription drugs to highlight certain risks, such as “an adverse reaction [that is] so serious in proportion to the potential benefit from the drug . . . that it is essential [to] be considered in assessing the risks and benefits of using the drug [or] there is a serious adverse reaction that can be prevented or reduced in frequency or severity by . . . avoiding use [of the drug] in a specific clinical situation.”[4]

In assessing evidence of a causal relationship for inclusion in the warnings section of a drug label, the FDA advises considering the following factors: “(1) the frequency of reporting; (2) whether the adverse event rate in the drug treatment group exceeds the rate in the placebo and active-control group in controlled trials; (3) evidence of a dose-response relationship; (4) the extent to which the adverse event is consistent with the pharmacology of the drug; (5) the temporal association between the drug administration and the event; (6) existence of dechallenge and rechallenge experience; and (7) whether the adverse event is known to be caused by related drugs.” Importantly, the agency advises that reasonable evidence of a causal association between an adverse event and the use of a particular drug is enough and that a causal relationship need not be definitively established.

Under federal law, the FDA must require revising drug labeling to include a warning about a clinically significant risk “as soon as there is reasonable evidence of a causal association with a drug.”[5]

1.3. Standard for expedited finalization of urgent warnings

Section 505(o)(4) of the FDCA describes requirements for safety labeling changes (SLCs) for approved drugs under the Food and Drug Administration Amendments Act of 2007 (FDAAA).[6] According to these FDAAA SLC requirements, the FDA is authorized to require or order application holders of certain approved drugs to implement drug labeling changes based on new safety information that emerges after drug approvals. The statute specifies certain time frames for application holders to submit such changes and grants the FDA tools to enforce noncompliance of the requested changes.

New safety information concerning a “serious” or “an unexpected serious” risk associated with use of a drug can be based on findings of a clinical trial, an adverse event report, a post-marketing study (including one that was required by the FDA), or peer-reviewed biomedical literature; data derived from the post-marketing risk identification and analysis system; or other scientific data deemed appropriate by the FDA.[7]

Under the FDAAA, the FDA has a short timeline for implementing new SLCs; once the agency has agreed that a newly identified serious risk merits an SLC, a drug manufacturer can implement the new changes as early as 30 days after being notified by the FDA.

2. Background

2.1. Key information about modafinil and armodafinil and their manufacturers

In 1998 and 2007 the FDA approved the centrally acting stimulants modafinil and armodafinil, respectively. The two drugs have similar chemical structures; armodafinil is the R-enantiomer of the racemic product modafinil (see Figure 1).[8]

Modafinil

Armodafinil

Figure 1. Chemical Structures of Modafinil and Armodafinil

Initially, the FDA approved modafinil for wakefulness promotion in adults with excessive sleepiness associated with narcolepsy with or without cataplexy. 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.[9] Cataplexy (sudden loss of muscle tone when experiencing various emotions like anger or excitement) occurs in type 1 narcolepsy and is absent in type 2 narcolepsy.

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

In contrast, since 2010 the European Medicines Agency (EMA) has recommended restricting the approved use of modafinil-containing drugs to treating sleepiness associated with narcolepsy and withdrawing all other previously approved indications from the marketing authorizations of this drug.[10] These recommendations were based on a review by the agency’s Committee for Medicinal Products for Human Use showing that the benefits of modafinil only outweighed their risks (neuropsychiatric disorders, skin or hypersensitivity reactions, and potential for abuse) in narcolepsy patients. Importantly, the committee also recommended that modafinil labeling should indicate that the drug should not be used in children because its risk of serious skin and hypersensitivity adverse events is higher in children than in adults. Notably, no controlled studies longer than 12 weeks have been conducted to assess the long-term efficacy of modafinil and armodafinil.[11] Therefore, prescribers should periodically reassess the long-term usefulness of these drugs in users.

Modafinil and armodafinil are classified as Schedule IV controlled substances because of their potential for abuse or dependency. The mechanism through which modafinil and armodafinil promote wakefulness is not known. The wake-promoting effects of both drugs are like those of sympathomimetic agents, including amphetamine sulfate (EVEKEO and generics) and methylphenidate (CONCERTA, JORNAY, RITALIN, others, and generics). Although the pharmacology of modafinil and armodafinil is not the same as that of sympathomimetic amines, both drugs share some pharmacologic properties with this drug class.

Importantly, the use of modafinil and armodafinil is significantly driven by off-label indications. For example, both drugs are used, often in combination with other medications, to treat attention-deficit hyperactivity disorder (ADHD) symptoms in adults and children. In 2006 the FDA declined to approve modafinil for ADHD, as recommended by an advisory committee convened by the agency.[12] Other common off-label uses of modafinil and armodafinil include treatment of cancer-related fatigue, chronic fatigue syndrome, cognitive impairment in schizophrenia, depression, eating disorders, jet lag, multiple sclerosis, and Parkinson’s disease.[13]

Modafinil is available in 100-milligram (mg) and 200-mg tablets; the recommended dosage is 200 mg once daily. The maximum modafinil dosage is 400 mg once daily; this higher dose is not more beneficial than the recommended dose per day, according to the drug label. Armodafinil is available in 50-, 150-, 200-, and 250-mg oral tablets; the recommended dosage is either 150 or 250 mg once daily (the maximum daily dosage is 250 mg once daily).

Modafinil and armodafinil decrease the effectiveness of hormonal (steroidal) contraceptives by inducing cytochrome P450 enzymes (CYP3A4).[14],[15] It is estimated that modafinil and armodafinil can decrease the level of hormonal contraceptives in the blood by 18%, which can lead to contraceptive failure.[16] Therefore, alternative methods of contraception (such as intrauterine devices and barrier contraceptives) are recommended among females of reproductive potential taking modafinil or armodafinil.

Importantly, Cephalon was the original applicant for modafinil and armodafinil. By 2011 the annual sales of Provigil (the brand-name version of modafinil) exceeded $1.1 billion.[17] To maintain monopoly over the sales of Provigil between 2006 and 2012, Cephalon and its new owner since 2011 (Teva) delayed the entry of generic competition of the drug through four payments to other generic manufacturers, resulting in artificially high costs for consumers taking the drug during this period.[18] In 2015 Teva agreed with the Federal Trade Commission to pay $1.2 billion to settle a lawsuit related to these illegal pay-for-delay agreements for Provigil.[19]

2.2. Relevant regulatory history

The FDA designated modafinil and armodafinil as “pregnancy category C” drugs when it approved them, indicating that, due to inadequate studies, their risk of fetal harm cannot be ruled out.[20],[21] Specifically, the original labeling of both drugs included the following pregnancy warning:

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Additionally, the original armodafinil label indicated that

[a]rmodafinil or modafinil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In 2007, FDA reviewers recommended the establishment of a pregnancy registry for modafinil and armodafinil due to evidence from an animal study of armodafinil showing that the drug causes fetal developmental toxicity at clinically relevant exposures (see section 3.1 below for the details).[22],[23] Subsequently, the FDA became aware of a signal for growth restriction in the offspring of women who used these drugs during pregnancy. Therefore, the agency required Cephalon to establish a U.S. pregnancy registry (that has been called the Nuvigil and Provigil Pregnancy Registry) 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.[24] Particularly, the agency required that the registry should assess major functional and structural birth defects (including intrauterine growth restriction [IUGR], low birth weight, microcephaly, and small-for-gestational-age babies) during the perinatal period and the first year of life in the exposed offspring.

In February 2010 the pregnancy registry was open to enroll U.S. women exposed to at least one dose of armodafinil or modafinil either within six weeks before conception or during pregnancy.[25] To encourage voluntary participation, information regarding the registry was posted on Teva’s website and on the labeling of both modafinil and armodafinil, which listed a toll-free telephone number for the registry. Also, direct mail to clinicians urged them to either register pregnant women taking these drugs or recommended that such women enroll themselves. Eligible participants were required to consent to participate in the registry, be contacted periodically, and provide the contact information of their clinicians.

The current modafinil labeling indicates that the drug “should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.” Although the latter statement is not explicitly included in the current armodafinil labeling, the medication guide urges pregnant women and those planning to become pregnant to notify their clinicians before treatment and notes that “based on animal data, [armodafinil] may cause fetal harm” and “[i]t is not known if [armodafinil] will harm [the] unborn baby.” Neither drug label includes a contraindication statement for modafinil or armodafinil during pregnancy or in females who may become pregnant.

2.3. Important factors supporting our requested actions

As emphasized by an FDA medical reviewer, the fact that modafinil and armodafinil are approved for shift work sleep disorder means that their potential embryofetal toxicity applies to a large segment of the population who are likely to use these drugs: females of reproductive potential who work evening and night shifts (including nurses).[26]

Importantly, the potential embryofetal toxicity of modafinil and armodafinil pertains to the first few months of pregnancy, a period that involves key developments of the fetus. Therefore, raising awareness among female users of these drugs about their risks is challenging because of the high rate of unintended pregnancy in the United States (approximately 42% in 2019).[27] This is particularly problematic among disparately affected females, including adolescent girls and women who are unmarried or have a low income, low education level, language barriers, or belong to an ethnic or racial minority group.[28]

Furthermore, the extent of prescribing effective contraceptives in U.S. women of reproductive potential taking modafinil and armodafinil is unknown. A prescription-event monitoring study in England showed that more than half of such women taking modafinil were not taking a recommended contraceptive before treatment.[29]

Other general evidence shows that although most females of reproductive age who are taking prescription drugs reported that they were confident that their prescribing clinicians would tell them if their medications may cause a birth defect, most of those taking such medications were not warned about these risks.[30]

As discussed earlier, there is a wide range of off-label uses of modafinil and armodafinil. Therefore, our requested labeling changes are critical to communicate the potential embryofetal risks of these drugs to clinicians and patients.

3. Research evidence

This section discusses evidence from animal and human studies supporting the potential embryofetal toxicity of modafinil and armodafinil.

3.1. Animal studies

Modafinil and its metabolites cross the placenta in rats.[31] Although placental transfer of armodafinil per se has not been studied, it is likely to be comparable to that of modafinil given the similar chemical structure of the two drugs.

3.1.1. Modafinil

Unfortunately, animal studies to assess the effects of modafinil on the developing fetus were not conducted at sufficiently high doses or according to procedures that would have been able to offer a comprehensive assessment of the potential of modafinil to cause embryolethality or teratogenicity.[32]

Overall, three premarketing and one post-marketing animal embryofetal development studies were conducted for modafinil: Two were conducted in rats and two in rabbits. In the first rat study, oral modafinil administered to pregnant rats (at dosages of 50, 100, or 200 mg per kilogram [kg] per day) resulted in embryotoxicity, in the absence of maternal toxicity, throughout the period of organogenesis (formation of organs from three germ layers).[33],[34] At the 200 mg/kg per day dosage — which is less than human exposure at the maximum daily clinical dose of 400 mg — there was an increase in resorption (disintegration) and hydronephrosis (swelling of kidneys due to a buildup of urine) as well as visceral and skeletal variations in the offspring. The higher no-effect dosage for rat embryofetal developmental toxicity in this study (100 mg/kg per day) was associated with a plasma modafinil area under the curve less than that in humans at the recommended human dose of modafinil (200 mg/day).

The second modafinil study in rats involved dosages up to 480 mg/kg per day (plasma modafinil exposure approximately 1-2 times the area under the curve in humans at the recommended human dose).[35] This study did not show embryofetal developmental effects for the drug. However, there were some questions about the study conduct based on the variability of maternal blood levels, according to FDA reviewers.[36] As noted earlier, neither of the rat studies of modafinil used optimal doses for the assessment of embryotoxicity.

In rabbits, the first modafinil embryofetal development study involved oral administration of up to 100 mg/kg per day of the drug to pregnant rabbits throughout organogenesis.[37] This study showed no effect of modafinil on embryofetal development. However, it involved doses that are “too low to adequately assess the effects of modafinil on embryofetal development,” as indicated in the U.S. modafinil label.

The second rabbit study of modafinil was a phase 4 study, conducted to fulfill an FDA post-marketing requirement.[38] Groups of pregnant rabbits were given oral doses of modafinil (either 45, 90, or 180 mg/kg) from gestation day 6 to 18 (in addition to a group that did not receive the drug). In the high-dose group, decreased maternal body-weight gain and certain clinical signs indicated sufficient maternal toxicity.[39] A slight decrease in fetal body weight was observed in the medium- and high-dose groups. The medium dose (which can be regarded as a no-observed-effect level for embryofetal development adverse effects) was associated with maternal plasma exposures approximately equal to those expected clinically in pregnant women. Importantly, increased incidences of resorption (that resulted in a reduced number of live fetuses) and fetal alterations (including skeletal malformations and some skeletal variations) were observed in the high-dose group. Therefore, in 2006, the FDA toxicology reviewer concluded that:

[B]ased on these data, modafinil should be identified as a developmental toxicant, based primarily on embryolethality, which could have masked a more obvious teratogenic effect.

3.1.2. Armodafinil

The effect of armodafinil on embryofetal development was examined in a single pre-marketing animal study in which groups of pregnant female rats were given 60, 200, or 600 mg/kg of the drug from days 7 to 17 of gestation (in addition to a control group that did not receive the drug).[40] Cesarean section and fetal evaluations showed a slight statistically significant increase in resorption (early) and reduced fetal body weights in the high-dose group. In addition, all doses were associated with an increase in the number of fetuses with any alteration (this effect was statistically significant at medium and high doses). Mostly, the fetal alterations involved visceral and skeletal variations (such as dilation of the renal pelvis and reduced ossification of sternal centra). Therefore, in 2006, the FDA pharmacological reviewer considered the combined changes “an index of developmental toxicity” and made the following conclusion:

[Armodafinil] should be labeled as a developmental toxicant, based on increased incidences of visceral and/or skeletal variations at the [medium] and [high doses] and decreased fetal [body weight] at the [high dose].

The developmental no-observed-effect level for armodafinil in the rat study was associated with maternal plasma levels that were below the detection limit in most cases. The lowest observed adverse-effect level that produced an area under the curve in this study was about one-fifth of that in humans at the clinical maximum recommended dose.

An FDA toxicology reviewer noted that the results of the rat embryofetal study for armodafinil conform to those from the first rat modafinil embryofetal study, in which resorption as well as skeletal and visceral variations were increased at the high drug dose (200 mg/kg).The reviewer also concluded that:

While the [p]hase 4 embryofetal development studies are adequate, the pre- and postnatal developmental toxicity evaluation of modafinil is incomplete and should be repeated according to current standards with armodafinil.

3.2 Human studies

There are no adequate and well-controlled studies of either modafinil or armodafinil in pregnant women to inform the discussion about their risks in patients and their offspring. Also, such studies are unethical given the currently available evidence discussed below. The next sections describe the available evidence, which is mostly based on registry data and observational studies.

3.2.1. Premarketing and post-marketing cases

The original modafinil label did not report the total number of pregnancies during the drug’s clinical trial. Instead, it indicated that seven normal births occurred in subjects who were treated with the drug during pregnancy. The label further stated that one pregnant woman, described as having “a history of spontaneous abortions,” had a spontaneous abortion while taking modafinil, and another woman gave birth to a healthy male infant three weeks earlier than the ultrasound-based estimated due date. No other information was provided about the remaining five live births.

In June 2007 the FDA medical reviewer of armodafinil reported that she discovered information in the drug’s database about a pregnant person who went to term and delivered a baby that subsequently died of IUGR and respiratory failure.[41] All details about this case, not just personal identifying information, were redacted from the publicly available version of the FDA review. When alerted about this case, another reviewer found a second pregnant subject in the drug’s database who had an elective abortion. According to the FDA reviewers, nine pregnancies were reported during the open-label trials of armodafinil: five elective abortions including the case of IUGR, two normal outcomes, and two lost to follow-up.

The current armodafinil label indicates that cases of IUGR and spontaneous abortion have been reported in association with the use of both drugs during pregnancy. Moreover, in 2019 the European Medicines Agency identified 51 reports associated with the use of modafinil and armodafinil in EudraVigilance (a European pharmacovigilance database) that suggested a signal of congenital anomalies.[42]

3.2.2. Interim results from the U.S. pregnancy registry

The FDA has been receiving interim reports about the registry findings and the final results are expected in July 2027, according to the agency.[43] However, since February 2024 the registry’s web page on clinicaltrials.gov indicates that the registry has been terminated and “is no longer feasible,” even though it has enrolled 191 participants.[44] As discussed below, various interim results from this registry showed higher prevalence of major congenital malformations among infants who were exposed to modafinil or armodafinil in utero.

A 2016 Teva report submitted to the FDA with preliminary results from the U.S. pregnancy registry found a signal for forms of microcephaly and prenatal or postnatal abnormal growth restriction, small-for-gestational-age baby, and failure to thrive following exposure to modafinil or armodafinil during pregnancy.[45] The FDA considered this information to be “new safety information” as defined in section 505-1(b)(3) of the FDCA.

A 2018 interim registry report submitted to the U.K.’s Medicines and Healthcare Products Regulatory Agency provided another set of preliminary results from the U.S. pregnancy registry.[46] These results were based on a prospective sample of 78 pregnancies with modafinil or armodafinil exposure. Among 61 reported live births from this sample, nine infants had major congenital anomalies (including three who had cardiac congenital anomalies). Therefore, the estimated prevalence of major congenital malformations was approximately 14.8% (95% confidence interval [CI], 5.9 – 23.7), which was higher than that in the general U.S. population (approximately 3%). In addition, the estimated prevalence of cardiac anomalies in the exposed live births was 4.9% (95% CI, 0.0 – 10.3), which also was higher than that in the general U.S. population (approximately 1%).

Using February 2010 to February 2019 data from the U.S. Nuvigil and Provigil pregnancy registry, Kaplan et al. (Teva researchers) published a 2021 peer-reviewed article with results from 148 pregnancies with modafinil or armodafinil exposure (96% had first-trimester exposures).[47] Of those, 122 were prospectively followed (i.e., before knowledge of pregnancy outcome or detection of a congenital malformation at a prenatal test) and the remaining 26 pregnancies were retrospectively ascertained (i.e., after knowledge of the pregnancy outcome or congenital malformation at a prenatal test). Overall, 81 women (55%) received modafinil, 66 (45%) received armodafinil, and one woman (1%) received both drugs during pregnancy. Seventy percent of the patients reported having narcolepsy.

Kaplan et al. found that among the 119 pregnancies with live births that had known fetal outcomes, 16 (13%) had major congenital malformations, a prevalence that is higher than that in the general U.S. population. Notably, 13 of the newborns with major congenital malformations were in the prospective group. Of those, four had congenital torticollis (a condition with contracted neck muscles, twisting the head to one side), two had hypospadias (a congenital condition in which the urethra does not develop completely in males, resulting in an abnormal location of its opening), and three had congenital heart defects. The cardiac malformation prevalence was 3%, which is higher than that in the general U.S. population. Additionally, spontaneous abortion occurred in 15% of the 148 pregnancies in the registry.

The Teva researchers concluded that the results of their analysis demonstrate that there is a potential increased risk of major congenital malformations due to exposure to modafinil or armodafinil during pregnancy. They acknowledged that this potential risk is not likely caused by the main underlying condition (narcolepsy), because previous studies show that narcolepsy does not increase the risk of abnormal pregnancy or fetal outcomes.[48],[49] As expected due to their industry affiliation, Kaplan et al. did not recommend contraindicating the use of modafinil and armodafinil during pregnancy. Instead, they stated that the potential increased risk of major congenital malformations provides an incentive for clinicians to increase the benefit-risk monitoring of the use of modafinil and armodafinil in pregnant females and those who may become pregnant.

However, a commentary by two maternal-fetal medicine experts on the Kaplan et al. study made the following recommendation, consistent with our requested labeling changes:[50]

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. 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.

Moreover, the 2023 Australian label of modafinil indicates that interim results from the U.S. pregnancy registry shows a prevalence of 17.3% for major congenital anomalies (including cardiac anomalies and microcephaly) due to exposure to modafinil or armodafinil.

Overall, the U.S. pregnancy registry is more robust than spontaneous adverse-event reports because it mostly recruited pregnant patients prior to the detection of congenital malformations. Additionally, participants in this registry are more likely to have taken modafinil and armodafinil during pregnancy than those in observational studies that rely on drug prescription databases. However, the limitations of this registry include the lack of comparison group, selection bias due to voluntary enrollment, and incomplete data reporting.

3.2.2. Observational studies

Davies et al. 2013 conducted a cross-sectional prescription-event monitoring study in England that included 599 women who filled out modafinil prescriptions (that had been prescribed by primary care physicians) from April 2004 to August 2005, a period during which shift work sleep disorder was an approved indication for modafinil in the country.[51] The researchers found that pregnancy was among the top 20 frequently reported events during the first month of treatment, as reported by prescribing clinicians. Overall, 11 women became pregnant while taking modafinil, including three who were taking an oral contraceptive during treatment. One of these women had a spontaneous abortion while taking the drug and subsequently had a “therapeutic termination” after she became pregnant again while taking the drug. It was unknown if there was any fetal abnormality in this case. The second woman had an ectopic pregnancy (she also was taking another drug, dexamphetamine [an ADHD drug], during pregnancy). The third woman had stopped modafinil during her first trimester and subsequently delivered a baby who had a left lower lid entropion (inversion of eyelid) that subsequently resolved without treatment. Of the remaining eight women, three had live births, two were terminated, and three had unknown or unspecified birth outcomes.

With funding from Novo Nordisk Foundation, Damkier and Broe 2020 identified all pregnancies from 2004 to 2017, excluding those exposed to known drug teratogens (such as lithium, retinoids, valproic acid, and vitamin K antagonists), from Danish national health registries.[52] The researchers then compared the risk of major congenital malformations for pregnancies that had a first-trimester exposure to modafinil (n = 49) with those exposed to the stimulant drug methylphenidate (n = 960) and pregnancies that were not exposed to either drug one year before or during pregnancy (n = 828,644). Overall, the reported rate of major congenital malformation was higher in modafinil-exposed pregnancies (12.0%) than in methylphenidate-exposed pregnancies (4.5%) and unexposed pregnancies (3.9%). After adjusting for potential confounders (diagnosis of diabetes and hypertension, as well as use of psychiatric medications at baseline), modafinil exposure was associated with significantly increased odds of malformation compared with methylphenidate or no exposure. Specifically, the adjusted odds ratio (OR) comparing first-trimester exposure to modafinil with exposure to methylphenidate was 3.4 (95% CI, 1.2 – 9.7). The corresponding ORs comparing first-trimester exposure to modafinil with pregnancies exposed to neither modafinil nor methylphenidate was 2.7 (95% CI, 1.1 – 6.9). The researchers concluded:

Although further research is needed, women contemplating pregnancy should currently avoid or discontinue modafinil.

With funding from Nordic governments, Cesta et al. 2020 identified national live births from birth registers in Norway (from 2005 to 2017) and Sweden (from 2006 to 2016) and linked them to corresponding prescription drug and other health data registries.[53] Overall, 133 pregnancies were exposed to modafinil (as determined by presence of at least one dispensed prescription of the drug within 30 days of the last menstrual period to the end of the first trimester) and 1,917,472 were not exposed to the drug. In the modafinil-exposure group, the rate of major malformations was 2.3% compared with 2.1% in the unexposed group. Compared with no exposure, exposure to modafinil was not associated with an increased risk of major malformations; the crude risk ratio for such exposure was 1.06 (95% CI, 0.4 – 3.3). The researchers noted that the low number of exposed pregnancies and major malformations did not permit rigorous analyses, including accounting for potential confounding factors. Unlike the study by Kaplan et al. 2021,[54] Cesta et al.’s study may not have included hypospadias, congenital torticollis, and possibly other defects, which are not usually reported in exposure studies.[55]

In 2024, Onken and other international researchers (including those from 18 teratology information services in 12 countries, such as Australia, France, Germany, and Italy) used a multicenter case series to identify a prospective sample of pregnancies with first-trimester exposure to modafinil that resulted in 153 live births before August 2019.[56] These researchers found that the percentiles of neonatal head circumference and birth weights for modafinil-exposed newborns tended to be lower than those in reference standards (values were available for 73 and 144 of the 153 live births, respectively). Unadjusted linear regression models estimated that each 100-mg increase of average dose of modafinil per pregnancy day was associated with a decrease in standard deviation score of -0.28 (95% CI, -0.6 – 0.0) for head circumference and -0.28 (95% CI, -0.5 – -0.1) for birth weight. There were three major congenital anomalies in the live births that were deemed non-chromosomal, corresponding to a rate of 2.0% (95% CI, 0.6% – 6.1%). Overall, the results, which were not adjusted for potential confounders, suggest that pregnancy exposure to modafinil may inhibit fetal growth, but it does not increase the risk of major birth defects, according to the researchers. Although they stated that these findings are preliminary and their clinical relevance is unknown, the researchers concluded:

Until safety concerns from this and other studies are more extensively investigated, patients should avoid modafinil intake during pregnancy.

4. Action by international regulators

Interim reports from the U.S. pregnancy registry for modafinil and armodafinil, along with other evidence, have suggested an increased risk of spontaneous abortion and major congenital malformations due to fetal exposure to these drugs. Despite this, the FDA has not issued any warnings or required labeling changes regarding the use of modafinil and armodafinil during pregnancy and in females who can become pregnant.

In contrast, since 2019, regulatory authorities in several countries alerted clinicians about these risks and contraindicated the use of modafinil and armodafinil during pregnancy and in females of reproductive age who are not using effective nonhormonal contraceptives. In certain countries (including Canada and the United Kingdom), the regulatory actions were limited to modafinil only because armodafinil is not marketed in these countries.

For example, in April 2019 the EMA adopted pregnancy-related labeling changes for modafinil based on recommendations from its Pharmacovigilance Risk Assessment Committee.[57] The recommendations were based on interim results from the U.S. pregnancy registry and additional spontaneous reports supporting a signal of congenital anomalies associated with fetal exposure to modafinil during pregnancy.[58] The labeling changes indicated that modafinil is “suspected to cause congenital malformations when administered during pregnancy” and “should not be used during pregnancy.” The EMA required updating the package leaflet (medication guide) of this drug accordingly.

European regulators embraced the EMA recommendations. For example, in June 2019 the Irish Health Products Regulatory Authority required modafinil manufacturers to update the labeling of this drug and send a “dear healthcare professional” letter to communicate the following warnings with clinicians:[59]

• Modafinil should not be used during pregnancy.
• Women of childbearing potential must use effective contraception during treatment with, and for 2 months after stopping, modafinil.
• You must ensure that all female patients of childbearing potential are informed of and fully understand
  • [T]he use of modafinil during pregnancy is suspected to cause congenital malformations
  • The potential risk to a [fetus] associated with modafinil use during pregnancy
  • That modafinil should not be used during pregnancy
  • The need to use effective contraception during treatment with and for 2 months after stopping modafinil. As modafinil may reduce the effectiveness of oral contraception, alternative or concomitant methods of contraception are required.
  • The need to discuss other treatment options with their doctor if planning a pregnancy before stopping contraception
• Non-pharmacological treatment options including [behavior] modifying measures, sleep hygiene, and scheduled daytime naps should be preferred during pregnancy.

In 2020 the U.K.’s Medicines and Healthcare products Regulatory Agency required updating modafinil labeling and sending related safety communication letters to prescribers.[60],[61] Similarly, in June 2019 Health Canada contraindicated the use of modafinil (available under the brand name ALERTEC in Canada) during pregnancy and in females of reproductive potential who are not using effective nonhormonal contraceptives, issued a related safety alert to clinicians, and required Teva to update the drug labeling accordingly.[62] The agency also indicated that women should take a pregnancy test within a week before starting treatment with modafinil to ensure they are not pregnant. As shown in the Table below, the United States has not followed other countries in terms of contraindicating modafinil and armodafinil during pregnancy and in females of reproductive potential who are not using effective nonhormonal contraceptives.

Table. Comparison of Main Recommendations Regarding Use of Modafinil (and Armodafinil, Where Available) During Pregnancy in Drug Labels of Select Countries

Australia[63],[64]	Canada[65]	Ireland & United Kingdom[66],[67]	United States
Modafinil and armodafinil are “contraindicated in women who are pregnant or may become pregnant … sexually active women of [childbearing] potential should be established on a contraceptive program before taking” these drugs.	Modafinil “is contraindicated … in women who are pregnant or may become pregnant. Women should be advised regarding the use of effective contraception during treatment as modafinil may reduce effectiveness of steroidal contraceptives.”	Modafinil “should not be used during pregnancy.” “Women of childbearing potential have to use effective contraception.”	Modafinil “should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.” “Before you take [armodafinil], tell your doctor ... if you ... are pregnant or planning to become pregnant. It is not known if [armodafinil] will harm your unborn baby.”

5. Conclusions

Animal studies demonstrate the potential embryofetal toxicity (including increased incidences of resorption and visceral or skeletal variations) of modafinil and armodafinil at clinically relevant doses. Although adequate and well-controlled trials for modafinil and armodafinil in pregnant women are lacking, various interim results of the U.S. pregnancy registry for these drugs show that major congenital birth defects occurred in 13% to 17% of exposed live births, which is four to six times higher than the prevalence in the general U.S. population. Modafinil and armodafinil also have been linked to spontaneous abortion, low fetal growth, and congenital malformations among newborns who were exposed to drugs in utero. This potential risk is unlikely to be due to the underlying condition of narcolepsy because previous studies suggest that narcolepsy does not increase the risk of abnormal pregnancy outcomes. Although evidence from additional observational studies is inconclusive in supporting the interim registry findings, various international regulators have already contraindicated these drugs during pregnancy and in females of reproductive potential.

Based on the precautionary principle of public health, the available evidence is enough for the FDA to require contraindicating the use of modafinil and armodafinil during pregnancy and in females of reproductive potential who are not using effective nonhormonal contraceptives and add a boxed warning about the potential embryofetal toxicity of both drugs. Such FDA action is urgently needed given the severity of the malformations reported, the extensive off-label use of these drugs, and the fact that nearly half of U.S. pregnancies are unplanned.

For the above reasons and according to FDCA 21 U.S.C. sections 352 and 505(o)(4) as well as FDA regulations at 21 C.F.R. sections 10.30, 201.56, 201.57(c)(1), and 201.57(c)(5), Public Citizen urges the FDA to promptly require that the following changes be made to the labeling of modafinil and armodafinil products:

(1) Contraindicate the use of modafinil and armodafinil during pregnancy and in females of reproductive potential who are not using effective nonhormonal contraceptives, and

(2) Add boxed warnings in the labeling of these drugs due to their potential embryofetal toxicity.

Public Citizen proposes the following boxed warnings:

Embryofetal Toxicity WARNINGs

Modafinil and armodafinil are contraindicated for use during pregnancy and in females of reproductive potential who are not using effective nonhormonal contraceptives because of their potential to cause serious fetal harm. Developmental toxicity and embryolethality due to exposure to modafinil and armodafinil during pregnancy occurred at clinically relevant exposures in animal studies. Interim results from a U.S. pregnancy registry and other post-marketing evidence suggest that modafinil and armodafinil are suspected to cause congenital malformations when used during pregnancy.

Rule out pregnancy before the start of treatment with modafinil or armodafinil in females of reproductive potential. Advise females of reproductive potential to use effective contraception during treatment with modafinil or armodafinil and for two months after discontinuing these drugs. Because modafinil and armodafinil may reduce the effectiveness of hormonal contraceptives, additional or alternative contraceptive methods are required. Stop modafinil and armodafinil if pregnancy occurs.

Corresponding changes should be made in the “Contraindications and Warnings,” “Precautions,” and “Limitations of Use” sections in the labeling of these drugs.

C. ENVIRONMENTAL IMPACT

Public Citizen claims categorical exclusion under 21 C.F.R. § 25.31(a) from the environmental assessment requirement. An assessment is not required because the requested action would not increase the use of the active moiety that is the subject of this petition.

D. ECONOMIC IMPACT

Will be submitted upon request.

E. CERTIFICATIONS

I certify that, to the best of the knowledge and belief of the undersigned, this petition includes all information and views on which this petition relies, and that it includes representative data and information known to the petitioners which are unfavorable to the petition.

Sincerely,

Azza AbuDagga, M.H.A., Ph.D.
Health Services Researcher
Public Citizen’s Health Research Group

1600 20th Street, N.W.
Washington, DC 20009
202-588-1000
aabudagga@citizen.org

—

[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 May 27, 2025.

[2] Teva Pharmaceuticals. U.S. label: armodafinil (NUVIGIL). December 2022. https://www.nuvigil.com/globalassets/nuvigil-consumer/prescribinginformation.pdf. Accessed May 27, 2025.

[3] Food and Drug Administration. Guidance for industry: Warnings and precautions, contraindications, and boxed warning sections of labeling for human prescription drug and biological products — content and format. October 2011. https://www.fda.gov/media/71866/download. Accessed May 27, 2025.

[4] Ibid.

[5] 21 C.F.R. § 201.57.

[6] Food and Drug Administration. Safety labeling changes under section 505(o)(4) of the FDCA. July 10, 2019. https://www.fda.gov/media/128660/download. Accessed May 27, 2025.

[7] Ibid.

[8] Trotti LM, Arnulf I. Idiopathic hypersomnia and other hypersomnia syndromes. Neurotherapeutics. 2021;18(1):20-31.

[9] Khan SS, Mujuruki C. Medication management of patient with narcolepsy during pregnancy and lactation. In: Khan SS, Mujuruki C, eds. A Clinical Casebook of Sleep Disorders in Women. Springer; 2023:77-84.

[10] 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 May 27, 2025.

[11] Department of Veteran Affairs Pharmacy Benefits Management Services. Armodafinil (Nuvigil) national drug monograph. March 2014. https://www.pbm.va.gov/clinicalguidance/drugmonographs/Armodafinil.docx. Accessed May 27, 2025.

[12] Hamilton J. FDA committee rejects ADHD use for modafinil. March 24, 2006. https://www.npr.org/2006/03/24/5298885/fda-committee-rejects-adhd-use-for-modafinil. Accessed May 27, 2025.

[13] Wagener N, Lehmann W, Weiser L, et al. Psychostimulants modafinil, atomoxetine and guanfacine impair bone cell differentiation and MSC migration. Int J Mol Sci. 2022;23(18):10257.

[14] Robertson PJ, Hellriegel ET, Arora S, Nelson M. Effect of modafinil on the pharmacokinetics of ethinyl estradiol and triazolam in healthy volunteers. Clin Pharmacol Ther. 2002;71(1):46-56.

[15] Khan SS, Mujuruki C. Medication management of patient with narcolepsy during pregnancy and lactation. In: Khan SS, Mujuruki C, eds. A Clinical Casebook of Sleep Disorders in Women. Springer; 2023:77-84.

[16] Hypersomnolence Australia. Do you take modafinil or armodafinil? https://www.hypersomnolenceaustralia.org.au/_files/ugd/a1218b_64d406a192df41ed81493a1a88bb8439.pdf. Accessed May 27, 2025.

[17] Par Pharmaceutical Companies, Inc. Par Pharmaceutical acquires three generic products from Teva Pharmaceuticals. October 18, 2011. https://www.prnewswire.com/news-releases/par-pharmaceutical-acquires-three-generic-products-from-teva-pharmaceuticals-132044783.html. Accessed May 27, 2025.

[18] California Department of Justice, Office of the Attorney General. Attorney general Becerra secures nearly $70 million against several drug companies for delaying competition and increasing drug prices. July 29, 2019.

https://oag.ca.gov/news/press-releases/attorney-general-becerra-secures-nearly-70-million-against-several-drug. Accessed May 27, 2025.

[19] Ruiz RR, Thomas K. Teva settles Cephalon generics case with F.T.C. for $1.2 billion. May 28, 2015. https://www.nytimes.com/2015/05/29/business/teva-cephalon-provigil-ftc-settlement.html. Accessed May 27, 2025.

[20] Cephalon, Inc. U.S. label: modafinil (PROVIGIL). December 1998. https://www.accessdata.fda.gov/drugsatfda_docs/label/1998/20717lbl.pdf. Accessed May 27, 2025.

[21] Cephalon, Inc. U.S. label: armodafinil (NUVIGIL). June 2007. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021875lbl.pdf. Accessed May 27, 2025.

[22] 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 May 27, 2025.

[23] 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 May 27, 2025.

[24] Food and Drug Administration. Letter to Calphalon re. NDA 21875/S-023 (for armodafinil [Nuvigil]). February 7, 2017. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/021875Orig1s023ltr.pdf. Accessed May 27, 2025.

[25] 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.

[26] 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 May 27, 2025.

[27] 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 May 27, 2025.

[28] Ghaffari N, Robertson PA. Caution in prescribing modafinil and armodafinil to individuals who could become pregnant. JAMA Intern Med. 2021;181(2):277-278.

[29] Davies M, Wilton L, Shakir S. Safety profile of modafinil across a range of prescribing indications, including off-label use, in a primary care setting in England. Results of a modified prescription-event monitoring study. Drug Saf. 2013;36(4):237-246.

[30] Schwarz EB, Mattocks K, Brandt C, et al. Counseling of female veterans about risks of medication-induced birth defects. J Gen Intern Med. 2013;28(Suppl 2):S598-S603.

[31] 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 May 27, 2025.

[32] 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 May 27, 2025.

[33] Ibid.

[34] 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 May 27, 2025.

[35] Teva Canada. Canadian label: Modafinil (ALERTEC). July 2023. https://pdf.hres.ca/dpd_pm/00071543.PDF. Accessed May 27, 2025.

[36] 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 May 27, 2025.

[37] 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 May 27, 2025.

[38] 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 May 27, 2025.

[39] Ibid.

[40] Ibid.

[41] 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 May 27, 2025.

[42] European Medicines Agency. Pharmacovigilance risk assessment committee (PRAC) Minutes of PRAC meeting on 11-14 February 2019. March 15, 2019.

https://www.ema.europa.eu/en/documents/minutes/minutes-prac-meeting-11-14-february-2019_en.pdf. Accessed May 27, 2025.

[43] Food and Drug Administration. Letter to Calphalon re. NDA 21875/S-023 (for armodafinil [Nuvigil]). February 7, 2017. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/021875Orig1s023ltr.pdf. Accessed May 27, 2025.

[44] The Nuvigil and Provigil pregnancy registry (clinical trial ID: NCT01792583). Last updated February 5, 2024. https://clinicaltrials.gov/study/NCT01792583. Accessed May 27, 2025.

[45] Food and Drug Administration. Letter to Calphalon re. NDA 21875/S-023 (for armodafinil [Nuvigil]). February 7, 2017. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/021875Orig1s023ltr.pdf. Accessed May 27, 2025.

[46] 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 May 27, 2025.

[47] 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.

[48] Calvo-Ferrandiz E, Peraita-Adrados R. Narcolepsy with cataplexy and pregnancy: a case-control study. J Sleep Res. 2018;27(2):268-272.

[49] Maurovich-Horvat E, Tormášiová M, Slonková J, et al. Assessment of pregnancy outcomes in Czech and Slovak women with narcolepsy. Med Sci Monit. 2010;16(12):SR35-SR40.

[50] Ghaffari N, Robertson PA. Caution in prescribing modafinil and armodafinil to individuals who could become pregnant. JAMA Intern Med. 2021;181(2):277-278.

[51] Davies M, Wilton L, Shakir S. Safety profile of modafinil across a range of prescribing indications, including off-label use, in a primary care setting in England. Results of a modified prescription-event monitoring study. Drug Saf. 2013;36(4):237-246.

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

[53] Cesta CE, Engeland A, Karlsson P, et al. Incidence of malformations after early pregnancy exposure to modafinil in Sweden and Norway. JAMA. 2020;324(9):895-897.

[54] 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.

[55] Nonacs R. Modafinil and armodafinil during pregnancy: Data to suggest increased risk of malformations. November 4, 2020. https://womensmentalhealth.org/posts/modafinil-pregnancy-2/. Accessed May 27, 2025.

[56] 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.

[57] European Medicines Agency, Pharmacovigilance Risk Assessment Committee. New product information wording—extracts from PRAC recommendations on signals: 2. modafinil—evaluation of data on foetal outcomes including congenital anomalies from a single observational study in the US (EPITT No. 19367). April 2019. https://www.ema.europa.eu/en/documents/other/new-product-information-wording-extracts-prac-recommendations-signals-adopted-8-11-april-2019-prac_en.pdf. Accessed May 27, 2025.

[58] European Medicines Agency. Pharmacovigilance risk assessment committee (PRAC) Minutes of PRAC meeting on 11-14 February 2019. March 15, 2019.

https://www.ema.europa.eu/en/documents/minutes/minutes-prac-meeting-11-14-february-2019_en.pdf. Accessed May 27, 2025.

[59] Irish Health Products Regulatory Authority. Modafinil: potential risk of congenital malformations when administered during pregnancy. June 2019. https://www.scribd.com/document/811861450/Important-Safety-Information-Modafinil99170c2697826eee9b55ff00008c97d0. Accessed May 27, 2025.

[60] 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 May 27, 2025.

[61] British Generic Manufacturers Association. Direct healthcare professional communication (DHPC) modafinil: potential risk of congenital malformations during pregnancy. January 8, 2020.

https://assets.publishing.service.gov.uk/media/5e43e03fe5274a6d34ddad60/Modafinil-Jan-2020.pdf. Accessed May 27, 2025.

[62] Health Canada. Recalls and safety alerts. Health professional risk communication. ALERTEC (modafinil) and the risk of congenital anomalies. June 20, 2019. https://recalls-rappels.canada.ca/en/alert-recall/alertec-modafinil-and-risk-congenital-anomalies. Accessed May 27, 2025.

[63] 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 May 27, 2025.

[64] 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 May 27, 2025.

[65] Teva Canada. Canadian label: Modafinil (ALERTEC). July 2023. https://pdf.hres.ca/dpd_pm/00071543.PDF. Accessed May 27, 2025.

[66] Bluefish Pharmaceuticals. Irish label: modafinil September 2022. https://assets.hpra.ie/products/Human/19717/Licence_PA1436-031-002_08092022120619.pdf. May 27, 2025.

[67] Teva Pharma B.V. U.K. label: modafinil (PROVIGIL). June 2021. https://www.medicines.org.uk/emc/product/5412/smpc/print. Accessed May 27, 2025.