Foreign Regulators Issue Warnings About Wakefulness Drugs Modafinil (PROVIGIL) and Armodafinil (NUVIGIL)

In June, drug regulators in Canada (Health Canada)[1] and Ireland (Health Products Regulatory Authority)[2] issued important notices to health care professionals regarding new evidence of an increased risk of congenital birth defects associated with use of the stimulant drugs modafinil (PROVIGIL) and armodafinil (NUVIGIL).

The notices warned that modafinil should never be used by women who are or may become pregnant. They also emphasized the need for a negative pregnancy test within one week of starting modafinil and for effective contraception during treatment with the drug and for two months after stopping it.

Importantly, the notices also warned that modafinil may reduce the effectiveness of oral contraceptives. Therefore, alternative or additional contraceptive methods are required for women during treatment with modafinil and for two months after stopping the drug.

Overview of modafinil and armodafinil

Modafinil and armodafinil are stimulant drugs with nearly identical chemical makeups. They belong to the same drug family as amphetamines. Both are approved by the Food and Drug Administration (FDA) for improving wakefulness in adults with excessive sleeping associated with the following three conditions:

• Narcolepsy (a rare neurological condition characterized by an extreme uncontrollable tendency to fall asleep during the day);
• 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).[3],[4]

Sleepiness is a legitimate health concern; people who have excess sleepiness are prone to accidents, including falls and motor vehicle accidents, and heart problems. However, because of the risks of the drugs, Public Citizen’s Health Research Group recommends that modafinil and armodafinil only be used to control narcolepsy symptoms.[5]

In 2004, Cephalon, the manufacturer of modafinil and armodafinil, sought FDA approval for the use of modafinil to treat attention deficit hyperactivity disorder (ADHD), but the FDA rejected the request in 2006 because of concerns about serious skin toxicity in children.[6] Importantly, almost one-half of the modafinil prescriptions for children aged 6 to 17 from March 2004 through March 2007 were for ADHD, according to FDA data.[7] The other half of prescriptions were also for off-label (unapproved) uses because the drug is not approved for any use in children, having also been rejected for treatment of narcolepsy in children in 2006.[8]

The most common adverse effects of modafinil and armodafinil seen during placebo-controlled clinical trials included headache, nausea, nervousness or anxiety, diarrhea, dizziness and insomnia.[9],[10] The FDA-approved labeling for both drugs also includes important warnings about several serious adverse effects (see Text Box below for warnings provided in the modafinil labeling).

Important Warnings in the FDA-Approved Labeling for Modafinil*

Serious rash:

Rare cases of serious or life-threatening rash requiring hospitalization and discontinuation of treatment have been reported in association with use of modafinil. These skin reactions include Stevens-Johnson syndrome (a painful blistering of the skin, mouth and nose) and toxic epidermal necrolysis (abnormal skin sloughing), among others. There are no factors that are known to predict the risk of occurrence or the severity of these rashes. Nearly all cases of serious rash associated with modafinil occurred within one to five weeks after the start of treatment.

Angioedema, anaphylaxis and multi-organ hypersensitivity reactions:Angioedema (a potentially life-threatening allergic reaction that can cause swelling in the skin, lips, mouth and throat, resulting in difficulty breathing) and hypersensitivity (with rash, difficulty swallowing and sudden narrowing of the airways in the lungs) were observed during clinical trials of armodafinil but were not observed in trials of modafinil. However, angioedema has been reported in patients prescribed modafinil since it was approved by the FDA. Hypersensitivity reactions involving multiple organs also have been reported within days of modafinil use, including at least one fatal case.

Persistent sleepiness:Patients treated with modafinil may not return to a normal level of wakefulness and may need to avoid driving or other potentially dangerous activities.

Psychiatric symptoms:Modafinil can cause anxiety, nervousness and insomnia. Mania, delusions, hallucinations, suicidal thoughts and aggression, sometimes resulting in hospitalization, also have been reported in patients using modafinil.

Cardiovascular effects:In clinical trials of modafinil, adverse cardiovascular reactions, including chest pain, palpitations, shortness of breath and abnormalities on electrocardiogram occurred in three subjects who had underlying heart disorders. The drug should be used with caution in patients who have cardiovascular disease.

*These warnings are excerpted and paraphrased in part from the FDA-approved product labeling.

Canadian and Irish notices

The Canadian and Irish regulators issued their notices after Teva Pharmaceuticals, which now owns Cephalon, informed them of the most recent results from an ongoing U.S. registry study that was created in 2009 to monitor for birth defects in children of mothers who used either drug during pregnancy. The registry was established at the request of the FDA because of prior evidence of fetal toxicity in animal studies of modafinil and armodafinil.[11]

The most recent results from the armodafinil and modafinil registry documented cases of spontaneous abortion and major birth defects, including heart defects, in the fetuses of women taking these drugs.[12] Specifically, major congenital birth defects occurred in the fetuses of 17% of the women in this registry compared with 3% of those of pregnant women in the general population. In addition, heart defects occurred in the fetuses of 4% of the pregnant women in this registry, compared with 1% of those of pregnant women in the general population. Notably, other reports have linked these drugs to low fetal growth and poor physical development among babies of women who used the drugs during pregnancy.

The warnings in these notices were limited to modafinil because armodafinil is not marketed in Canada or the European Union. However, the restrictions on modafinil also apply to armodafinil.

Disturbingly, at press time, the FDA has not yet issued similar warnings about these drugs to health care professionals and patients in the U.S. The current labeling of modafinil and armodafinil only include a general warning that animal data suggest that these drugs may cause fetal harm.

What You Can Do

Do not use modafinil or armodafinil if you are a woman who is currently pregnant or may become pregnant. Women capable of childbearing who opt to use these drugs should use effective contraception (other than or in addition to oral contraceptives, if applicable) when taking these drugs and for two months after stopping them.
 

References

[1] Health Canada. Recalls and safety alerts: ALERTEC (modafinil) and the risk of congenital anomalies. June 20, 2019. http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2019/70201a-eng.php. Accessed August 7, 2019.

[2] Health Products Regulatory Authority. Modafinil - Important safety information from Teva Pharmaceuticals Ireland, Clonmel Healthcare Ltd and Fannin Limited as approved by HPRA. June 11, 2019. https://www.hpra.ie/homepage/medicines/safety-notices/item?t=/modafinil---important-safety-information-from-teva-pharmaceuticals-ireland-clonmel-healthcare-ltd-and-fannin-limited-as-approved-by-hpra&id=ad170c26-9782-6eee-9b55-ff00008c97d0. Accessed August 7, 2019.

[3] Cephalon, Inc. Label: modafinil (PROVIGIL). July 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=e16c26ad-7bc2-d155-3a5d-da83ad6492c8&type=display. Accessed August 7, 2019.

[4] Cephalon, Inc. Label: armodafinil (NUVIGIL). November 2018. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=d878aed0-ddbf-8fa1-abf7-d3e480260845&type=display. Accessed August 7, 2019.

[5] A review of modafinil (PROVIGIL) for narcolepsy. Worst Pills, Best Pills News. May 2008. /newsletters/view/591. Accessed August 7, 2019.

[6] Ibid.

[7] Ibid.

[8] Ibid.

[9] Cephalon, Inc. Label: modafinil (PROVIGIL). July 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=e16c26ad-7bc2-d155-3a5d-da83ad6492c8&type=display. Accessed August 7, 2019.

[10] Cephalon, Inc. Label: armodafinil (NUVIGIL). November 2018. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=d878aed0-ddbf-8fa1-abf7-d3e480260845&type=display. Accessed August 7, 2019.

[11] Teva Pharmaceuticals. NUVIGIL pregnancy registry. http://www.nuvigilpregnancyregistry.com/. Accessed August 7, 2019.

[12] Health Canada. Recalls and safety alerts: ALERTEC (modafinil) and the risk of congenital anomalies. June 20, 2019. http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2019/70201a-eng.php. Accessed August 7, 2019.