Provigil and Nuvigil Side Effects

The most common Provigil and Nuvigil side effects are mild and include headaches, nausea and dizziness. In rare cases, these wakefulness drugs can cause potentially fatal skin rashes, including Stevens-Johnson Syndrome. Some patients may experience an increase in heart rate and blood pressure. New warnings issued in June 2019 say Provigil may be linked to birth defects.

Provigil 200mg and Nuvigil 200mg
Provigil and Nuvigil Side Effects
  1. Common Side Effects headache, nausea, diarrhea, anxiety, insomnia, dizziness and indigestion
  2. Serious Side Effects Rashes, angioedema, cardiovascular effects, hepatitis, liver issues, psychiatric symptoms, risk of birth defects
  3. Manufacturer Warnings Risk of congenital malformations (birth defects) when taken by pregnant women

The majority of Provigil and Nuvigil side effects reported in clinical trials were mild or moderate, and the most reported adverse event in clinical trials and studies was headache.

Since the original clinical trials, the Food and Drug Administration has received thousands of voluntary postmarketing side effect reports. The reports in the FDA Adverse Events Reporting System (FAERS) database confirm most of the side effects are mild or moderate.

But Provigil and Nuvigil have some rare, serious risks mentioned on their drug labels, including potentially fatal skin rashes, psychiatric symptoms and cardiovascular risks. The drugs also have the potential for abuse and are listed as Schedule IV controlled substances.

In June 2019, Teva Pharmaceuticals Ireland issued a warning that modafinil, the active ingredient in Provigil, is suspected to cause birth defects when taken by pregnant women.

Health Canada issued a similar warning a few days after Teva issued its warning, and the European Medicine Agency’s drug labeling for modafinil states pregnant women shouldn’t use the drug. As of July 24, 2019, the FDA and Teva’s U.S. branch had yet to issue any warnings to American mothers-to-be.

Headaches and Other Common Side Effects

Cephalon Inc., the drugs’ original manufacturer, evaluated Provigil in over 3,500 patients and Nuvigil in over 1,100 patients and added the most common side effects to the drugs’ labels.

The most common reactions occurred in 5 percent or more of the participants. With Nuvigil, these were headache, nausea, dizziness and insomnia. Participants who took Provigil reported those same common side effects plus nervousness, swelling of the mucous membrane of the nose, back pain, diarrhea, anxiety and indigestion.

Side effects reported in clinical trials were:
  • Abnormal liver function
  • Agitation
  • Anorexia
  • Anxiety
  • Back pain
  • Chest pain
  • Constipation
  • Decreased appetite
  • Depression
  • Diarrhea
  • Dizziness
  • Dry Mouth
  • Dyspepsia (indigestion)
  • Headache
  • Heart palpitations
  • Hyperhydrosis (increased sweating)
  • Hypertension (high blood pressure)
  • Insomnia
  • Nausea
  • Nervousness
  • Paresthesia (pins-and-needles sensations)
  • Pharyngitis (sore throat)
  • Rash
  • Rhinitis (swelling of the mucous membranes in the nose)
  • Somnolence (sleepiness)
  • Upper abdominal pain
  • Vomiting

Side effects in people who take these drugs are rarely severe.

A study published in 2002 in the Journal of Neurology, Neurosurgery & Psychiatry followed 72 patients with multiple sclerosis using modafinil for fatigue. K.W. Rammohan and colleagues found 63 percent of side effects were mild and 37 percent were moderate in nature at 200 mg. Numbers were similar at a 400 mg dose.

“Serious adverse events were not found at either dose,” the authors wrote. “The most common adverse events were headache, nausea and asthenia.”

Side Effects Reported to the FDA

FAERS side effect data is a close match to the data gathered by Cephalon during its clinical trials. From 1999 to March 2019, the FDA received 9,665 combined reports of adverse events for brand name Provigil and Nuvigil as well as their generics, modafinil and armodafinil.

Of those, 4,159 were serious, including 370 deaths. Since these reports are voluntary, there is no way of verifying whether the drug caused the side effects, but the FDA uses this information to track trends and decide whether it should investigate further.

Bar Graph that displays the Five Most Commonly Reported Provigil/Nuvigil Side Effects
Expand
A closer look at FAERS data from 1999 to March 2019 shows the top five side effects associated with Provigil, Nuvigil and their generics. Source: FDA Adverse Event Reporting System (FAERS)

Stevens-Johnson Syndrome and Other Serious Side Effects

Though uncommon, serious side effects associated with Provigil and Nuvigil include serious rashes, angioedema, anaphylaxis, organ sensitivities, psychiatric symptoms and cardiovascular events.

Stevens-Johnson Syndrome (SJS)

There have been reports of serious rashes associated with modafinil and armodafinil. In modafinil clinical trials involving children, 0.8 percent of participants stopped taking the drug because of a rash. There was one case of possible Stevens-Johnson Syndrome, a serious skin condition that starts with flu-like symptoms and turns into a reddish, purplish rash that blisters. SJS is life-threatening.

In addition to SJS, other life-threatening rashes that have been reported in adults and children worldwide include Toxic Epidermal Necrolysis (TEN) and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS). Reported symptoms include skin and mouth sores, blistering and ulceration.

The majority of cases of serious rash associated with modafinil occurred within one to five weeks after patients starting taking the drug, but isolated cases have been reported after three months of treatment.

Provigil, Nuvigil and Life-Threatening Rashes
At the first sign of a rash, discontinue taking modafinil or armodafinil unless the rash is clearly not drug-related.

Because these rashes occurred in young people, the FDA has not approved Provigil or Nuvigil for pediatric use.

Provigil and Nuvigil’s labels warn that the drug should be discontinued at the first sign of a rash, but “discontinuation of treatment may not prevent a rash from becoming life-threatening or permanently disabling or disfiguring.”

In a case report by Dr. Steven Holfinger and colleagues published in 2018 in the Journal of Clinical Sleep Medicine, a 21-year-old woman developed SJS after taking armodafinil for 12 days. She developed a fever and neck swelling. Doctors advised her to discontinue the drug, but 12 hours after she stopped it, she developed blisters and ulcerations. She was hospitalized, and it took several weeks to resolve.

Skin rash on a person's back
Serious allergic reactions can occur with modafinil and armodafinil. Source: Science Photo

Multi-organ Hypersensitivity

Multi-organ hypersensitivity is different in each patient. It can result in hospitalization and be life-threatening. At least one person has died within roughly a month of starting treatment with Provigil.

It may start with fever, rash, enlarged lymph nodes or facial swelling together with myocarditis, hepatitis, liver function test abnormalities, blood cell abnormalities, itchiness, and abnormal weakness or fatigue. The label recommends patients stop treatment immediately if a multi-organ hypersensitivity reaction occurs.

Psychiatric Symptoms

In clinical trials, psychiatric symptoms such as anxiety, nervousness, insomnia, confusion and depression caused some participants to quit the trials. The Provigil drug label says between 0.3 percent and 1 percent of people stopped taking the drug because of these side effects.

Since Nuvigil is closely related to Provigil, psychiatric symptoms are similar in both drugs, according to the drugs’ labels.

Postmarketing reactions include delusions, mania, hallucinations suicidal ideation and aggression. Some patients ended up in the hospital. The risk increases in people with preexisting psychiatric issues.

“Patients who are prescribed modafinil should be carefully followed for psychosis development, even when they are previously healthy and doses are small.”

Özgür Aytaş and Hayriye Dilek Yalvaç

A case report by Ozgur Aytas and Hayriye Dilek Yalvac published in 2015 in Archives of Neuropsychiatry described psychiatric issues in an 18-year-old woman who had been prescribed modafinil to help her study for exams. She had no history of mental issues or substance abuse, but after the third day of taking the drug, she developed paranoia, aggression and delusions.

“Her gaze was very suspicious and furious. Motor restlessness was apparent in her movements. She had paranoid delusions,” the authors said. “Patients who are prescribed modafinil should be carefully followed for psychosis development, even when they are previously healthy and doses are small.”

Doctors treated the woman with antipsychotic medication, and after six days her symptoms subsided.

Cardiovascular Risks

Since Provigil and Nuvigil are wakefulness drugs, they may increase heart rate and blood pressure. But unlike amphetamines such as Adderall, this effect is not as pronounced. Some studies found no clinically significant increase in blood pressure or heart rate with these drugs, but other studies recommend caution.

A study by Indu Taneja and colleagues published in 2005 in Hypertension showed modafinil increased resting heart rate by about nine points, resting systolic blood pressure by about seven points and resting diastolic blood pressure by about five points in healthy people.

Did You Know?
Provigil and Nuvigil may raise heart rate and blood pressure in some people.

Study authors encouraged caution in patients with cardiovascular disease. The drugs’ labels warn that health care providers should monitor heart rate and blood pressure in patients taking modafinil and armodafinil.

In clinical trials, three participants with mitral valve prolapse or left ventricular hypertrophy suffered chest pain, palpitations and difficulty breathing. The labels warn against using these drugs in people with these conditions.

Warnings for Women Taking Modafinil and Armodafinil

Women who are pregnant or may become pregnant need to be cautious about using modafinil and armodafinil. The U.S. drug labels say pregnant women should only use the drugs if the benefits outweigh the risks. New data shows modafinil may be linked to birth defects.

Lawyers are filing Provigil and Nuvigil lawsuits on behalf of children with birth defects born to mothers who used the drugs while pregnant.

The FDA rated Provigil and Nuvigil in the pregnancy category C. This means there aren’t enough studies in pregnant women, but the drugs caused problems in animal fetuses. This led the FDA to call for a pregnancy registry to monitor the drugs’ safety in pregnant women.

On June 7, 2019, Teva Pharmaceuticals Ireland released a warning based on findings from the registry and other sources.

““The use of modafinil during pregnancy is suspected to cause congenital malformations” and “modafinil should not be used during pregnancy.””

Johns Holmes, UK & Ireland Director Medical Services, Teva Pharmaceuticals Ireland

“The use of modafinil during pregnancy is suspected to cause congenital malformations” and “modafinil should not be used during pregnancy,” according to the warning.

Based on the data from the 2018 Annual Registry report, “the rate of major congenital malformations was approximately 15% compared to 3%1 in the general population.” Birth defects found in the data include congenital heart defects, orofacial clefts and hypospadias, a condition where the opening of the penis is on the underside instead of on the tip.

In response, Health Canada released its own warning for modafinil. The agency said pregnant women or women who plan to become pregnant should not use the drug. The FDA has yet to respond to the warning.

Women of childbearing age should also be careful when taking these drugs.

Modafinil and armodafinil can interfere with how hormonal contraceptives work and make them less effective. This means women taking these drugs need to make sure they use other contraception methods such as a condom to prevent pregnancy.

Please seek the advice of a medical professional before making health care decisions.

Related Pages
Michelle Llamas, Senior Content Writer
Written By Michelle Llamas Senior Writer

Michelle Llamas has been writing articles and producing podcasts about drugs, medical devices and the FDA for seven years. She specializes in fluoroquinolone antibiotics and products that affect women’s health such as Essure birth control, transvaginal mesh and talcum powder. Michelle collaborates with experts, including board-certified doctors, patients and advocates, to provide trusted health information to the public. Some of her qualifications include:

  • American Medical Writers Association (AMWA) Engage Committee and Membership Committee member
  • Centers for Disease Control and Prevention (CDC) Health Literacy certificates
  • Original works published or cited in The Lancet, British Journal of Clinical Pharmacology and the Journal for Palliative Medicine
Edited By

14 Cited Research Articles

  1. Aytas, O. & Yalvac, H.D. Modafinil-Induced Psychosis: A Case Report. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5353011/
  2. Chapman, J.L. et al. (2016). Modafinil/armodafinil in obstructive sleep apnoea: a systematic review and meta-analysis. Retrieved from https://erj.ersjournals.com/content/47/5/1420
  3. DailyMed. (2018, November 7). Nuvigil. Retrieved from https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d878aed0-ddbf-8fa1-abf7-d3e480260845&audience=consumer#section-8.4
  4. DailyMed. (2018, November 7). Provigil. Retrieved from https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e16c26ad-7bc2-d155-3a5d-da83ad6492c8&audience=consumer#section-5.3
  5. European Medicines Agency. (n.d.). Modafinil: Summary of Product Characteristics Labelling and Package Leaflet. Retrieved from https://www.ema.europa.eu/en/documents/referral/modafinil-annex-iii-summary-product-characteristics-labeling-package-leaflet_en.pdf
  6. Health Canada. (2019, June 20). ALERTEC (modafinil) and the Risk of Congenital Anomalies. Retrieved from https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2019/70201a-eng.php
  7. Holfinger, S. et al. (2018, May 15). Stevens-Johnson Syndrome After Armodafinil Use. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940442/
  8. MedlinePlus. (n.d.). Modafinil. Retrieved from https://medlineplus.gov/druginfo/meds/a602016.html
  9. Mitler, M.M. et al. (2000). Long-term efficacy and safety of modafinil (PROVIGIL((R))) for the treatment of excessive daytime sleepiness associated with narcolepsy. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/10828434
  10. Rammohan, K.W. et al. (2002). Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. Retrieved from https://jnnp.bmj.com/content/72/2/179
  11. Taneja, I. et al. (2005, March 7). Modafinil Elicits Sympathomedullary Activation. Retrieved from https://www.ahajournals.org/doi/full/10.1161/01.HYP.0000158267.66763.63
  12. Teva Pharmaceuticals Ireland. (2019, June 7). Modafinil: potential risk of congenital malformations when administered during pregnancy. Retrieved from http://www.hpra.ie/docs/default-source/default-document-library/important-safety-information---modafinil99170c2697826eee9b55ff00008c97d0.pdf?
  13. U.S. Food and Drug Administration. (2018, July 23). FDA Adverse Event Reporting System (FAERS) Public Dashboard. Retrieved from https://www.fda.gov/drugs/fda-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard
  14. Zukkoor, S. (2015, April 28). The Safety of Stimulant Medication Use in Cardiovascular and Arrhythmia Patients. Retrieved from https://www.acc.org/latest-in-cardiology/articles/2015/04/28/10/06/the-safety-of-stimulant-medication-use-in-cardiovascular-and-arrhythmia-patients
View All Sources
Who Am I Calling?

Calling this number connects you with a Drugwatch representative. We will direct you to one of our trusted legal partners for a free case review.

Drugwatch's sponsors support the organization's mission to keep people safe from dangerous drugs and medical devices. For more information, visit our sponsors page.

(877) 578-5444