Provigil and Nuvigil Side Effects

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

Since the original clinical trials of Provigil and Nuvigil, 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 in 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. Although these new findings have not led to a change in the labeling of the US FDA-approved products, these alerts from Ireland and Canada suggested that modafinil should not be used in women who are pregnant or may become pregnant.

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 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 November 2019, the FDA received 9,916 combined reports of adverse events for brand name Provigil and Nuvigil as well as their generics, modafinil and armodafinil.

Of those, 4,291 were serious, including 384 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.

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 started taking the drug, but isolated cases have been reported after three months of treatment.

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

The labels of Provigil and Nuvigil warn that the drugs 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.

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 about 1 percent or less of people stopped taking the drug because of these side effects in clinical trials.

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

Reactions that have been reported after the drugs were studied in clinical trials since they came to market include delusions, mania, hallucinations, suicidal ideation, and aggression. Some patients ended up in the hospital. The risk increases in people with preexisting psychiatric issues.

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. She had no history of mental issues or substance abuse, but after the third day of taking the drug, she developed paranoia, aggression, restlessness, and delusions.

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

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 meaningful 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 beats per minute, resting systolic blood pressure by about seven mm Hg and resting diastolic blood pressure by about five mm Hg in healthy people.

Patients with cardiovascular disease who take modafinil and armodafinil should do so with caution. 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.

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.

Birth defects potentially linked to modafinil or armodafinil include:

• Cleft lips or palate
• Microcephaly
• Congenital heart defects
• Hypospadias
• Death caused by any of the above conditions

The labeling of Provigil and Nuvigil states that 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.

A 2022 article in Breathe showed that data from a Danish registry found women who took modafinil during the thirst trimester had an increased risk of having babies with birth defects.

“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 percent compared to 3 percent 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.

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 make any statements regarding these findings from the pregnancy registry.

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.