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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Last Update: August 18, 2021.



Modafinil and its R-enantiomer armodafinil are central nervous system stimulants used to improve wakefulness in patients with excessive sleepiness. Both modafinil and armodafinil are associated with a low rate of serum aminotransferase elevations during therapy, but they have not been implicated in cases of clinically apparent acute liver injury.


Modafinil (moe daf' i nil) is a non-amphetamine central nervous system (CNS) stimulant whose mechanism of action is not entirely clear. Modafinil is structurally unrelated to the amphetamines, and it does not appear to affect release of CNS norepinephrine or dopamine. Modafinil is a racemic mixture of S and R enantiomers, whereas armodafinil (ar" moe daf' i nil) is the R enantiomer only. Both enantiomers have CNS activating actions, but they differ in pharmacokinetics and half-life. Modafinil and armodafinil increase wakefulness and both have been shown to be helpful in conditions with excessive sleepiness including narcolepsy, obstructive sleep apnea and shift-work sleep disorder. They have also been studied off label to treat fatigue associated with chronic illness such as cancer, Parkinson’s disease, HIV/AIDs and multiple sclerosis. Modafinil was approved for use in the United States in 1998 and armodafinil in 2007. Their indications are for improvement in wakefulness in adults with excessive sleepiness due to narcolepsy, obstructive sleep apnea, and shift-work disorder. Modafinil is available in tablets of 100 and 200 mg in generic forms and under the brand name Provigil, the usual dose in adults being 200 mg once daily in the morning or an hour before a work shift. Armodafinil is available in tablets of 50, 150, 200 and 250 mg generically and under the brand name Nuvigil, the usual dose in adults being 150 to 250 mg once daily. Armodafinil is also approved for treatment of sleepiness due to jet lag, a lower dose of 50 to 150 mg being recommended. The most common side effects of both agents include headache, anxiety nervousness, nausea, decreased appetite, palpitations and disturbed sleep. Modafinil and armodafinil are now classified as category IV controlled substances, indicating that they have a potential for abuse and can lead to physical or psychological dependence. Rare but potentially severe adverse reactions include rash and severe hypersensitivity reactions such as drug-reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, and toxic epidermal necrolysis. Also reported are cardiac adverse events and acute psychiatric syndromes such as mania, delusions, hallucinations, and suicidal ideation.


In clinical trials, modafinil and armodafinil were associated with a low rate of serum aminotransferase and alkaline phosphatase elevations (<1%). Furthermore, despite widescale use, there have not been reports of clinically apparent liver injury due to modafinil or armodafinil. Rare instances of hypersensitivity reactions and even Stevens Johnson syndrome have been reported after modafinil use and these reactions may be accompanied by evidence of hepatic involvement or injury.

Likelihood score: E (unlikely causes of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which modafinil and armodafinil might cause liver injury is unknown. Modafinil and armodafinil are extensively metabolized in the liver largely by CYP 3A4 and 2C91 and are susceptible to drug-drug interactions with agents that are substrates for these microsomal enzymes.

Drug Class: CNS Stimulants, Narcolepsy Agents

Other Drugs in the Subclass, Narcolepsy Agents: Amphetamines, Dextroamphetamine, Methylphenidate, Oxybate, Pitolisant, Solriamfetol



Armodafinil – Generic, Nuvigil®

Modafinil – Generic, Provigil®


Central Nervous System Stimulants



Product labeling at DailyMed, National Library of Medicine, NIH


Armodafinil 112111-43-0 C15-H15-N-O2-S image 135200656 in the ncbi pubchem database
Modafinil 68693-11-8 C15-H15-N-O2-S image 135010588 in the ncbi pubchem database


References updated: 18 August 2021

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