warnings
WARNINGS Serious Rash, including Stevens-Johnson Syndrome Serious rash requiring hospitalization and discontinuation of treatment has been reported in adults in association with the use of modafinil and armodafinil and in children in association with the use of modafinil. Armodafinil has not been studied in pediatric patients in any setting and is not approved for use in pediatric patients for any indication. In clinical trials of modafinil (a racemic mixture of S and R enantiomers), the incidence of rash resulting in discontinuation was approximately 0.8% (13 per 1,585) in pediatric patients (age <17 years); these rashes included 1 case of possible Stevens-Johnson Syndrome (SJS) and 1 case of apparent multi-organ hypersensitivity reaction. Several of the cases were associated with fever and other abnormalities (e.g., vomiting, leukopenia). The median time to rash that resulted in discontinuation was 13 days. No such cases were observed among 380 pediatric patients who received placebo. No serious skin rashes have been reported in adult clinical trials (0 per 4,264) of modafinil. Rare cases of serious or life-threatening rash, including SJS, Toxic Epidermal Necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have been reported in adults and children in worldwide post-marketing experience with modafinil. The reporting rate of TEN and SJS associated with modafinil use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate. Estimates of the background incidence rate for these serious skin reactions in the general population range between 1 to 2 cases per million-person years. No serious skin rashes have been reported in adult clinical trials (0 per 1,595) of armodafinil. However, cases of serious rash similar to those observed with modafinil including skin and mouth blistering have been reported in adults in postmarketing experience. There are no factors that are known to predict the risk of occurrence or the severity of rash associated with armodafinil or modafinil. Nearly all cases of serious rash associated with these drugs occurred within 1 to 5 weeks after treatment initiation. However, isolated cases have been reported after prolonged treatment with modafinil (e.g., 3 months). Accordingly, duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the first appearance of a rash. Although benign rashes also occur with armodafinil, it is not possible to reliably predict which rashes will prove to be serious. Accordingly, armodafinil should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not drug-related. Discontinuation of treatment may not prevent a rash from becoming life-threatening or permanently disabling or disfiguring. Angioedema and Anaphylactoid Reactions One serious case of angioedema and one case of hypersensitivity (with rash, dysphagia, and bronchospasm), were observed among 1,595 patients treated with armodafinil. Patients should be advised to discontinue therapy and immediately report to their physician any signs or symptoms suggesting angioedema or anaphylaxis (e.g., swelling of face, eyes, lips, tongue or larynx; difficulty in swallowing or breathing; hoarseness). Multi-organ Hypersensitivity Reactions Multi-organ hypersensitivity reactions, including at least one fatality in postmarketing experience, have occurred in close temporal association (median time to detection 13 days: range 4-33) to the initiation of modafinil. A similar risk of multi-organ hypersensitivity reactions with armodafinil cannot be ruled out. Although there have been a limited number of reports, multi-organ hypersensitivity reactions may result in hospitalization or be life-threatening. There are no factors that are known to predict the risk of occurrence or the severity of multi-organ hypersensitivity reactions associated with modafinil. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations included myocarditis, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, leukopenia, thrombocytopenia), pruritus, and asthenia. Because multi-organ hypersensitivity is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If a multi-organ hypersensitivity reaction is suspected, NUVIGIL should be discontinued. Although there are no case reports to indicate cross-sensitivity with other drugs that produce this syndrome, the experience with drugs associated with multi-organ hypersensitivity would indicate this to be a possibility. Persistent Sleepiness Patients with abnormal levels of sleepiness who take NUVIGIL should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking NUVIGIL, should be frequently reassessed for their degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity. Prescribers should also be aware that patients may not acknowledge sleepiness or drowsiness until directly questioned about drowsiness or sleepiness during specific activities. Psychiatric Symptoms Psychiatric adverse experiences have been reported in patients treated with modafinil. Modafinil and armodafinil (NUVIGIL) are very closely related. Therefore, the incidence and type of psychiatric symptoms associated with armodafinil are expected to be similar to the incidence and type of these events with modafinil. Postmarketing adverse events associated with the use of modafinil have included mania, delusions, hallucinations, suicidal ideation and aggression, some resulting in hospitalization. Many, but not all, patients had a prior psychiatric history. One healthy male volunteer developed ideas of reference, paranoid delusions, and auditory hallucinations in association with multiple daily 600 mg doses of modafinil and sleep deprivation. There was no evidence of psychosis 36 hours after drug discontinuation. In the controlled trial NUVIGIL database, anxiety, agitation, nervousness, and irritability were reasons for treatment discontinuation more often in patients on NUVIGIL compared to placebo (NUVIGIL 1.2% and placebo 0.3%). In the NUVIGIL controlled studies, depression was also a reason for treatment discontinuation more often in patients on NUVIGIL compared to placebo (NUVIGIL 0.6% and placebo 0.2%). Two cases of suicide ideation were observed in clinical trials. Caution should be exercised when NUVIGIL is given to patients with a history of psychosis, depression, or mania. If psychiatric symptoms develop in association with NUVIGIL administration, consider discontinuing NUVIGIL.