Armodafinil

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 multiorgan 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 postmarketing experience with modafinil. The reporting rate of TEN and SJS associated with modafinil use, which is generally accepted to be an underestimate due to under reporting, 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 were 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.

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).

Multiorgan hypersensitivity reactions, including at least one fatality in postmarketing experience, have occurred in close temporal association (median time to detection 13 days: range 4 to 33) to the initiation of modafinil. A similar risk of multiorgan hypersensitivity reactions with armodafinil cannot be ruled out.

Although there have been a limited number of reports, multiorgan 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 multiorgan 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 multiorgan hypersensitivity is variable in its expression, other organ system symptoms and signs, not noted here, may occur.

If a multiorgan hypersensitivity reaction is suspected, armodafinil tablets 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 multiorgan hypersensitivity would indicate this to be a possibility.

Patients with abnormal levels of sleepiness who take armodafinil tablets should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking armodafinil tablets, 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 adverse experiences have been reported in patients treated with modafinil. Modafinil and armodafinil 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 armodafinil tablets database, anxiety, agitation, nervousness, and irritability were reasons for treatment discontinuation more often in patients on armodafinil tablets compared to placebo (armodafinil tablets 1.2% and placebo 0.3%). In the armodafinil tablets controlled studies, depression was also a reason for treatment discontinuation more often in patients on armodafinil tablets compared to placebo (armodafinil tablets 0.6% and placebo 0.2%). Two cases of suicide ideation were observed in clinical trials. Caution should be exercised when armodafinil tablets are given to patients with a history of psychosis, depression, or mania. If psychiatric symptoms develop in association with armodafinil tablets administration, consider discontinuing armodafinil tablets.