• 22
    Feb
  • Pharmaceutical Approval Update: Armodafinil (Nuvigil)

Indication: Armodafinil is designed to improve wakefulness in patients with excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome, narcolepsy, and shift work sleep disorder.

In obstructive sleep apnea/hypopnea syndrome, armodafinil is indicated as an adjunct to standard therapy for the underlying obstruction. If continuous positive airway pressure (CPAP) is the treatment of choice, a maximal effort should be made to treat with CPAP for an adequate period of time before armo-dafi nil is initiated. If armodafinil is used as an adjunct with CPAP, encouragement and periodic assessment of compliance with CPAP are essential.

In all cases, it is of the utmost importance to pay careful attention to the diagnosis and treatment of the underlying sleep disorder. Some patients might have more than one sleep disorder that is contributing to their excessive sleepiness.

Drug Class: Armodafinil is the R-enantiomer of modafinil (Provigil, Cephalon), which is a mixture of the R- and S-enan-tiomers. The chemical name for armodafinil is 2-[(R)-(diphenyl-methyl)sulfinyljacetamide. cialis soft tablets

Uniqueness of Product: The precise mechanism through which armodafinil and modafinil promote wakefulness is unknown.

At pharmacologically relevant concentrations, armodafinil does not bind to or inhibit several receptors and enzymes potentially relevant for sleep/wake regulation, including those for serotonin, dopamine, adenosine, galanin, melatonin, melanocortin, orexin-1, orphanin, pituitary adenylate cyclase-activating polypeptide (PACAP) or benzodiazepines, or transporters for gamma-butyric acid (GABA), serotonin, nor-epinephrine, and choline or phosphodiesterase VI, catechol-O-methytransferase (COMT), GABA transaminase, and tyrosine hydroxylase. Modafinil does not inhibit the activity of monoamine oxidase-B or phosphodiesterases II, III, and IV.

Armodafinil and modafinil have wake-promoting actions similar to those of sympathomimetic agents, including amphetamine and methylphenidate, but their pharmacological profile differs from that of the sympathomimetic amines.

Warnings:

Serious rash (including Stevens-Johnson Syndrome). Modafinil has been associated with serious rash requiring hospitalization, and there have been reports of discontinuation of treatment in adults and children. Armodafinil has not been studied and is not approved for use in children for any indication.

In clinical trials of modafinil (the racemate), the incidence of rash resulting in discontinuation was approximately 0.8% (13 per 1,585) in pediatric patients (age younger than 17 years); these rashes included one case of possible Stevens-Johnson syndrome (SJS) and one case of apparent multiorgan hyper-sensitivity reaction. Several of the cases were associated with fever and other abnormalities such as vomiting and leuko-penia. The median time to rash development 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 Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms (DRESS) have been reported in adults and children in worldwide postmarketing experienc e. canadian antibiotics

The reported rate of toxic epidermal necrolysis and Stevens-Johnson syndrome associated with modafinil use, which is generally considered an underestimate because of underreporting, exceeds the background incidence rate. Estimates of the background incidence rate for these serious skin reactions in the general population range from 1 to 2 cases per million-person years.

No serious skin rashes have been reported in clinical trials of adults (0 per 1,595). However, because armodafinil is the R-isomer of racemic modafinil, a similar risk of serious rash with armodafinil cannot be ruled out.

No factors are known to predict the risk of occurrence or the severity of rash associated with modafinil or armodafinil. Nearly all cases of serious rash associated with modafinil occurred within one to five weeks after treatment began. However, isolated cases have been reported after prolonged treatment (e.g., three months). Accordingly, the duration of therapy cannot be relied upon 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 predict which rashes will prove serious. Ordinarily, armodafinil should be discontinued at the first sign of a rash unless the rash is clearly not related to use of the drug. Discontinuing treatment might 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 receiving armodafinil. Patients should be advised to discontinue therapy and to immediately notify their physician of any signs or symptoms that suggest angioedema or anaphylaxis (e.g., facial swelling, difficulty swallowing or breathing; or hoarseness).

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

Despite a limited number of reports, these reactions may result in hospitalization or may 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—but 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, throm-bocytopenia), pruritus, and asthenia.

Because multiorgan hypersensitivity varies in its expression, other organ system symptoms and signs may occur. If a multiorgan hypersensitivity reaction is suspected, armodafinil should be discontinued. Although no case reports have indicated cross-sensitivity with other drugs that produce this syndrome, the experience with drugs associated with multiorgan hypersensitivity indicates such a possibility.

Persistent sleepiness. Patients with abnormal levels of sleepiness who take armodafinil should be advised that their level of wakefulness might not return to normal. Patients with excessive sleepiness, including those taking armodafinil, should be frequently reassessed for their degree of sleepi­ness. If appropriate, patients should be advised to avoid driving or any other potentially dangerous activity. Prescribers should be aware that patients might not acknowledge feeling sleepy or drowsy until they are directly questioned about drowsiness or sleepiness during specific activities. eriacta

Psychiatric symptoms: Psychiatric adverse experiences have been reported in patients using modafinil. Because modafinil and armodafinil are closely related, the incidence and type of psychiatric symptoms associated with the drug are expected to be similar to the incidence and type of these events with modafinil.

Postmarketing adverse events associated with modafinil have included mania, delusions, hallucinations, and suicidal ideation, sometimes resulting in hospitalization. Many patients had a prior psychiatric history. In one healthy male volunteer, ideas of reference (a false belief that irrelevant things in the world have a special personal significance), paranoid delusions, and auditory hallucinations developed in association with multiple daily doses of modafinil 600 mg and sleep deprivation. There was no evidence of psychosis 36 hours after the drug was discontinued.

In the controlled trial’s armodafinil database, anxiety, agitation, nervousness, and irritability were reasons for treated patients (1.2%) to discontinue treatment, compared with those receiving placebo (0.3%). In the controlled studies, depression was also a reason for stopping treatment, more often with armodafinil (0.6% of patients) than with placebo (0.2%).

Two cases of suicidal ideation were observed in clinical trials. Caution should be exercised in patients with a history of psychosis, depression, or mania. If psychiatric symptoms develop in association with armodafinil, prescribers should consider discontinuing therapy.

Precautions:

Hepatic impairment: The pharmacokinetics and metabolism of modafinil were examined in six men and three women with cirrhosis of the liver. Three patients had stage B or B+ cirrhosis, and six patients had stage C or C+ cirrhosis (per Child-Pugh criteria). Clinically, eight of nine patients were icteric, and all had ascites. In these patients, the oral clearance of modafinil was decreased by about 60%, and the steady-state concentration was doubled, compared with normal patients. The armodafinil dose should be reduced in patients with severe hepatic impairment.

Dosage and Administration:

Obstructive sleep apnea/hypopnea syndrome and narcolepsy: The recommended dose is 150 mg or 250 mg given as a single dose in the morning. In patients with obstructive sleep apnea/hypopnea syndrome, doses up to 250 mg/day, given as a single dose, have been well tolerated, but there is no consistent evidence that additional benefit is conferred beyond a dose of 150 mg/day.

Shift work sleep disorder: The recommended dose is 150 mg, given daily approximately one hour prior to the start of the work shift. The dosage can be adjusted for concomitant medications that are substrates for cytochrome CYP 3A4 and 3A5, such as steroidal contraceptives, triazolam, and cyclosporine. Drugs that are eliminated largely via CYP 2C19 metabolism, such as diazepam (Valium, Roche), propranolol (Pfizer) may have prolonged elimination upon co­administration with armodafinil. Consequently, the dosage might need to be reduced and monitored for toxicity.

Hepatic impairment: In patients with severe hepatic impairment, armodafinil should be administered at a reduced dose, because adequate information is lacking to determine the safety and efficacy of the drug in these patients.

Elderly patients: In elderly patients, elimination of armo-dafinil and its metabolites may be reduced as a consequence of aging. Therefore, lower doses should be considered in this population.

Commentary: Excessive sleepiness is the primary symptom and often the most debilitating feature in patients with narcolepsy, shift work sleep disorder, and obstructive sleep apnea/hypopnea syndrome. The defining characteristic of excessive sleepiness is a consistent inability to stay awake and alert enough to accomplish tasks of daily living safely and successfully. This condition is associated with reduced activity in the cerebral cortex of the brain. Although millions of Americans have excessive sleepiness associated with these three disorders, misdiagnosis is common. The rate of underdiagnosis ranges from 50% to 90%. Persons experiencing excessive sleepiness who seek medical attention typically complain of fatigue, tiredness, lapses of attention, lack of energy, low motivation, difficulty concentrating, disrupted sleep, snoring, or difficulties at work. erectalis 20 mg

Armodafinil is the second product available for the treatment of conditions associated with excessive sleepiness. Modafinil (Provigil) is currently approved to treat excessive sleepiness associated with narcolepsy, obstructive apnea/hypopnea syndrome, and shift work sleep disorder. Provigil and Nuvigil have similar ingredients but different enantiomers. Armodafinil promotes wakefulness later in the day, suggesting that it has a long duration of action.

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