AHFS Class:

• Wakefulness-promoting Agents 28:20.80

Generic Name(s):

• Armodafinil

Armodafinil, the R -enantiomer of racemic modafinil, is a wakefulness-promoting agent.1

Obstructive Sleep Apnea

Armodafinil is used to improve wakefulness in adults with excessive sleepiness associated with obstructive sleep apnea (OSA).1 Armodafinil is used for treatment of excessive sleepiness, but not for treatment of underlying obstruction.1 If continuous positive airway pressure (CPAP) is considered the treatment of choice for a patient with OSA, every effort should be made to optimize CPAP therapy for an adequate period of time prior to initiating armodafinil therapy.1

Clinical Experience

Efficacy of armodafinil as adjunctive therapy for reducing excessive sleepiness in patients with OSA was principally established in 2 similarly designed multicenter, placebo-controlled, double-blind, parallel-group studies of 12 weeks' duration.1,2,3,4,7,8 Both studies enrolled outpatients with a diagnosis of OSA according to criteria established by the International Classification of Sleep Disorders (ICSD), which also are consistent with DSM-IV criteria.1,2,3,4,7,8 These criteria include either excessive sleepiness or insomnia with frequent episodes of impaired breathing during sleep and associated features (e.g., loud snoring, morning headaches, dry mouth upon awakening) or excessive sleepiness or insomnia with polysomnography demonstrating one or more of the following: more than 5 obstructive apneic episodes (each greater than 10 seconds in duration) per hour of sleep, frequent arousals from sleep associated with the apneic episodes, bradytachycardia, or arterial oxygen desaturation in association with the apneic episodes.1 In addition, all patients had moderate to severe illness as indicated by a Clinical Global Impression of Severity of Illness (CGI-S) score of at least 4 and excessive sleepiness despite regular use of CPAP (based on a score of 10 or higher on the Epworth Sleepiness Scale [ESS]).1,2,3,4,8 Compliance with CPAP therapy, defined as CPAP use for 4 hours or more per night on at least 70% of the nights, was required and monitored throughout the studies.1,2,3,4,7

In the first study, 395 patients were randomized to receive armodafinil 150 mg daily, armodafinil 250 mg daily, or placebo; in the second study, 263 patients were randomized to receive armodafinil 150 mg daily or placebo.1,2,3,7 Efficacy of armodafinil was principally evaluated by the sleep latency on the Maintenance of Wakefulness Test (MWT), an objective measure of the ability to remain awake for a defined period of time, and by the Clinical Global Impression of Change (CGI-C) Scale, an investigator-rated assessment of the patient's overall disease status.1,2,3,4,7 In both studies, armodafinil (at the 2 dosages studied) was found to be more effective than placebo in improving daytime wakefulness.1,2,3,4,7,8 In addition, a substantially greater proportion of armodafinil-treated patients (71-74%) showed improvement in overall clinical status compared with those receiving placebo (37-53%) as indicated by CGI-C scores.1,2,3,7,8 Both the 150- and 250-mg daily dosages of armodafinil produced similar clinical efficacy.1,2 Nighttime sleep as measured by polysomnography was not affected by use of armodafinil in either of these studies.1,2,3 However, there was a slight trend toward decreased CPAP use over time with armodafinil (mean reductions of 18 minutes in patients receiving armodafinil and 6 minutes in those receiving placebo).1,2,3,4

Findings from a flexible-dose, open-label, extension study in patients treated with armodafinil for excessive sleepiness associated with CPAP-treated OSA indicate that therapy for 12 months or longer is associated with sustained improvement in wakefulness in patients with this condition.24 At the final visit, 65% of patients with treated OSA were rated as ”much” or “very much” improved, based on CGI-C scores.24

Clinical Perspective

Guidelines from the American Academy of Sleep Medicine (AASM) recommend the use of positive airway pressure (PAP) as a first-line therapy in patients with excessive sleepiness associated with OSA.52 Additional recommendations include weight reduction and positional therapy to alleviate airway obstruction.53 Oral appliances and surgical treatment also may be considered in selected patients.53 Modafinil is recommended for OSA patients with residual excessive daytime sleepiness despite effective PAP treatment and no other identifiable cause for sleepiness.53 Armodafinil was not yet approved at the time the AASM guideline was published; thus, its place in therapy is not addressed.53

Narcolepsy

Armodafinil is used to improve wakefulness in adults with excessive sleepiness associated with narcolepsy.1

Clinical Experience

Efficacy of armodafinil in reducing excessive sleepiness associated with narcolepsy was established in a 12-week, double-blind, multicenter, placebo-controlled, parallel-group study in 196 adult outpatients who met the ICSD criteria for narcolepsy.1,5,7,8,19 Such criteria include either recurrent daytime naps or lapses into sleep that occur almost daily for at least 3 months, with sudden bilateral loss of postural muscle tone associated with intense emotion (cataplexy), or a complaint of excessive sleepiness or sudden muscle weakness with sleep paralysis, hypnagogic hallucinations, automatic behaviors, disrupted major sleep episode, and polysomnography demonstrating one of the following: sleep latency of less than 10 minutes or a REM sleep latency of less than 20 minutes and a mean sleep latency of less than 5 minutes on the Multiple Sleep Latency Test (MSLT) and 2 or more sleep onset REM periods; no other medical or mental disorders can account for these symptoms.1 Enrolled patients also were required to have a mean sleep latency of 6 minutes or less on the MSLT and a CGI-S score of at least 4 (moderately ill); the majority of patients enrolled in the study had marked or severe excessive daytime sleepiness.1,5,8 In this study, patients were randomized to receive armodafinil 150 mg, armodafinil 250 mg, or placebo once daily for 12 weeks.1,5,7 Both dosages of armodafinil were associated with substantially greater improvements in daytime wakefulness relative to placebo as measured by the MWT.1,5,7,8 In addition, the proportion of patients with at least minimal improvement in overall disease status (measured by the CGI-C Scale) was substantially greater for those who received armodafinil versus placebo at all time points in the study; about 71% of patients in the combined armodafinil treatment groups (150- and 250-mg daily groups) were rated as having an overall clinical improvement compared with 33% of those in the placebo group.1,5,7,8 Both dosages of armodafinil produced similar effects on the CGI-C outcome, but a greater magnitude of effect was seen on the MWT variable with the higher (250-mg daily) dosage.1,5 Both armodafinil dosages were also associated with significant improvements in memory, attention, and fatigue.5 Nighttime sleep as measured by polysomnography was not adversely affected by use of armodafinil in this study.1,5

Findings from a flexible-dose, open-label, extension study enrolling 156 patients treated with armodafinil for excessive sleepiness associated with narcolepsy indicate that therapy for 12 months or longer is associated with sustained improvement in wakefulness in patients with this condition.24 At the final visit, 62% of patients with narcolepsy were rated as ”much” or “very much” improved, based on CGI-C scores.24

Clinical Perspective

Narcolepsy is a CNS disorder characterized by somnolence, often accompanied by sudden attacks of muscle weakness (cataplexy) while awake and disturbed nocturnal sleep, and occasionally accompanied by hypnagogic hallucinations and/or sleep paralysis before falling asleep or upon awakening.54,55,56 Cataplexy occurs in about 60-75% of patients with narcolepsy and may be precipitated by laughter or other emotions such as anger, surprise, or excitement.54 The excessive sleepiness of narcolepsy consists of both a background feeling of sleepiness that is present much of the time and a strong, sometimes irresistible, urge to sleep at recurring intervals throughout the day.56

The American Academy of Sleep Medicine (AASM) provides a strong recommendation for the use of several agents including modafinil, pitolisant, sodium oxybate, and solriamfetol for the treatment of adults with narcolepsy (versus no treatment).57 A conditional recommendation is given for armodafinil, dextroamphetamine, and methylphenidate.57

Shift Work Disorder

Armodafinil is used in the symptomatic treatment of shift work disorder (SWD) to improve wakefulness in adults with excessive sleepiness.1

Clinical Experience

Efficacy of armodafinil in reducing excessive sleepiness associated with SWD was demonstrated in a 12-week, multicenter, double-blind, placebo-controlled, parallel-group study in 254 adults with chronic SWD (who met the ICSD criteria, which are consistent with DSM-IV criteria for circadian rhythm sleep disorder: shift work type).1,6,7,8 Such criteria require a primary complaint of excessive sleepiness or insomnia that is temporally associated with a work period (usually night work) that occurs during the habitual sleep phase or loss of a normal sleep-wake pattern (i.e., disturbed chronobiological rhythmicity) as demonstrated on polysomnography and the MSLT and that the manifestations are not accounted for by another medical or mental disorder and do not meet criteria for any other sleep disorder that produces insomnia or excessive sleepiness (e.g., time zone change [jet lag] syndrome).1 Not all patients engaged in shift work who complain of sleepiness meet the criteria for the diagnosis of SWD; only patients who were symptomatic for at least 3 months were enrolled in this study.1 Patients enrolled in this study were also required to work a minimum of 5 night shifts per month, have excessive sleepiness at the time of their night shifts (MSLT score of 6 minutes or less), and have daytime insomnia documented by a daytime polysomnogram.1,6,8 Patients who were treated with armodafinil (150 mg daily before each work shift) demonstrated a significant prolongation of the time to sleep onset (as measured by the nighttime MSLT at the final visit) compared with those receiving placebo (mean sleep latency increased by 3 versus 0.4 minutes, respectively).1,6,7,8 In addition, a substantially greater proportion of armodafinil-treated patients showed an improvement in overall clinical status as measured by CGI-C scores compared with those who received placebo.1,6,8 Despite these improvements, a proportion of patients who received active treatment in this study continued to have residual sleepiness, suggesting that armodafinil 150 mg daily may not be equally effective in all patients with SWD.6 Use of armodafinil did not adversely affect daytime sleep variables (e.g., sleep latency, sleep duration, sleep-stage distribution) as measured by polysomnography in this study.1,6

Findings from a flexible-dose, open-label, extension study enrolling 113 patients treated with armodafinil for excessive sleepiness associated with SWD indicate that therapy for 12 months or longer is associated with sustained improvement in wakefulness in patients with this condition.24 At the final visit, 88% of patients with SWD were rated as ”much” or “very much” improved, based on CGI-C scores.24

Clinical Perspective

Shift work disorder is defined as insomnia or excessive sleepiness during times of wakefulness, with a reduction in total sleep time associated with a work schedule that overlaps with normal sleep hours.58 This disturbance in the normal sleep/wake cycle can result in impairment of normal functioning and an increase in adverse medical consequences.58

Guidelines from the American Academy of Sleep Medicine (AASM) on circadian rhythm sleep disorders recommend planned sleep schedules as standard therapy for SWD.59 The following additional treatment strategies are recommended: timed light exposure, timed melatonin administration, hypnotics, and alerting agents (i.e., modafinil).59 Stimulants (i.e., caffeine) are recommended as an option.59

General

Patient Monitoring

• Increased monitoring of blood pressure and heart rate may be appropriate during armodafinil therapy.1

Administration

Armodafinil is administered orally.1 In patients with obstructive sleep apnea (OSA) or narcolepsy, armodafinil usually is administered once daily in the morning.1 In patients with shift work disorder (SWD), armodafinil should be taken approximately 1 hour prior to the start of their work shift.1

The manufacturer makes no specific recommendations regarding administration of armodafinil with regard to meals.1

Store armodafinil tablets at 20-25°C.1

Dosage

Obstructive Sleep Apnea (OSA)

The usual recommended dosage of armodafinil to improve wakefulness in adults with excessive sleepiness associated with OSA is 150 or 250 mg orally, once daily in the morning.1 Although dosages up to 250 mg daily, have been well tolerated in patients with OSA, there is no consistent evidence indicating that this dosage provides additional clinical benefit beyond that provided by the 150-mg daily dosage.1

Narcolepsy

The usual recommended dosage of armodafinil to improve wakefulness in adults with excessive sleepiness associated with narcolepsy is 150 or 250 mg orally once daily in the morning.1

Shift Work Disorder

The usual recommended dosage of armodafinil to improve wakefulness in adults with SWD is 150 mg once daily, taken as a single dose approximately 1 hour prior to the start of the work shift.1

Special Populations

Hepatic Impairment

Dosage of armodafinil should be reduced in patients with severe hepatic impairment.1 The manufacturer makes no specific dosage recommendations in patients with mild or moderate hepatic impairment.1

Renal Impairment

The manufacturer makes no specific dosage recommendations in patients with renal impairment.1

Geriatric Patients

Because elimination of armodafinil and its metabolites may be reduced with age in geriatric patients, consideration should be given to using dosages lower than the usual recommended dosages and closely monitoring in this age group.1

Contraindications

• Known hypersensitivity to armodafinil, modafinil, or any ingredient in the formulation.1

Warnings/Precautions

Serious Dermatologic Reactions

Serious rash (including Stevens-Johnson syndrome [SJS]) requiring hospitalization and drug discontinuance has been reported in patients receiving armodafinil and modafinil.1 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 pediatric patients during worldwide postmarketing experience with modafinil and armodafinil.1 Skin and mouth sores, blistering, and ulceration have also been reported during the postmarketing period with armodafinil and modafinil.1 Following drug rechallenge, cases of recurrent signs and symptoms of serious dermatologic conditions have been reported.1 Severe rashes, including 1 case of possible SJS and 1 case of multi-organ hypersensitivity reaction/DRESS also were observed in modafinil clinical trials in pediatric patients younger than 17 years of a several of these cases were associated with fever and other abnormalities (e.g., vomiting, leukopenia).1 Rashes that resulted in the discontinuation of modafinil occurred after a median of 13 days.1 Armodafinil is not FDA-labeled for use in pediatric patients for any indication.1

No risk factors are known to predict the occurrence or severity of rash associated with armodafinil or modafinil.1 Nearly all the cases of serious rash occurred within 1 day to 2 months following initiation of therapy with either drug; however, isolated cases have presented after prolonged treatment (e.g., 3 months).1 Accordingly, duration of therapy cannot be used to predict the potential risk associated with the first appearance of a rash.1 Although benign rashes also occur with armodafinil, it is not possible to predict which rashes will become serious; therefore, the drug should ordinarily be discontinued at the first sign of a rash unless the rash is clearly not drug related.1 However, treatment discontinuance may not prevent a rash from becoming life-threatening or permanently disabling or disfiguring.1

DRESS/Multiorgan Hypersensitivity

Multiorgan hypersensitivity reactions, also known as DRESS, including at least 1 fatality during postmarketing experience, have been reported.1 The DRESS fatality occurred within 3 weeks following the initiation of armodafinil.1 Additionally, multiorgan hypersensitivity reactions, including at least 1 fatality that occurred in the postmarketing setting, occurred in close temporal association (median time to detection: 13 days; range: 4-33 days) with initiation of modafinil therapy.1 Although there have been only a limited number of cases reported to date, such reactions may result in hospitalization or be life-threatening.1 Although the clinical presentation of such reactions is variable, patients typically presented with fever, rash, lymphadenopathy, and/or facial swelling; these symptoms often occur in association with involvement of other organ systems (e.g., hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection).1 Eosinophilia is also common.1 Early manifestations of hypersensitivity reactions (e.g., fever, lymphadenopathy) can present without an evident rash.1

If a multiorgan hypersensitivity reaction is suspected, armodafinil should be discontinued.1 Although there are no reports of cross-sensitivity with other drugs that produce this syndrome, the potential for cross-sensitivity exists.1

Angioedema and Anaphylaxis Reactions

Angioedema and hypersensitivity (with rash, dysphagia, and bronchospasm) were reported in clinical studies of armodafinil.1 Patients should be advised to discontinue therapy and immediately report to their clinician any signs or symptoms suggestive of angioedema or anaphylaxis (e.g., swelling of face, eyes, lips, tongue, or larynx; difficulty swallowing or breathing; hoarseness).1

Persistent Sleepiness

Patients who have abnormal levels of sleepiness and are receiving armodafinil should be advised that the drug will not eliminate this abnormal tendency to fall asleep.1 Levels of wakefulness may not return to normal.1

All patients with excessive sleepiness, including those receiving armodafinil, should be frequently reassessed for their degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity.1 Clinicians should be aware that patients may not acknowledge sleepiness or drowsiness until directly questioned about these symptoms during specific activities.1

Psychiatric Symptoms

Adverse psychiatric effects have been reported in patients receiving modafinil.1 Because modafinil and armodafinil are closely related, the incidence and type of psychiatric effects are expected to be similar.1 Postmarketing adverse psychiatric effects associated with modafinil include mania, delusions, hallucinations, suicidal ideation, and aggression and have resulted in hospitalization in some cases.1 Many, but not all, of the patients had a prior psychiatric history.1 Reported dosages in these cases ranged from 50-450 mg daily.1 In the controlled clinical trial database for armodafinil, psychiatric symptoms requiring treatment discontinuance more often in armodafinil-treated patients than in placebo recipients included anxiety, agitation, nervousness, and irritability.1 Depression also required treatment discontinuance in controlled clinical trials more often in armodafinil-treated patients compared with those receiving placebo; cases of suicidal ideation were observed in these trials.1

The manufacturer states that armodafinil should be used with caution in patients with a history of psychosis, depression, or mania.1 If psychiatric symptoms develop in patients receiving armodafinil, discontinuance of the drug should be considered.1

Effects on Ability to Drive and Use Machinery

Although armodafinil has not been shown to cause functional impairment, the possibility that the drug, like any other drug affecting the CNS, may alter judgment, thinking, or motor skills should be considered.1 Patients should be cautioned about operating an automobile or other hazardous machinery until they are reasonably certain that armodafinil will not adversely affect their ability to engage in such activities.1

Cardiovascular Events

In clinical studies with modafinil, a few patients have experienced adverse cardiovascular effects such as chest pain, palpitations, dyspnea, and transient ischemic T-wave changes in association with mitral valve prolapse or left ventricular hypertrophy.1 The manufacturer recommends that armodafinil not be used in patients with a history of left ventricular hypertrophy or in patients with mitral valve prolapse who have experienced the mitral valve prolapse syndrome with previous use of CNS stimulants.1 Clinical manifestations of mitral valve prolapse syndrome include, but are not limited to, ischemic ECG changes, chest pain, or arrhythmia.1 If new onset of any of these symptoms occurs during armodafinil therapy, a cardiac evaluation should be considered.1

In short-term (i.e., 3 months or less) clinical studies, small average increases in mean systolic and diastolic blood pressure were observed in patients receiving armodafinil compared with placebo.1 In these studies, new or increased use of antihypertensive agents was observed in a slightly greater proportion of patients receiving armodafinil (2.9%) compared with those receiving placebo (1.8%).1 Small, but consistent increases in heart rate were also observed more frequently in patients receiving armodafinil compared to placebo, and ranged from 0.9-3.5 beats/minute.1 The manufacturer states that increased monitoring of blood pressure and heart rate may be appropriate during armodafinil therapy.1 Exert caution when armodafinil is prescribed in patients with preexisting cardiovascular conditions.1

Drug Abuse and Dependence

Abuse and drug diversion in patients receiving armodafinil have been reported, with patterns of abuse involving euphoric mood and the recurrent use of armodafinil or the use of increasingly large doses of drug to achieve desired effects.1 Misuse of the drug (e.g., taking against prescriber's recommendation, or obtaining prescription from multiple prescriber's) has been reported with postmarketing experience.1 Modafinil produces psychoactive and euphoric effects and alterations in mood, perception, thinking, and feelings similar to those observed with other CNS stimulants (e.g., amphetamines, methylphenidate).1 Evidence indicates that the abuse potential of modafinil is consistent with other scheduled CNS stimulants such as methylphenidate.1

Abuse of armodafinil may result in overdosage signs and symptoms like that observed with modafinil, which include tachycardia, insomnia, agitation, dizziness, anxiety, nausea, headache, dystonia, tremor, chest pain, hypertension, seizures, delirium, and hallucinations.1 Signs and symptoms of CNS stimulant abuse may also include tachypnea, diaphoresis, dilated pupils, hyperactivity, restlessness, decreased appetite, loss of coordination, skin flushing, vomiting, and abdominal pain.1

Physical dependence, a state of physiological adaptation from repeated drug use manifested by signs and symptoms of withdrawal after abrupt cessation or significant dose reduction, can occur in patients receiving armodafinil.1 Tolerance, or the physiological state of a reduced response to a drug with repeated administration, has been reported with armodafinil in the postmarketing period.1 With chronic use, the abrupt cessation or dosage reduction of armodafinil may result in withdrawal symptoms, which can include shaking, sweating, chills, nausea, vomiting, confusion, aggression, or atrial fibrillation.1 Abrupt cessation of armodafinil has caused deterioration of psychiatric symptoms such as depression.1 In the postmarketing period, drug withdrawal convulsions, suicidality, fatigue, insomnia, aches, depression, and headache have also occurred.1

The manufacturer states that patients should be closely followed during armodafinil therapy for possible signs of misuse or abuse (e.g., incrementation of doses, drug-seeking behavior), particularly in those with a history of drug or stimulant abuse (e.g., amphetamine, cocaine, methylphenidate).1

Specific Populations

Pregnancy

A pregnancy registry is available that monitors pregnancy outcomes in women exposed to armodafinil during pregnancy.1 Clinicians are encouraged to register patients, or pregnant patients can register themselves, by calling 1-866-404-4106.1

Limited data are available to assess the drug-associated risk of adverse developmental outcomes with armodafinil use during pregnancy; however, armodafinil and modafinil have been associated with intrauterine growth restriction and spontaneous abortion.1 Animal reproductive studies with armodafinil and modafinil in rats and rabbits during the period of organogenesis showed evidence of developmental toxicity (increased embryofetal and offspring mortality, decreased fetal growth) at clinically relevant plasma concentrations.1

Lactation

It is not known whether armodafinil or its metabolites are distributed into human milk, although modafinil has been detected in the milk of lactating rats.1 The effects of armodafinil or its metabolites on milk production and on the breast-fed infant are not known.1 Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for the drug and the potential for adverse effects on the breast-fed infant from armodafinil and from the underlying maternal condition.1

Females and Males of Reproductive Potential

Fertility studies have not been conducted with armodafinil.1 Oral modafinil dosages of up to 480 mg/kg/day administered to female and male rats during the mating period and continued through 7 days of gestation in females resulted in an increased time to mating at the highest dose.1 No other effects on fertility or reproduction were observed.1

Efficacy of hormonal contraceptives may be reduced during and for 1 month after discontinuance of armodafinil therapy.1 Women using hormonal contraceptives should be advised to use an additional barrier method or concomitant non-hormonal method of contraception while on the drug and for 1 month following its discontinuation.1

Pediatric Use

Safety and effectiveness of armodafinil have not been established in pediatric patients.1 Serious rash has occurred in pediatric patients taking modafinil.1

Geriatric Use

Elimination of armodafinil and its metabolites may be reduced in geriatric patients.1 In a clinical study with armodafinil, systemic exposure was increased by 15% in geriatric patients ≥65 years of age, corresponding to a 12% lower oral clearance, when compared to younger adults 18-45 years of age.1 Peak plasma concentrations and total exposure of the metabolite (armodafinil acid), was increased approximately 61% and 73%, respectively, compared to younger patients; however, exposure of the sulfone metabolite was approximately 20% lower.1 Systemic exposure of armodafinil was increased by approximately 10% and 27% in patients 65-74 years of age and ≥75 years of age, respectively, compared to younger patients.1 The manufacturer states that this difference is not likely clinically significant, but since there is increased armodafinil exposure in some geriatric patients, the use of lower dosages and close monitoring should be considered.1

Hepatic Impairment

Information specific to armodafinil use in patients with hepatic impairment is not available.1 In patients with severe hepatic impairment and cirrhosis (Child-Pugh class B, B+, C, or C+) receiving modafinil, clearance of the drug was decreased by 60% and steady-state concentrations were doubled.1 Reduced dosages of armodafinil are therefore recommended in patients with severe hepatic impairment.1

Renal Impairment

Information specific to armodafinil use in patients with renal impairment is not available.1 In a single-dose study with racemic modafinil, severe chronic renal impairment (creatinine clearance of ≤20 mL/minute) did not substantially affect the pharmacokinetics of modafinil, but increased exposure to modafinil acid (a metabolite of the drug) by ninefold.1

Common Adverse Effects

Adverse effects reported in ≥5% of patients receiving armodafinil in clinical trials and more frequently than with placebo include headache, nausea, dizziness, and insomnia.1

In vitro and in vivo data have shown that armodafinil is primarily metabolized via amide hydrolysis, and to a lesser extent by cytochrome P-450 (CYP) isoenzymes 3A4/5.1 In vitro studies indicate that armodafinil is a weak inducer of CYP1A2 and possibly CYP3A, and a reversible inhibitor of CYP2C19.1 Other CYP activities do not appear to be affected by armodafinil.1 In vitro studies have also shown that armodafinil is a substrate of the efflux transporter P-glycoprotein, although the impact of this inhibition is not known.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Strong inducers (e.g., carbamazepine, phenobarbital, rifampin) or inhibitors (e.g., erythromycin, ketoconazole) of cytochrome P-450 (CYP) 3A isoenzymes can potentially alter plasma concentrations of armodafinil because of partial involvement of these enzymes in the drug's metabolism.1

In clinical interaction studies in healthy individuals, chronic administration of armodafinil moderately induced the activity of CYP3A4; therefore, dosage adjustments of CYP3A4/5 substrates (e.g., cyclosporine, midazolam, steroidal contraceptives, triazolam) may be necessary when such drugs are used concomitantly with armodafinil.1

Because armodafinil was shown in healthy individuals to moderately inhibit CYP2C19 activity, reduced dosages of some drugs that are CYP2C19 substrates (e.g., clomipramine, diazepam, phenytoin, propranolol, omeprazole) may be necessary when such drugs are administered concomitantly with armodafinil.1

Caffeine

In a clinical study, armodafinil administration did not affect the pharmacokinetics of caffeine, which is a probe substrate for CYP1A2 activity.1

Cyclosporine

Blood concentrations of cyclosporine (a CYP3A4/5 substrate) may be reduced when cyclosporine is given concomitantly with armodafinil, which may reduce the effectiveness of the immunosuppressive agent.1 Monitoring of cyclosporine concentrations and appropriate cyclosporine dosage adjustments should be considered when these drugs are used concomitantly.1

Hormonal Contraceptives

The possibility of decreased plasma concentrations of ethinyl estradiol secondary to induction of CYP3A4 by armodafinil resulting in decreased efficacy of hormonal contraceptives and possible contraceptive failure should be considered.1 Women using hormonal contraceptives should be advised to use an additional barrier method or concomitant non-hormonal method of contraception during and for 1 month following discontinuance of armodafinil therapy.1

Midazolam

Following administration of single oral (5 mg) and IV (2 mg) doses of midazolam in healthy individuals receiving armodafinil 250 mg daily, systemic exposure to midazolam was reduced by approximately 32 and 17%, respectively.1 Dosage adjustment of midazolam may be necessary when used concomitantly with armodafinil.1

Omeprazole

Concomitant administration of a single oral dose of armodafinil (400 mg) and omeprazole (40 mg), a CYP2C19 substrate, increased systemic exposure to omeprazole by approximately 40% compared with administration of omeprazole alone.1 Dosage reduction of omeprazole and other CYP2C19 substrates may be necessary when these drugs are used concomitantly.1

Quetiapine

Concomitant administration of armodafinil (250 mg) and quetiapine (300-600 mg daily), a CYP3A4/5 substrate, reduced systemic exposure to quetiapine by approximately 29%; however, the manufacturer states that no dosage adjustment of quetiapine is necessary.1

Protein-bound Drugs

Because armodafinil is not highly bound to plasma proteins, a pharmacokinetic interaction with drugs that are highly protein bound is considered unlikely.1

Other CNS-active Drugs

Specific drug interaction studies have not been conducted with armodafinil and many CNS-active drugs; however, the manufacturer states that available drug interaction information with modafinil should also apply to armodafinil.1

Clomipramine

Concomitant administration of modafinil and clomipramine did not produce a clinically important pharmacokinetic interaction with either drug.1 However, 1 incident of increased levels of clomipramine and desmethylclomipramine (the active metabolite of clomipramine) occurred in a patient with narcolepsy who was treated with both agents.1

Because armodafinil appears to moderately inhibit CYP2C19 activity, the manufacturer states that a reduced dosage of clomipramine, a CYP2C19 substrate, may be necessary when clomipramine is administered concomitantly with armodafinil.1

Dextroamphetamine

Concomitant administration of modafinil with dextroamphetamine did not produce a clinically important pharmacokinetic interaction with either drug.1 However, the absorption of modafinil was delayed by approximately 1 hour when these drugs were given concurrently in this study.1

Methylphenidate

Concomitant administration of modafinil and methylphenidate did not significantly alter the pharmacokinetics of either drug.1 GI absorption of modafinil was delayed by approximately 1 hour.1

Monoamine Oxidase Inhibitors

Because drug interaction studies have not been performed with monoamine oxidase (MAO) inhibitors and either armodafinil or modafinil, caution is advised when these drugs are administered concomitantly.1

Warfarin

In a study performed in healthy individuals, chronic administration of racemic modafinil did not substantially alter the single-dose pharmacokinetics of warfarin when compared with placebo.1 However, a potential pharmacodynamic interaction cannot be ruled out with multiple-dose administration.1 Pending further evaluation of this potential interaction, more frequent monitoring of prothrombin time and/or international normalized ratio (INR) is recommended whenever armodafinil and warfarin are given concurrently.1

Description

Armodafinil is a non-amphetamine wakefulness-promoting agent.1,2,3,4,5,6,7,8,10,11,12,13,26 The drug is the R -enantiomer of modafinil, which is a racemic compound containing equal amounts of the R - and S - isomers.1,2,3,4,5,6,7,8,10,11,12,13,26 Both armodafinil and modafinil are benzhydrylsulfinylacetamides.8 Armodafinil is the longer-lasting R -isomer of modafinil, having a half-life approximately 3-4 times longer than that of S -modafinil.1,2,3,4,5,6,7,8,10,11,12,13 In vitro and animal studies have shown that armodafinil and modafinil have similar pharmacologic actions.1

The exact mechanism by which armodafinil and modafinil promote wakefulness is not known, but may involve activation of certain arousal centers of the brain (e.g., hypothalamus, prefrontal cortex, anterior cingulate cortex).1,7,8,26 Armodafinil and modafinil have wake-promoting effects similar to sympathomimetic agents (e.g., amphetamine, methylphenidate); however, their pharmacologic profile is not identical to such agents.1 Additionally, modafinil produces effects commonly described with other CNS stimulants in humans, including psychoactive and euphoric effects and alterations in mood, perception, thinking, and feelings.1 Armodafinil is an indirect dopamine receptor agonist, and has been shown in in vitro studies to bind to the dopamine transporter and inhibit dopamine reuptake.1,7 Such inhibitory effects have been associated with increased extracellular dopamine concentrations in animal models.1,7 The stimulant effects of modafinil can be attenuated by the α₁-adrenergic receptor antagonist prazosin, but modafinil is inactive in other assay systems known to be responsive to α₁-adrenergic receptor agonists.1,7

The active component of Nuvigil^® is armodafinil, which is the longer-acting enantiomer (R-enantiomer) of modafinil.1 Armodafinil is readily absorbed following oral administration, with peak plasma concentrations occurring at approximately 2 hours in the fasted state.1 The effect of food on the overall bioavailability of armodafinil appears minimal, but time to achieve peak concentrations may be delayed by approximately 2-4 hours in the fed state.1 Armodafinil exhibits linear pharmacokinetics following administration of single or multiple oral doses of the drug over the dosage range of 50-400 mg.1 Steady-state plasma concentrations of armodafinil are achieved within 7 days of daily administration, and the mean elimination half-life of the drug is approximately 15 hours.1 Peak plasma concentrations and total exposure of armodafinil at steady state are approximately 37% and 70% higher, respectively, following 200 mg of armodafinil compared to 200 mg of modafinil, which is due to the more rapid clearance of the S-enantiomer compared to the R-enantiomer.1 Although the plasma protein binding of armodafinil is not known, modafinil is 60% bound to plasma proteins, predominantly albumin.1 Interactions with highly-protein bound drugs are expected to be minimal.1 Armodafinil undergoes hydrolytic deamidation, S-oxidation, and aromatic ring hydroxylation, with subsequent glucuronide conjugation of the hydroxylated products.1 The 2 principal metabolites ( R -modafinil acid and modafinil sulfone) of armodafinil or modafinil do not appear to contribute to the CNS-activating properties of the parent compounds.1 Although the metabolic fate of armodafinil has not been specifically studied, racemic modafinil is mainly eliminated via metabolism, predominantly in the liver, with 80% of the drug excreted in urine and 1% in feces, mainly as metabolites.1 Pharmacokinetic analyses indicate gender has no impact on armodafinil pharmacokinetics.1 It is not known whether race/ethnicity affects the pharmacokinetics of armodafinil.1

Advice to Patients

• Advise patients to read the patient information leaflet provided by the manufacturer prior to initiating therapy.1
• Advise patients to inform their clinician of existing or contemplated therapy, including prescription and OTC drugs and/or herbal supplements, as well as any concomitant illnesses.1 Advise patients that it is prudent to avoid alcohol while taking armodafinil since combined use has not been studied.1
• Advise patients about the potential increased risk of pregnancy in women taking hormonal contraceptives (including injectable or implantable contraceptives) during and for 1 month after discontinuing armodafinil therapy.1 Advise women to use an additional barrier method or concomitant non-hormonal method of contraception during these periods.1
• Advise patients to inform their clinician if they plan to become pregnant or plan to breast-feed.1 Inform women who become pregnant while receiving armodafinil that a registry is available that monitors pregnancy outcomes.1 Patients or prescribers can enroll by calling 1-866-404-4106.1
• Inform patients of the risk of potentially fatal skin reactions.1 Advise patients to immediately discontinue armodafinil and notify their clinician if they develop a skin reaction such as a rash, mouth sores, blisters, or peeling skin during treatment.1
• Inform patients that a fever associated with other signs of organ system involvement (e.g., rash, lymphadenopathy, liver dysfunction) could be associated with armodafinil and to notify clinicians immediately.1
• Inform patients of the risk of severe allergic reactions (e.g., hives, difficulty breathing or swallowing, hoarseness, swelling of the face, eyes, lips or tongue) that can occur.1 Instruct patients to discontinue armodafinil and immediately report symptoms to a clinician.1
• Risk of psychiatric symptoms.1 Stress importance of discontinuing armodafinil and informing clinician if depression, anxiety, hallucinations, mania, suicidal thoughts, aggression, or other psychiatric symptoms associated with psychosis or mania occur.1
• Advise patients that armodafinil may improve, but not eliminate, the abnormal tendency to fall asleep.1 Advise against altering previous behavior with regard to potentially dangerous activities (e.g., driving, operating machinery) or other activities requiring appropriate levels of wakefulness until and unless armodafinil has been shown to produce levels of wakefulness that permit such activities.1 Advise patients that armodafinil is not a replacement for sleep.1
• Stress importance of continuing previously prescribed therapy (e.g., advising patients with OSA that armodafinil is used along with other medical therapies for this condition and that the drug is not a replacement for the continuous positive airway pressure [CPAP] machine).1 Advise patients with OSA to continue using their CPAP machine while sleeping.1
• Inform patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Cephalon, Inc. Nuvigil^® (armodafinil) tablets prescribing information. Parsippany, NJ; 2022 Dec.

2. Roth T, White D, Schmidt-Nowara W et al. Effects of armodafinil in the treatment of residual excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome: a 12-week, multicenter, double-blind, randomized, placebo-controlled study in nCPAP-adherent adults. Clin Ther . 2006; 28:689-706. [PubMed 16861091]

3. Hirshkowitz M, Black JE, Wesnes K et al. Adjunct armodafinil improves wakefulness and memory in obstructive sleep apnea/hypopnea syndrome. Respir Med . 2007; 101:616-27. [PubMed 16908126]

4. Roth T, Rippon GA, Arora S. Armodafinil improves wakefulness and long-term episodic memory in nCPAP-adherent patients with excessive sleepiness associated with obstructive sleep apnea. Sleep Breath . 2008; 12:53-62. [PubMed 17874255]

5. Harsh JR, Hayduk R, Rosenberg R et al. The efficacy and safety of armodafinil as treatment for adults with excessive sleepiness associated with narcolepsy. Curr Med Res Opin . 2006; 22:761-74. [PubMed 16684437]

6. Czeisler CA, Walsh JK, Wesnes KA et al. Armodafinil for treatment of excessive sleepiness associated with shift work disorder: a randomized controlled study. Mayo Clin Proc . 2009; 84:958-72. [PubMed 19880686]

7. Lankford DA. Armodafinil: a new treatment for excessive sleepiness. Expert Opin Investig Drugs . 2008; 17:565-73. [PubMed 18363520]

8. Garnock-Jones KP, Dhillon S, Scott LJ. Armodafinil. CNS Drugs . 2009; 23:793-803. [PubMed 19689169]

10. Dinges DF, Arora S, Darwish M et al. Pharmacodynamic effects on alertness of single doses of armodafinil in healthy subjects during a nocturnal period of acute sleep loss. Curr Med Res Opin . 2006; 22:159-67. [PubMed 16393442]

11. Darwish M, Kirby M, Hellriegel ET et al. Armodafinil and modafinil have substantially different pharmacokinetic profiles despite having the same terminal half-lives: analysis of data from three randomized, single-dose, pharmacokinetic studies. Clin Drug Investig . 2009; 29:613-23. [PubMed 19663523]

12. Darwish M, Kirby M, Hellriegel ET. Comparison of steady-state plasma concentrations of armodafinil and modafinil late in the day following morning administration: post hoc analysis of two randomized, double-blind, placebo-controlled, multiple-dose studies in healthy male subjects. Clin Drug Investig . 2009; 29:601-12. [PubMed 19663522]

13. Darwish M, Kirby M, Hellriegel ET et al. Pharmacokinetic profile of armodafinil in healthy subjects: pooled analysis of data from three randomized studies. Clin Drug Investig . 2009; 29:87-100. [PubMed 19133704]

19. Wise MS, Arand DL, Auger RR et al. Treatment of narcolepsy and other hypersomnias of central origin. Sleep . 2007; 30:1712-27. [PubMed 18246981]

24. Black JE, Hull SG, Tiller J, Yang R, Harsh JR. The long-term tolerability and efficacy of armodafinil in patients with excessive sleepiness associated with treated obstructive sleep apnea, shift work disorder, or narcolepsy: an open-label extension study. J Clin Sleep Med . 2010;6(5):458-466.

26. Anon. Armodafinil (Nuvigil) for wakefulness. Med Lett Drugs Ther . 2010; 52:61-2. [PubMed 20697340]

52. Patil S, Ayappa I, Caples S, et al. Treatment of adult obstructive sleep apnea with positive airway pressure: an American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med . 2019;15(2):335-343.

53. Morgenthaler T, Kapen S, Lee-Chiong T, et al. Practive parameters for the medical therapy of obstructive sleep apnea. SLEEP . 2006;29(8):1031-1035.

54. Anon. Gamma hydroxybutyrate (Xyrem) for narcolepsy. Med Lett Drugs Ther. 2002; 44:103-5

55. The U.S. Xyrem^® Multicenter Study Group. A randomized, double-blind, placebo-controlled multicenter trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy. Sleep . 2002; 25:42-9.

56. Zeman A, Britton T, Douglas N et al. Narcolepsy and excessive daytime sleepiness. BMJ . 2004; 329:724-8

57. Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med . 2021 Sep 1;17(9):1881-1893.

58. Cheng P, Drake C. Shift work disorder. Neurol Clin . 2019;37:563-577.

59. Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. SLEEP . 2007;30(11):1445-1459.