Armodafinil

Class: Wakefulness-promoting Agents
VA Class: CN809
Chemical Name: 2-[(Diphenylmethyl)sulfinyl]acetamide
Molecular Formula: C15H15NO2S
CAS Number: 112111-43-0
Brands: Nuvigil

Introduction

Wakefulness-promoting agent; R-enantiomer of racemic modafinil.1 2 3 4 5 6 7 8 10 11 12 13 14 26 34

Uses for Armodafinil

Obstructive Sleep Apnea/Hypopnea Syndrome (OSAHS)

Symptomatic treatment (in combination with standard treatment[s] for underlying obstruction) of OSAHS to improve wakefulness in adults with excessive sleepiness.1 2 3 4 7 8 24

If continuous positive airway pressure (CPAP) is the treatment of choice for a patient, make every effort to optimize treatment with CPAP for an adequate period of time prior to initiating armodafinil.1 If armodafinil is used adjunctively with CPAP, encourage and periodically assess CPAP compliance.1

Careful attention to diagnosis and treatment of the sleep disorder is essential.1 (See Diagnosis of Sleep Disorders under Cautions.)

Slideshow: Flashback: FDA Drug Approvals 2013

No well-controlled clinical studies directly comparing armodafinil and modafinil in OSAHS.34 Further studies needed to determine whether pharmacokinetic differences (armodafinil’s longer elimination half-life, higher plasma concentrations later in the waking day1 8 10 11 12 14 ) affect armodafinil's clinical efficacy compared with modafinil.12

Narcolepsy

Symptomatic treatment of narcolepsy to improve wakefulness in adults with excessive sleepiness.1 5 7 8 19

Careful attention to diagnosis and treatment of the sleep disorder is essential.1 (See Diagnosis of Sleep Disorders under Cautions.)

No well-controlled clinical studies directly comparing armodafinil and modafinil in narcolepsy.34 Further studies needed to determine whether pharmacokinetic differences (armodafinil’s longer elimination half-life, higher plasma concentrations later in the waking day1 8 10 11 12 14 ) affect armodafinil's clinical efficacy compared with modafinil.12

Shift Work Sleep Disorder (SWSD)

Symptomatic treatment of SWSD to improve wakefulness in adults with excessive sleepiness.1 6 7 8

Careful attention to diagnosis and treatment of the sleep disorder is essential.1 (See Diagnosis of Sleep Disorders under Cautions.)

No well-controlled clinical studies directly comparing armodafinil and modafinil in SWSD.34 Further studies needed to determine whether pharmacokinetic differences (armodafinil’s longer elimination half-life, higher plasma concentrations later in the waking day1 8 10 11 12 14 ) affect armodafinil's clinical efficacy compared with modafinil.12

Armodafinil Dosage and Administration

Administration

Oral Administration

Administer orally once daily.1 Manufacturer makes no specific recommendations regarding administration with regard to meals.1 (See Food under Pharmacokinetics.)

In patients with narcolepsy or OSAHS, usually administer as a single dose in the morning.1 In patients with SWSD, administer dose approximately 1 hour prior to start of work shift.1

Dosage

Adults

OSAHS
Oral

150 or 250 mg daily.1

Dosages up to 250 mg daily have been well tolerated, but may not provide additional clinical benefit beyond 150-mg daily dosage.1 2

Long-term efficacy (>12 weeks) not systematically evaluated,1 but use for ≥12 months was associated with sustained improvement in wakefulness in patients with OSAHS in an extension study.24 If clinician elects to prescribe for an extended period, periodically reassess long-term usefulness in the individual patient.1

Narcolepsy
Oral

150 mg or 250 mg daily.1

Long-term efficacy (>12 weeks) not systematically evaluated,1 but use for ≥12 months was associated with sustained improvement in wakefulness in patients with narcolepsy in an extension study.24 If clinician elects to prescribe for an extended period, periodically reassess long-term usefulness in the individual patient.1

SWSD
Oral

150 mg daily.1

Long-term efficacy (>12 weeks) not systematically evaluated,1 but use for ≥12 months was associated with sustained improvement in wakefulness in patients with SWSD in an extension study.24 If clinician elects to prescribe for an extended period, periodically reassess long-term usefulness in the individual patient.1

Special Populations

Hepatic Impairment

Reduce dosage in patients with severe hepatic impairment (with or without cirrhosis).1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Current information inadequate to make specific dosage recommendations in patients with severe renal impairment.1 (See Renal Impairment under Cautions.)

Geriatric Patients

Consider use of lower than usual recommended dosage.1 7 (See Geriatric Use under Cautions.)

Cautions for Armodafinil

Contraindications

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

Warnings/Precautions

Warnings

Serious Dermatologic Reactions

Serious rash (e.g., Stevens-Johnson syndrome [SJS]) requiring hospitalization and drug discontinuance reported in adults receiving armodafinil and in adults and pediatric patients receiving modafinil.1 30

Serious or life-threatening rash (e.g., SJS, toxic epidermal necrolysis [TEN]) and drug rash with eosinophilia and systemic symptoms (DRESS) reported rarely in adults and pediatric patients during postmarketing experience with modafinil.1 30 Severe rash (e.g., possible SJS, multiorgan hypersensitivity reaction), sometimes associated with fever and other abnormalities (e.g., vomiting, leukopenia), also observed in pediatric clinical trials of modafinil.1 30 A similar risk of serious rash in pediatric patients receiving armodafinil cannot be excluded.1 Armodafinil is not approved for use in pediatric patients for any indication.1 (See Pediatric Use under Cautions.)

No known risk factors predict the occurrence or severity of rash.1 30 Nearly all cases occurred within 1–5 weeks following initiation of modafinil or armodafinil therapy, but cases also reported after prolonged (e.g., 3 months) treatment.1 30

Benign rashes also occur with armodafinil; not possible to predict which rashes will become serious.1 Therefore, discontinue drug at first sign of rash unless clearly not drug related.1 (See Advice to Patients.) Rash may become potentially life-threatening or permanently disabling or disfiguring despite drug discontinuance.1

Persistent Sleepiness

In patients with abnormal levels of sleepiness, level of wakefulness may improve with armodafinil therapy, but may not return to normal.1 (See Advice to Patients.)

Frequently reassess degree of sleepiness, and, if appropriate, advise patients to avoid driving or other potentially dangerous activity.1 Patients may not acknowledge sleepiness or drowsiness until directly questioned about these symptoms during specific activities.1 (See Advice to Patients.)

Psychiatric Effects

Adverse psychiatric effects (e.g., mania, delusions, hallucinations, suicidal ideation, aggression), sometimes resulting in hospitalization, reported in modafinil-treated patients;1 7 32 many, but not all, such patients had a psychiatric history.1 7 Incidence and type of psychiatric effects expected to be similar with armodafinil.1 7 32

In controlled clinical trials, psychiatric symptoms requiring treatment discontinuance more often for armodafinil than for placebo include anxiety, agitation, nervousness, irritability, and depression; suicidal ideation also reported.1

Use with caution in patients with a history of psychosis, depression, or mania.1

Some clinicians recommend careful monitoring of patients receiving armodafinil or other CNS stimulants for possible psychiatric effects.32 If psychiatric symptoms develop, consider drug discontinuance.1 (See Advice to Patients.)

Sensitivity Reactions

Angioedema and Anaphylactoid Reactions

Angioedema and hypersensitivity (with rash, dysphagia, and bronchospasm) reported.1

Immediately discontinue therapy if any signs or symptoms of angioedema or anaphylaxis (e.g., swelling of face, eyes, lips, tongue or larynx; difficulty swallowing or breathing; hoarseness) develop.1

Multiorgan Hypersensitivity Reactions

Multiorgan hypersensitivity reactions, including at least 1 fatality, reported with modafinil.1 Similar risk with armodafinil cannot be ruled out.1

Reactions detected a median of 13 days (range: 4–33 days) after initiation of modafinil.1 Clinical presentation is variable but typically included fever and rash associated with other organ system involvement (e.g., myocarditis, hepatitis, liver function test abnormalities, hematological abnormalities [e.g., eosinophilia, leukopenia, thrombocytopenia], pruritus, asthenia).1

No risk factors known to predict occurrence or severity.1

If a multiorgan hypersensitivity reaction is suspected, discontinue therapy.1 Cross-sensitivity with other drugs that produce this syndrome not yet reported but is possible.1

General Precautions

Diagnosis of Sleep Disorders

Use only in patients who have had a complete evaluation (e.g., complete history, physical examination, testing in a laboratory setting [polysomnography]) of excessive sleepiness and in whom a diagnosis of narcolepsy, OSAHS, and/or SWSD has been made in accordance with International Classification of Sleep Disorders (ICSD) or DSM diagnostic criteria.1

Consider that >1 sleep disorder may contribute to daytime sleepiness in some patients (e.g., OSAHS and SWSD concurrently in the same patient).1

Continuous Positive Airway Pressure (CPAP) in OSAHS

In OSAHS, armodafinil is indicated as an adjunct to standard treatment(s) for the underlying obstruction.1 If CPAP is the treatment of choice, make a maximal effort to treat with CPAP for an adequate period of time prior to initiating armodafinil therapy.1 If armodafinil is used adjunctively with CPAP, necessary to encourage and periodically assess CPAP compliance.1 (See Advice to Patients.)

Cognitive/Psychomotor Impairment Effects

Although armodafinil has not been shown to cause functional impairment, altered judgment, thinking, or motor skills is possible with any drug affecting the CNS.1 (See Advice to Patients.)

Abuse and Misuse Potential

Armodafinil is subject to control as a schedule IV (C-IV) drug.1 18 Abuse potential not specifically studied, but expected to be similar to that of modafinil.1 18

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), but current evidence indicates risk of abuse or misuse is lower with armodafinil and modafinil than with schedule II CNS stimulants (e.g., amphetamine, methylphenidate).1 7 8 17 18 25 (See Actions.)

Monitor patients closely during treatment 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 7

Cardiovascular Effects

Adverse cardiovascular effects (e.g., chest pain, palpitations, dyspnea, transient ischemic T-wave changes on ECG) reported with modafinil; similar risk expected with armodafinil.1

Not recommended in patients with history of left ventricular hypertrophy or in patients with mitral valve prolapse who have experienced mitral valve prolapse syndrome (e.g., ischemic ECG changes, chest pain, arrhythmia) with CNS stimulant use.1 If new onset of any of these symptoms of mitral valve prolapse syndrome occurs during armodafinil therapy, consider cardiac evaluation.1

Use with caution in patients with recent history of MI or unstable angina.1

Increased monitoring of BP may be appropriate during therapy.1

Contraceptive Precautions

Possible reduced efficacy of hormonal contraceptives during and for 1 month after discontinuance of therapy.1 7 Alternative or concomitant contraceptive methods recommended during these periods.1 7 (See Specific Drugs under Interactions and see Advice to Patients.)

Drug Interaction with Cyclosporine

Possible reduced cyclosporine blood concentrations when given concurrently with armodafinil.1 (See Specific Drugs under Interactions.)

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether armodafinil or its metabolites are distributed into milk.1 Caution if used in nursing women.1

Pediatric Use

Armodafinil is not approved for use in pediatric patients for any indication.1 Safety and efficacy not established in children <17 years of age.1

Serious rashes (e.g., erythema multiforme, Stevens-Johnson syndrome) associated with use of modafinil in pediatric patients.1 30 (See Serious Dermatologic Reactions under Cautions.)

Geriatric Use

Safety and efficacy not established in patients >65 years of age.1

Elimination of armodafinil and its metabolites may be reduced; consider reduced dosage.1 7 (See Geriatric Patients under Dosage and Administration and see Special Populations under Pharmacokinetics.)

Hepatic Impairment

Armodafinil not specifically studied in patients with hepatic impairment.1 However, possible reduced clearance in patients with severe hepatic impairment based on pharmacokinetic studies with modafinil.1 Reduce dosage in patients with severe hepatic impairment, with or without cirrhosis.1 7 (See Hepatic Impairment under Dosage and Administration and see Special Populations under Pharmacokinetics.)

Renal Impairment

Inadequate information to determine safety and efficacy in patients with severe renal impairment.1 (See Renal Impairment under Dosage and Administration and see Special Populations under Pharmacokinetics.)

Common Adverse Effects

Headache, nausea, dizziness, insomnia.1 2 3 4 5 7 10 12 13 19

Interactions for Armodafinil

Partially metabolized by CYP3A enzymes.1 Slightly induces CYP1A2 and possibly CYP3A, and reversibly inhibits CYP2C19 in vitro.1 7 14 Moderately induces CYP3A4 and moderately inhibits CYP2C19, but does not appear to substantially induce CYP1A2, in vivo.1 7 8 14

Substrate of P-glycoprotein.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent inducers or inhibitors of CYP3A4/5: Potential pharmacokinetic interaction (altered plasma concentrations of armodafinil).1

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4/5: Potential pharmacokinetic interaction (decreased plasma concentrations of substrate); dosage adjustment of substrate drug may be necessary.1 7 8 14

Substrates of CYP2C19: Potential pharmacokinetic interaction (increased plasma concentrations of substrate); dosage reduction and monitoring for toxicity of substrate drug may be necessary.1 7 14

Protein-bound Drugs

Potential for interactions with highly protein-bound drugs considered unlikely.1

Specific Drugs

Drug

Interaction

Comments

Alcohol

Concomitant use not evaluated1

Concomitant use not recommended1

Antifungals, azoles (itraconazole, ketoconazole)

Possible increased plasma armodafinil concentrations1

Caffeine

Pharmacokinetics of caffeine not substantially affected during chronic armodafinil administration1

Carbamazepine

Possible decreased plasma armodafinil concentrations1

Clomipramine

Possible increased plasma concentrations of clomipramine and its active desmethyl metabolite1

May need to reduce clomipramine dosage and monitor for toxicity1

CNS-active agents

Specific drug interaction studies not conducted between armodafinil and CNS-active drugs; available drug interaction information with modafinil should also apply to armodafinil1

Cyclosporine

Possible decreased blood concentrations and effectiveness of cyclosporine1

Consider monitoring circulating cyclosporine concentrations; adjust cyclosporine dosage if necessary1 14

Dextroamphetamine

Specific drug interaction studies not conducted between armodafinil and dextroamphetamine; clinically important pharmacokinetic interaction unlikely with racemic modafinil, although modafinil absorption may be delayed by approximately 1 hour1 15 23

Diazepam

Possible increased plasma diazepam concentrations1

May need to reduce diazepam dosage and monitor for toxicity1

Erythromycin

Possible increased armodafinil plasma concentrations1

Hormonal contraceptives

Potential for decreased plasma concentrations of ethinyl estradiol; possible hormonal contraceptive failure1

Alternative or concomitant methods of contraception recommended during and for 1 month after discontinuance of armodafinil therapy 1

Ketoconazole

Possible increased armodafinil plasma concentrations1

MAO inhibitors

Interaction studies not performed to date1

Acute chorea, confusion, and hyperthermia (possibly related to serotonin syndrome) reported with concurrent modafinil and tranylcypromine35

Use concomitantly with caution1

Methylphenidate

Specific drug interaction studies not conducted between armodafinil and methylphenidate; clinically important pharmacokinetic interaction unlikely with racemic modafinil, although modafinil absorption may be delayed by approximately 1 hour1 22 30

Midazolam

Potential for reduced systemic exposure of midazolam1 14

Dosage adjustment of midazolam may be necessary1

Omeprazole

Potential for increased plasma concentrations and systemic exposure to omeprazole1 14

May need to reduce omeprazole dosage and monitor for toxicity1

Phenobarbital

Possible decreased plasma armodafinil concentrations1

Phenytoin

Possible increased plasma phenytoin concentrations1

May need to reduce phenytoin dosage and monitor for toxicity1

Propranolol

Possible increased plasma propranolol concentrations1

May need to reduce propranolol dosage and monitor for toxicity1

Rifampin

Possible decreased plasma armodafinil concentrations1

Triazolam

Potential for reduced plasma concentrations and effectiveness of triazolam1 14

Dosage adjustment of triazolam may be necessary1 14

Warfarin

Single-dose pharmacokinetics of warfarin not substantially affected by chronic administration of modafinil1 16

Monitor PT and/or INR more frequently1 16

Armodafinil Pharmacokinetics

Absorption

Bioavailability

Readily absorbed following oral administration, with peak plasma concentrations occurring at approximately 2 hours (in the fasted state).1 7 8 12 13 Steady-state concentrations are reached within 7 days of once-daily administration.1 7 8 13

Absolute oral bioavailability not determined because of low aqueous solubility.1

In healthy individuals, armodafinil produces consistently higher plasma concentrations later in the dosing period relative to modafinil on a mg-to-mg basis.1 8 10 11 12 14

Food

Food may delay time to peak plasma concentrations by approximately 2–4 hours, but does not appear to affect overall bioavailability.1 7 8 13

Distribution

Extent

Large volume of distribution (42 L following oral administration) suggests extensive extravascular distribution.1 8 13

Not known whether armodafinil or its metabolites are distributed into milk.1

Plasma Protein Binding

Armodafinil: Data not available.1

Modafinil: approximately 60% (mainly albumin).1

Elimination

Metabolism

Metabolized to inactive metabolites via hydrolytic deamidation, S-oxidation, and aromatic ring hydroxylation, with subsequent glucuronide conjugation.1 Partially metabolized by CYP3A isoenzymes.1

Elimination Route

Metabolic fate of armodafinil not specifically studied; however, modafinil is excreted in urine (80%) and in feces (1%), mainly as metabolites.1

Half-life

Approximately 15 hours.1 12 13

Special Populations

In patients with severe hepatic impairment and cirrhosis (Child-Pugh class B, B+, C, or C+), clearance of modafinil is decreased and steady-state concentrations are increased.1

In patients with severe chronic renal impairment (Clcr ≤20 mL/minute), pharmacokinetics of modafinil are not substantially altered, but exposure to modafinil acid (an inactive metabolite) is increased ninefold compared with healthy individuals.1

In geriatric patients, clearance of armodafinil and its metabolites may be reduced.1

Stability

Storage

Oral

Tablets

20–25°C.1

Actions

  • Armodafinil, a nonamphetamine wakefulness-promoting agent, is the longer-lasting R-enantiomer of racemic modafinil (a 50:50 mixture of the of the R- and S-enantiomers); exhibits pharmacologic properties similar to those of modafinil.1 2 3 4 5 6 7 8 10 11 12 13 26 34

  • Armodafinil and modafinil differ primarily in their pharmacokinetic profiles.1 8 10 11 12 14 Compared with modafinil, armodafinil produces consistently higher plasma drug concentrations later in the day; however, further study is needed to determine whether this difference results in improved clinical response.1 4 5 7 10 11 12 14

  • Promotes vigilance and wakefulness.1 Exact mechanism of action unknown, but may involve activation of certain areas of the brain that control wakefulness.1 7 8 21

  • Does not appear to act as a direct- or indirect-acting dopamine-receptor or α1-adrenergic agonist, but has been shown in in vitro studies to bind to the dopamine transporter and inhibit dopamine reuptake.1 7 Modafinil blocked dopamine transporters and increased dopamine concentrations in the human brain (including the nucleus accumbens) in one study; drugs with such activity generally have abuse potential.27 Stimulant effects of modafinil can be attenuated by the α1-adrenergic receptor antagonist, prazosin.1 7

  • At pharmacologically relevant concentrations, does not bind to or inhibit certain receptors and enzymes (e.g., serotonin, dopamine, adenosine, galanin, melatonin, melanocortin, orexin-1, orphanin, pituitary adenylate cyclase-activating polypeptide [PACAP], benzodiazepines); transporters for GABA, serotonin, norepinephrine, or choline; or phosphodiesterase VI, catechol-O-methyl transferase (COMT), GABA transaminase, or tyrosine hydroxylase, which may regulate sleep and wakefulness.1 7

  • Does not inhibit activity of type B MAO (MAO-B) or phosphodiesterases II-IV.1

  • Reinforcing properties in animals; produces psychoactive (e.g., alterations in mood and thinking), euphoric, and subjective effects typical of classic CNS stimulants (e.g., amphetamines, methylphenidate) in humans.1 7 18

Advice to Patients

  • Importance of reading patient information leaflet provided by the manufacturer prior to initiating therapy.1

  • Importance of advising clinician of existing or contemplated therapy, including prescription and OTC drugs and/or herbal supplements, as well as any concomitant illnesses.1 Advise patient that it is prudent to avoid alcohol since combined use has not been studied.1

  • Potential increased risk of pregnancy in women taking hormonal contraceptives (including oral contraceptives, injectable or implantable contraceptives, transdermal systems, vaginal rings, and intrauterine devices) during and for 1 month after discontinuing armodafinil therapy; discuss use of alternative or concomitant methods of contraception during these periods.1 (See Contraceptive Precautions under Cautions.) Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Risk of serious rash or serious allergic reaction.1 Advise patient to immediately discontinue armodafinil and notify their clinician if they develop a rash or other manifestations of an allergic reaction (e.g., hives, mouth sores, blisters, peeling skin, difficulty swallowing or breathing, related allergic phenomenon).1

  • Risk of mental (psychiatric) symptoms.1 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

  • Risk of heart problems.1 Importance of discontinuing armodafinil and informing clinician if heart problems, including chest pain, occur.1

  • Advise that armodafinil may affect judgment, thinking, or motor skills.1 Use caution when operating machinery or driving a motor vehicle until effects of the drug are known.1

  • Advise patient that armodafinil may improve, but not eliminate, the abnormal tendency to fall asleep.1 Therefore, stress importance of not 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 produces sufficient wakefulness that permits such activities.1 Advise that armodafinil therapy is not a replacement for sleep.1

  • Importance of continuing previously prescribed therapy (e.g., patients with OSAHS should continue using their CPAP machine while sleeping).1

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.1 18

Armodafinil

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

50 mg

Nuvigil (C-IV)

Cephalon

150 mg

Nuvigil (C-IV)

Cephalon

250 mg

Nuvigil (C-IV)

Cephalon

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Nuvigil 150MG Tablets (CEPHALON): 30/$421.99 or 90/$1,245.02

Nuvigil 250MG Tablets (CEPHALON): 30/$417.98 or 90/$1,234.98

Nuvigil 50MG Tablets (CEPHALON): 30/$153.74 or 90/$426.21

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 3, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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