Provigil

Pronunciation

Generic Name: Modafinil
Class: Wakefulness-promoting Agents
VA Class: CN809
Chemical Name: 2-((Diphenylmethyl)sulfinyl)acetamide
Molecular Formula: C15H15NO2S
CAS Number: 68693-11-8

Warning(s)

REMS:

FDA approved a REMS for modafinil to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of modafinil and consists of the following: medication guide and communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Wakefulness-promoting agent.55 50:50 racemic mixture of the R- and S-enantiomers; the R-enantiomer of modafinil also is commercially available as armodafinil.55 56

Uses for Provigil

Narcolepsy

Symptomatic treatment of narcolepsy to improve wakefulness in adults with excessive daytime sleepiness.1 15 16 17 18 27 28 29 30 32 34

Careful attention to diagnosis and treatment of the sleep disorder is essential.55 (See Diagnosis of Sleep Disorders under Cautions.)

Slideshow: Grapefruit and Medicines: A Possible Deadly Mix?

Grapefruit and grapefruit juice can react adversely with over 85 prescription medications.

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 26 37 38 39 40 41 42

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 prior to initiating modafinil.1 If modafinil is used adjunctively with CPAP, encourage and periodically assess CPAP compliance.1 38

Careful attention to diagnosis and treatment of the sleep disorder is essential.55 (See Diagnosis of Sleep Disorders under Cautions.)

Shift Work Sleep Disorder (SWSD)

Symptomatic treatment of SWSD to improve wakefulness in adults with excessive sleepiness.1 40 44

Careful attention to diagnosis and treatment of the sleep disorder is essential.55 (See Diagnosis of Sleep Disorders under Cautions.)

Provigil Dosage and Administration

Administration

Oral Administration

Administer orally once daily without regard to meals.16 19 34 55 (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 44

In patients with narcolepsy, modafinil also has been administered in 2 divided doses daily, in the morning and at noon.15 34

Dosage

Adults

Narcolepsy
Oral

200 mg once daily.1 16 34

Dosages up to 400 mg daily have been well tolerated, but may not provide additional clinical benefit beyond 200-mg daily dosage.1 15 16 37

Long-term efficacy (>9 weeks) not systematically established.1 If clinician elects to prescribe for an extended period, periodically reassess long-term usefulness in the individual patient.1

OSAHS
Oral

200 mg once daily.1

Dosages up to 400 mg daily have been well tolerated, but may not provide additional clinical benefit beyond 200-mg daily dosage.1

Long-term efficacy (>12 weeks) not systematically established.1 If clinician elects to prescribe for an extended period, periodically reassess long-term usefulness in the individual patient.1

SWSD
Oral

200 mg once daily.1

Dosages up to 400 mg daily have been well tolerated, but may not provide additional clinical benefit beyond 200-mg daily dosage.1

Long-term efficacy (>12 weeks) not systematically established.1 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 to 100 mg daily 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 (See Geriatric Use under Cautions.)

Cautions for Provigil

Contraindications

  • Known hypersensitivity to modafinil, armodafinil, or any ingredient in the formulation.54 55

Warnings/Precautions

Warnings

Serious Dermatologic Reactions

Serious skin rash (e.g., Stevens-Johnson syndrome [SJS]) requiring hospitalization and drug discontinuance reported in adult and pediatric patients receiving modafinil.47 48 51 55

Severe rash (e.g., possible SJS, multiorgan hypersensitivity reaction), sometimes associated with fever and other abnormalities (e.g., vomiting, leukopenia), reported in pediatric clinical trials.55 No serious rashes reported in clinical trials in adults.55 Serious or life-threatening rash (e.g., SJS, toxic epidermal necrolysis [TEN], drug rash with eosinophilia and systemic symptoms [DRESS]) reported rarely during postmarketing experience.55 Modafinil is not approved for use in pediatric patients for any indication.47 48 55 (See Pediatric Use under Cautions.)

No known risk factors predict the occurrence or severity of rash.55 Nearly all cases occurred within 1–5 weeks following initiation of therapy, but cases also reported after prolonged (e.g., 3 months) treatment.55

Benign rashes also occur with modafinil; not possible to predict which rashes will become serious.55 Therefore, discontinue drug at first sign of rash unless clearly not drug related.55 (See Advice to Patients.) Rash may become potentially life-threatening or permanently disabling or disfiguring despite drug discontinuance.48 55

Persistent Sleepiness

In patients with abnormal levels of sleepiness, level of wakefulness may improve with modafinil 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;55 58 59 many, but not all, patients had a psychiatric history.1 59

In controlled clinical trials, psychiatric symptoms that required treatment discontinuance in ≥0.3% of patients and more often for modafinil than for placebo included anxiety, nervousness, insomnia, confusion, agitation, and depression.55

Use with caution in patients with a history of psychosis, depression, or mania.55 59

Some clinicians recommend careful monitoring of patients receiving modafinil or other CNS stimulants for possible psychiatric effects.58 If psychiatric symptoms develop, consider drug discontinuance.55 (See Advice to Patients.)

Sensitivity Reactions

Angioedema and Anaphylactoid Reactions

Angioedema and hypersensitivity (with rash, dysphagia, and bronchospasm) reported with armodafinil.55 Angioedema also reported during postmarketing experience with modafinil.55

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.55

Multiorgan Hypersensitivity Reactions

Multiorgan hypersensitivity reactions, including at least 1 fatality, reported with modafinil.55

Reactions detected a median of 13 days (range: 4–33 days) after initiation of modafinil.55 Clinical presentation was variable but typically included fever and rash associated with other organ system involvement (e.g., myocarditis, hepatitis, liver function test abnormalities, hematologic abnormalities [e.g., eosinophilia, leukopenia, thrombocytopenia], pruritus, asthenia).55

No risk factors known to predict occurrence or severity.55

If a multi-organ hypersensitivity reaction is suspected, discontinue therapy.55 Cross-sensitivity with other drugs that produce this syndrome not yet reported but is possible.55

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.55

Consider that >1 sleep disorder may contribute to excessive sleepiness in some patients (e.g., OSAHS and SWSD concurrently in the same patient).55

Cognitive/Psychomotor Impairment

Although modafinil has not been shown to cause functional impairment, altered judgment, thinking, or motor skills is possible with any drug affecting the CNS.55 (See Advice to Patients.)

Continuous Positive Airway Pressure (CPAP) in OSAHS

In OSAHS, modafinil is indicated as an adjunct to standard treatment(s) for the underlying obstruction.55 If CPAP is the treatment of choice, make a maximal effort to treat with CPAP for an adequate period of time prior to initiating modafinil therapy.55 If modafinil is used adjunctively with CPAP, encourage and periodically assess CPAP compliance.55 (See Advice to Patients.)

Cardiovascular Effects

Adverse cardiovascular effects (e.g., chest pain, palpitations, dyspnea, transient ischemic T-wave changes on ECG) reported in several modafinil-treated patients in association with mitral valve prolapse or left ventricular hypertrophy.55

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 previous CNS stimulant use.55 If new onset of any of these symptoms of mitral valve prolapse syndrome occurs during modafinil therapy, consider cardiac evaluation.55

Use with caution in patients with recent history of MI or unstable angina.55

A greater proportion of modafinil-treated patients required new or increased use of antihypertensive medication compared with those receiving placebo in a retrospective analysis (2.4 and 0.7%, respectively).55 Increased monitoring of BP may be appropriate during therapy.55

Abuse and Misuse Potential

Modafinil is subject to control as a schedule IV (C-IV) drug.1 34 35

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 modafinil than with schedule II CNS stimulants (e.g., amphetamine, methylphenidate).1 34 35 (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 history of drug or stimulant abuse (e.g., amphetamine, cocaine, methylphenidate).1

Contraceptive Precautions

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

Drug Interaction with Cyclosporine

Possible reduced blood cyclosporine concentrations when given concurrently with modafinil.55 (See Specific Drugs under Interactions.)

Specific Populations

Pregnancy

Category C.1

Provigil Pregnancy Registry (for clinicians or patients) at 866-404-4106, or .55

Lactation

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

Pediatric Use

Modafinil is not approved for use in pediatric patients for any indication, including attention deficit hyperactivity disorder (ADHD).47 48 55 Safety and efficacy not established in children <17 years of age.55

Serious skin rashes (e.g., erythema multiforme, Stevens-Johnson syndrome) associated with use of modafinil in pediatric patients.55 (See Serious Dermatologic Reactions under Cautions.)

Geriatric Use

Limited experience indicates that the incidence of adverse effects in patients >65 years of age is similar to that in younger patients.55

Elimination of modafinil and its metabolites may be reduced; consider reduced dosage.55 (See Geriatric Patients under Dosage and Administration and see Special Populations under Pharmacokinetics.)

Hepatic Impairment

Reduce dosage in patients with severe hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration and see Special Populations under Pharmacokinetics.)

Renal Impairment

Use with caution in patients with severe renal impairment.1 (See Renal Impairment under Dosageand Administration and see Special Populations under Pharmacokinetics.)

Common Adverse Effects

Headache, 1 15 16 17 23 24 25 27 nausea,1 15 16 17 nervousness,1 15 16 rhinitis,1 diarrhea,1 back pain,1 anxiety,1 insomnia,1 25 dizziness,1 dyspepsia.1

Interactions for Provigil

Partially metabolized by CYP3A4 enzymes.55 Modafinil and modafinil sulfone metabolite reversibly inhibit CYP2C19.55 Slightly induces CYP1A2, CYP2B6, and CYP3A4 and produces suppression of CYP2C9 activity in a concentration-dependent manner in vitro.1

Possible auto-induction of modafinil metabolism after multiple weeks of dosing; magnitude of decreases in modafinil trough concentrations and inconsistency of occurrence suggest clinical importance is minimal.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent inducers or inhibitors of CYP3A4: Potential pharmacokinetic interaction (altered elimination of modafinil).1

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP1A2, CYP2B6, and CYP3A4: Potential pharmacokinetic interaction (decreased plasma substrate concentrations).1 Caution if used concomitantly.1

Substrates of CYP2C19: Potential pharmacokinetic interaction (possible prolonged elimination of substrate).1

Substrates of CYP2C9: Potential metabolic interaction.1

Protein-bound Drugs

Potential for interactions with highly protein-bound drugs considered unlikely.55

Specific Drugs

Drug

Interaction

Comments

Alcohol

Concomitant use not evaluated1

Avoid alcohol during therapy1

Antidepressants, SSRIs

Possible increased SSRI concentration in patients who are CYP2D6 deficient1

Dosage adjustment of SSRI may be necessary1

Antidepressants, tricyclics

Possible increased concentration of certain tricyclic antidepressants (e.g., clomipramine, desipramine) in patients who are CYP2D6 deficient1

Dosage reduction of tricyclic antidepressant may be necessary1

Antifungals, azoles (itraconazole, ketoconazole)

Possible increased plasma modafinil concentrations1

Carbamazepine

Possible decreased modafinil plasma concentrations1

Clomipramine

Pharmacokinetic interaction unlikely; however, increased concentrations of clomipramine and its active desmethyl metabolite reported in a patient who was a poor CYP2D6 metabolizer21 55

Dosage reduction of clomipramine may be necessary55

Clozapine

Possible elevation in serum clozapine concentrations and resulting clozapine toxicity53

Use concomitantly with caution; closely monitor serum clozapine concentrations53

Cyclosporine

Possible decreased blood concentrations and effectiveness of cyclosporine1 54

Consider monitoring cyclosporine concentrations; adjust cyclosporine dosage if necessary55

Dextroamphetamine

Clinically important pharmacokinetic interaction unlikely, although modafinil absorption may be delayed by approximately 1 hour1 25

Diazepam

Possible increased plasma diazepam concentrations1

May need to reduce diazepam dosage and monitor for toxicity1

Hormonal contraceptives

Potential for decreased plasma concentrations of ethinyl estradiol; possible hormonal contraceptive failure1 45

Alternative or concomitant nonhormonal methods of contraception recommended during and for 1 month after discontinuance of modafinil therapy1

MAO inhibitors

Interaction studies not performed to date55

Acute chorea, confusion, and hyperthermia (possibly related to serotonin syndrome) reported with concurrent modafinil and tranylcypromine56

Use concomitantly with caution54 55

Methylphenidate

Clinically important pharmacokinetic interaction unlikely, although modafinil absorption may be delayed by approximately 1 hour1 20

Phenobarbital

Possible decreased plasma modafinil 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 modafinil concentrations1

Triazolam

Potential for reduced plasma concentrations and effectiveness of triazolam 1 45 54

Dosage adjustment of triazolam may be necessary1

Warfarin

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

Monitor PT and/or INR more frequently1 43

Provigil Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed from the GI tract after oral administration, with peak plasma concentrations attained within 2–4 hours.1 b Absolute oral bioavailability not determined due to low aqueous solubility.1 b

Food

Food may delay GI absorption by approximately 1 hour, but does not affect extent of absorption.1

Distribution

Extent

Well distributed into body tissues.1

Not known whether modafinil or its metabolites are distributed into milk.55

Plasma Protein Binding

Approximately 60% (mainly albumin).1

Elimination

Metabolism

Metabolized to inactive metabolites via hydrolytic deamidation, S-oxidation, aromatic ring hydroxylation, and glucuronide conjugation.1 b

Elimination Route

Excreted in urine (80%) and in feces (1%), mainly as metabolites.1

Half-life

Approximately 10–15 hours after multiple dosing.1 b

Special Populations

In patients with severe hepatic impairment and cirrhosis (Child-Pugh class B, B+, C, or C+), clearance of modafinil is decreased by about 60% and steady-state concentrations are doubled compared with healthy individuals.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 modafinil and metabolites may be reduced.1

Stability

Storage

Oral

Tablets

20–25°C.1

Actions

  • Modafinil, a nonamphetamine wakefulness-promoting agent, is a 50:50 racemic mixture of the R- and S-enantiomers; exhibits pharmacologic properties similar to those of armodafinil.54 55

  • Promotes vigilance and wakefulness.1 2 3 4 6 8 10 26 27 28 30 32 34 37 38 39 40 41 42 44 Exact mechanism of action unknown,1 but may alter metabolic activity and increase neuronal activity in areas of the brain that control sleep/wakefulness and the biologic clock.1 9 10 11 16

  • Inhibits release of GABA2 4 5 6 14 and increases release of glutamate from the cerebral cortex,12 hippocampus,10 12 nucleus accumbens,6 12 medial preoptic area,5 6 12 and posterior hypothalamus in animals.5 12

  • Does not appear to act as a direct- or indirect-acting dopamine-receptor or α1-adrenergic agonist1 2 10 13 16 or as a sympathomimetic agent; 1 may stimulate central α1-adrenergic activity8 15 32 33 but has no important peripheral adrenergic activity.1 2 8 32 Blocked dopamine transporters and increased dopamine concentrations in the human brain (including the nucleus accumbens); drugs with such activity generally have abuse potential.57

  • At usual pharmacologic concentrations, does not bind to certain receptors that regulate sleep and wakefulness (e.g., norepinephrine, serotonin, dopamine, GABA, adenosine, histamine H3, melatonin, benzodiazepine).1

  • Does not inhibit MAO-B or phosphodiesterases 2-5; does not alter plasma melatonin or cortisol hormone profiles.7 55

  • Reinforcing properties in animals; produces psychoactive, euphoric, and subjective effects typical of classic CNS stimulants (e.g., amphetamines, methylphenidate) in humans.35 55

Advice to Patients

  • Importance of providing copy of written patient information (medication guide) each time modafinil is dispensed; importance of reading this information prior to taking modafinil.55

  • Importance of advising clinician of existing or contemplated therapy, including prescription and OTC drugs and/or herbal supplements, as well as any concomitant illnesses.55 Advise patient that it is prudent to avoid alcohol since combined use has not been studied.55

  • Potential increased risk of pregnancy in women taking hormonal contraceptives (e.g., oral contraceptives, injectable or implantable contraceptives, transdermal systems, vaginal rings, intrauterine devices) during and for 1 month after discontinuing modafinil therapy; discuss use of alternative or concomitant methods of contraception during these periods.55 (See Contraceptive Precautions under Cautions.) Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.55 Importance of clinicians informing women about the existence of and encouraging enrollment in the Provigil pregnancy registry (see Pregnancy under Cautions).55

  • Risk of serious rash or serious allergic reaction.55 Advise patient to immediately discontinue modafinil and notify their clinician if they develop a rash or other manifestations of an allergic reaction (e.g., hives; mouth sores; blisters; peeling skin; swelling of face, eyes, lips, tongue, or larynx; difficulty swallowing or breathing; hoarseness; a related allergic phenomenon).55

  • Risk of mental (psychiatric) symptoms.55 Importance of discontinuing modafinil and informing clinician if depression, anxiety, hallucinations, mania, suicidal thoughts, aggression, or other psychiatric symptoms occur.55

  • Risk of heart problems.55 Importance of discontinuing modafinil and informing clinician if symptoms of a heart problem, including chest pain, abnormal heart beats, and trouble breathing, occur.55

  • Advise that modafinil 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 modafinil may improve, but not eliminate, the abnormal tendency to fall asleep.55 Therefore, stress importance of not altering previous behavior with regard to activities that require appropriate levels of wakefulness (e.g., driving, operating machinery) until and unless modafinil produces sufficient wakefulness to permit such activities.55 Advise that modafinil is not a replacement for sleep.55

  • Importance of continuing previously prescribed therapy (e.g., patients with OSAHS should continue using their CPAP machine while sleeping).55

  • 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 34 35

Modafinil

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

100 mg

Provigil ( C-IV)

Cephalon

200 mg

Provigil ( C-IV; scored)

Cephalon

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Modafinil 100MG Tablets (CEPHALON): 30/$459.99 or 90/$1,329.97

Modafinil 200MG Tablets (CEPHALON): 30/$759.99 or 90/$2,229.97

Provigil 100MG Tablets (CEPHALON): 30/$608.38 or 90/$1,798.69

Provigil 200MG Tablets (CEPHALON): 30/$907.01 or 90/$2,696.03

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 20, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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