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    Modafinil

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    Mar.28.2024

    Modafinil

    Indications/Dosage

    Labeled

    • narcolepsy
    • obstructive sleep apnea
    • shift work sleep disorder

    Off-Label

    • attention-deficit hyperactivity disorder (ADHD)
    • cocaine dependence
    • depression
    • fatigue
    † Off-label indication

    For the treatment of narcolepsy to improve wakefulness in patients with excessive sleepiness

    Oral dosage

    Adults, including Geriatric Adults

    The recommended dose is 200 mg PO once daily as a single dose in the morning. While doses up to 400 mg PO once daily have been well tolerated, there is no consistent evidence that doses greater than 200 mg/day confer additional clinical benefit. Max: 400 mg/day PO.[41243] For elderly patients, consideration of a lower initial dose is recommended, with careful monitoring.[41243]

    Adolescents 17 years and older

    The recommended dose is 200 mg PO once daily as a single dose in the morning. While doses up to 400 mg PO once daily have been well tolerated, there is no consistent evidence that doses greater than 200 mg/day confer additional clinical benefit. Max: 400 mg/day PO.[41243]

    Children and Adolescents less than 17 years

    Safety and efficacy have not been established.[41243]

    For the treatment of shift work sleep disorder to improve wakefulness in patients with excessive sleepiness

    Oral dosage

    Adults, including Geriatric Adults

    200 mg PO once daily as a single dose approximately 1 hour prior to the start of the work shift.[41243] For geriatric patients, consideration should be given to the use of lower initial doses and close monitoring.[41243]

    For the treatment of obstructive sleep apnea to improve wakefulness in patients with excessive sleepiness

    Oral dosage

    Adults, including Geriatric Adults

    The recommended dose is 200 mg PO once daily as a single dose in the morning. While doses up to 400 mg PO once daily have been well tolerated, there is no consistent evidence that doses greater than 200 mg/day confer additional clinical benefit. Max: 400 mg/day PO. For the geriatric patient, consider use of lower initial doses with close monitoring.[41243] For obstructive sleep apnea, modafinil is indicated to improve wakefulness in patients with excessive sleepiness and not as treatment for the underlying obstruction. If continuous positive airway pressure (CPAP) is the treatment of choice for a patient, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating modafinil for excessive sleepiness.[41243]

    Adolescents 17 years and older

    The recommended dose is 200 mg PO once daily as a single dose in the morning. While doses up to 400 mg PO once daily have been well tolerated, there is no consistent evidence that doses greater than 200 mg/day confer additional clinical benefit. Max: 400 mg/day PO.[41243] For obstructive sleep apnea, modafinil is indicated to improve wakefulness in patients with excessive sleepiness and not as treatment for the underlying obstruction. If continuous positive airway pressure (CPAP) is the treatment of choice for a patient, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating modafinil for excessive sleepiness.[41243]

    For the treatment of fatigue† associated with various medical conditions

    for fatigue† associated with multiple sclerosis

    Oral dosage

    Adults, including Geriatric Adults

    Initiate at 200 mg PO once daily in the morning. 200 to 400 mg/day PO has been reported effective. Max: 400 mg/day PO.[27095] For geriatric patients, consider lower initial dosage and use careful monitoring.

    for fatigue† or excessive daytime sleepiness associated with Parkinson's disease†

    Oral dosage

    Adults, including Geriatric Adults

    Limited data are available. Initiate with 200 mg PO once daily in the morning. Consideration of lower initial dosage and careful monitoring is recommended for geriatric patients. Max: 400 mg/day PO.[27094]

    For the adjunct treatment of symptoms (e.g., fatigue†, sleepiness) associated with major depression†

    Oral dosage

    Adults

    100 mg/day PO initially, followed by titration up to a maximum of 400 mg/day PO based upon tolerability and response, has been studied. In some clinical trials, modafinil has improved fatigue and wakefulness compared to placebo for up to 2 weeks in patients with major depressive disorder (MDD) receiving a selective serotonin-reuptake inhibitor (SSRI) antidepressant. Use has been primarily in partial responders to antidepressants with continuing fatigue and related symptoms. Clinical benefits appear to diminish beyond 2 weeks.[58267] [58268]

    For the treatment of attention-deficit hyperactivity disorder (ADHD)† in adults

    Oral dosage

    Adults

    Use cannot be routinely recommended. An initial single dose (200 mg/day PO) trial of modafinil in adult ADHD appeared promising for increasing focus, cognition and reducing impulsivity relative to placebo.[58773] However, clinical trials did not support the single-dose findings. Compared to placebo, modafinil therapy showed no benefit in reducing the symptoms of ADHD in adults, as measured by the DSM-IV ADHD Rating Scale (Cephalon, 2000). Teva Pharmaceuticals has since sponsored a dose-finding trial of adult patients with ADHD. The study randomized patients to modafinil 255-mg, 340-mg, 425-mg, or 510-mg PO once daily or placebo for 9 weeks. The primary efficacy outcome was the change from baseline at final visit in the Adult ADHD Investigator Symptom Rating Scale (AISRS) total score. No statistically significant difference in the AISRS total score was observed at final visit between any modafinil group and placebo; modafinil did not demonstrate a primary benefit on ADHD symptoms in adults; secondary rating scales also failed to show statistically significant differences of modafinil over placebo. The overall withdrawal rate of the study was high (43%). Some ADHD symptoms were reported as improved by select subgroups. Patient self-assessment, cognition, and quality of life/productivity ratings were reported as improved in subgroups of patients receiving modafinil 340 mg/day and 425 mg/day PO.[58772]

    For the treatment of cocaine dependence†

    Oral dosage

    Adults

    200 to 400 mg PO once daily has been studied. The evidence is mixed regarding modafinil efficacy. Two meta-analyses found no effect on sustained cocaine abstinence but a positive effect on end-of-trial cocaine abstinence rates. Certain subpopulations, including those without concurrent alcohol use disorder and those with high treatment adherence despite high frequency of cocaine use, may benefit (low certainty, conditional recommendation). One guideline suggests that use of psychostimulants for this indication be limited to physician specialists who are board certified in addiction medicine, addiction psychiatry, or have commensurate training and competencies.[70082]

    Therapeutic Drug Monitoring

    Maximum Dosage Limits

    • Adults

      400 mg/day PO.

    • Geriatric

      400 mg/day PO.

    • Adolescents

      >= 17 years: 400 mg/day PO.

      <= 16 years: Safety and efficacy have not been established.

    • Children

      Safety and efficacy have not been established.

    • Infants

      Safety and efficacy have not been established.

    • Neonates

      Safety and efficacy have not been established.

    Patients with Hepatic Impairment Dosing

    Dosages of modafinil should be reduced in patients with Child-Pugh stage B or C cirrhosis. The normal modafinil dosage should be reduced by 50% in patients with moderate to severe hepatic impairment. The manufacturer recommends 100 mg PO once daily in the morning for patients with severe hepatic impairment.

    Patients with Renal Impairment Dosing

    CrCl 20—90 ml/min: Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are necessary.

    CrCl <= 20 ml/min: Although the clearance of a single 200 mg modafinil dose does not differ from that of normal subjects; the AUC of the inactive metabolite, modafinil acid, increases 9-fold. There is inadequate information to determine the safety and efficacy of repeated doses of modafinil in patients with severe renal impairment. It is unknown if modafinil is eliminated by hemodialysis.

    † Off-label indication
    Revision Date: 03/28/2024, 01:48:00 AM

    References

    27094 - Nieves AV, Lang AE. Treatment of excessive daytime sleepiness in patients with Parkinson's disease with modafinil. Clin Neuropharmacol 2002;25:111-114.27095 - Rammohan KW, Rosenberg JH, Lynn DJ, et al. Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry 2002;72:179-183.41243 - Provigil (modafinil) package insert. Frazer, PA: Cephalon; 2015 Jan.58267 - DeBattista C, Doghramji K, Menza MA, et al; Modafinil in Depression Study Group. Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double-blind, placebo-controlled study. J Clin Psychiatry. 2003;64:1057-1064.58268 - Fava M, Thase ME, DeBattista C, et al. A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry 2005;66:85-93.58772 - Arnold VK, Feifel D, Earl CQ, et al. A 9-week, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study to evaluate the efficacy and safety of modafinil as treatment for adults with ADHD. J Atten Disord. 2014;18:133-144. Epub 2012 May 22.58773 - Turner DC, Clark L, Dowson J, et al. Modafinil improves cognition and response inhibition in adult attention-deficit/hyperactivity disorder. Biol Psychiatry. 2004;55:1031-1040.70082 - American Society of Addiction Medicine, American Academy of Addiction Psychiatry. The ASAM/AAAP clinical practice guideline on the management of stimulant use disorder. 2023 Nov. Accessed December 15, 2023. Available online at: https://www.asam.org/quality-care/clinical-guidelines/stimulant-use-disorders

    How Supplied

    Modafinil Oral tablet

    Modafinil 100mg Tablet (62332-0105) (Alembic Pharmaceuticals, Inc.) null

    Modafinil Oral tablet

    Modafinil 100mg Tablet (62332-0385) (Alembic Pharmaceuticals, Inc.) null

    Modafinil Oral tablet

    Modafinil 100mg Tablet (68084-0621) (American Health Packaging) null

    Modafinil Oral tablet

    Modafinil 100mg Tablet (60505-2526) (Apotex Corp) null

    Modafinil Oral tablet

    Modafinil 100mg Tablet (65862-0601) (Aurobindo Pharma USA Inc.) null

    Modafinil Oral tablet

    Modafinil 100mg Tablet (23155-0604) (Avet Pharmaceuticals Inc.) nullModafinil 100mg Tablet package photo

    Modafinil Oral tablet

    Modafinil 100mg Tablet (42291-0599) (AvKARE, Inc.) (off market)

    Modafinil Oral tablet

    Modafinil 100mg Tablet (50268-0570) (AvPAK; a Division of AvKARE Inc) null

    Modafinil Oral tablet

    Modafinil 100mg Tablet (69452-0342) (Bionpharma Inc) nullModafinil 100mg Tablet package photo

    Modafinil Oral tablet

    Modafinil 100mg Tablet (57237-0154) (Citron Pharma LLC) null

    Modafinil Oral tablet

    Modafinil 100mg Tablet (60429-0581) (Golden State Medical Supply, Inc.) (off market)

    Modafinil Oral tablet

    Modafinil 100mg Tablet (00143-9968) (Hikma Pharmaceuticals USA Inc.) (off market)

    Modafinil Oral tablet

    Modafinil 100mg Tablet (50742-0152) (Ingenus Pharmaceuticals, LLC) null

    Modafinil Oral tablet

    Modafinil 100mg Tablet (00904-6423) (Major Pharmaceuticals Inc, a Harvard Drug Group Company) (off market)

    Modafinil Oral tablet

    Modafinil 100mg Tablet (00904-6791) (Major Pharmaceuticals Inc, a Harvard Drug Group Company) null

    Modafinil Oral tablet

    Modafinil 100mg Tablet (51079-0561) (Mylan Institutional LLC) null

    Modafinil Oral tablet

    Modafinil 100mg Tablet (00378-5573) (Mylan Pharmaceuticals Inc.) null

    Modafinil Oral tablet

    Modafinil 100mg Tablet (42043-0160) (OrchidPharma, Inc) null

    Modafinil Oral tablet

    Modafinil 100mg Tablet (49884-0534) (Par Pharmaceuticals, an Endo Company) (off market)

    Modafinil Oral tablet

    Modafinil 100mg Tablet (00603-4661) (Par Pharmaceuticals, an Endo Company) (off market)

    Modafinil Oral tablet

    Modafinil 100mg Tablet (71205-0477) (Proficient Rx LP) null

    Modafinil Oral tablet

    Modafinil 100mg Tablet (55253-0801) (Teva Pharmaceuticals USA) (off market)

    Modafinil Oral tablet

    Modafinil 100mg Tablet (00591-3499) (Teva/Actavis US) (off market)

    Modafinil Oral tablet

    Modafinil 100mg Tablet (72578-0005) (Viona Pharmaceuticals Inc.) nullModafinil 100mg Tablet package photo

    Modafinil Oral tablet

    Provigil 100mg Tablet (63459-0101) (Teva/Cephalon Inc) null

    Modafinil Oral tablet

    Provigil 100mg Tablet (63459-0100) (Teva/Cephalon Inc) (off market)

    Modafinil Oral tablet

    Modafinil 200mg Tablet (62332-0106) (Alembic Pharmaceuticals, Inc.) null

    Modafinil Oral tablet

    Modafinil 200mg Tablet (62332-0386) (Alembic Pharmaceuticals, Inc.) null

    Modafinil Oral tablet

    Modafinil 200mg Tablet (68084-0721) (American Health Packaging) null

    Modafinil Oral tablet

    Modafinil 200mg Tablet (60505-2527) (Apotex Corp) null

    Modafinil Oral tablet

    Modafinil 200mg Tablet (65862-0602) (Aurobindo Pharma USA Inc.) null

    Modafinil Oral tablet

    Modafinil 200mg Tablet (23155-0605) (Avet Pharmaceuticals Inc.) nullModafinil 200mg Tablet package photo

    Modafinil Oral tablet

    Modafinil 200mg Tablet (23155-0862) (Avet Pharmaceuticals Inc.) null

    Modafinil Oral tablet

    Modafinil 200mg Tablet (42291-0600) (AvKARE, Inc.) (off market)

    Modafinil Oral tablet

    Modafinil 200mg Tablet (50268-0571) (AvPAK; a Division of AvKARE Inc) null

    Modafinil Oral tablet

    Modafinil 200mg Tablet (69452-0343) (Bionpharma Inc) nullModafinil 200mg Tablet package photo

    Modafinil Oral tablet

    Modafinil 200mg Tablet (57237-0155) (Citron Pharma LLC) null

    Modafinil Oral tablet

    Modafinil 200mg Tablet (60429-0582) (Golden State Medical Supply, Inc.) (off market)

    Modafinil Oral tablet

    Modafinil 200mg Tablet (00143-9969) (Hikma Pharmaceuticals USA Inc.) (off market)

    Modafinil Oral tablet

    Modafinil 200mg Tablet (50742-0153) (Ingenus Pharmaceuticals, LLC) null

    Modafinil Oral tablet

    Modafinil 200mg Tablet (00904-6424) (Major Pharmaceuticals Inc, a Harvard Drug Group Company) (off market)

    Modafinil Oral tablet

    Modafinil 200mg Tablet (00904-6792) (Major Pharmaceuticals Inc, a Harvard Drug Group Company) null

    Modafinil Oral tablet

    Modafinil 200mg Tablet (51079-0562) (Mylan Institutional LLC) null

    Modafinil Oral tablet

    Modafinil 200mg Tablet (00378-5575) (Mylan Pharmaceuticals Inc.) null

    Modafinil Oral tablet

    Modafinil 200mg Tablet (42043-0161) (OrchidPharma, Inc) null

    Modafinil Oral tablet

    Modafinil 200mg Tablet (49884-0535) (Par Pharmaceuticals, an Endo Company) null

    Modafinil Oral tablet

    Modafinil 200mg Tablet (00603-4662) (Par Pharmaceuticals, an Endo Company) (off market)

    Modafinil Oral tablet

    Modafinil 200mg Tablet (55253-0802) (Teva Pharmaceuticals USA) (off market)

    Modafinil Oral tablet

    Modafinil 200mg Tablet (00591-3500) (Teva/Actavis US) (off market)

    Modafinil Oral tablet

    Modafinil 200mg Tablet (72578-0006) (Viona Pharmaceuticals Inc.) nullModafinil 200mg Tablet package photo

    Modafinil Oral tablet

    Provigil 200mg Tablet (55289-0253) (PD-Rx Pharmaceuticals, Inc.) null

    Modafinil Oral tablet

    Provigil 200mg Tablet (63459-0201) (Teva/Cephalon Inc) null

    Modafinil Oral tablet

    Provigil 200mg Tablet (63459-0200) (Teva/Cephalon Inc) (off market)

    Description/Classification

    Description

    Modafinil is a racemic compound with unique properties in promoting wakefulness; modafinil's mechanism of action appears to be distinct from that of other CNS stimulants. The potential for abuse liability with modafinil is apparently lower than that of other controlled stimulants, though still present. In clinical trials for narcolepsy, modafinil improved daytime vigilance, as assessed by decreases in the number and duration of daytime sleep episodes. Surveys of patient satisfaction in clinical trials for narcolepsy noted that modafinil produces a decreased sense of fatigue and an increase in mental alertness.[25609] Modafinil appears to selectively decrease somnolence and does not affect activities of memory, concentration, or learning, or sleep latency/sleep structure in narcoleptic patients; the drug has no appreciable effects on the incidence of cataplectic attacks associated with narcolepsy. Due to its unique pharmacologic profile, modafinil has shown promise in clinical trials as a treatment for fatigue or excessive sleepiness associated with sleep apnea [26718], or Parkinson's disease.[26719] Proposed military applications include the use of modafinil as an alternative to amphetamines to fight fatigue during prolonged combat missions. Modafinil (Provigil) was FDA-approved for use in patients with narcolepsy in December 1998; at that time, it was the first new molecular entity for use in narcolepsy in 20 years. On October 24, 2003 the FDA approved modafinil for the Shift Work Sleep Disorder (SWSD) indication and on January 26, 2004 for obstructive sleep apnea/hypopnea syndrome (OSAHS) in adults. In July 2000, Cephalon Inc. reported that, compared to placebo, modafinil therapy did not reduce the symptoms of attention-deficit hyperactivity disorder (ADHD) in adults, as measured by the DSM-IV ADHD Rating Scale in a phase III trial. Modafinil has not been proven safe or effective for pediatric patients for any condition; the drug was no more effective than placebo in children with narcolepsy. Modafinil was studied for ADHD in pediatric patients age 6 years and older; however, the FDA denied pediatric approval due to the risk for serious side effects, including reported cases of serious dermatologic reactions, Stevens-Johnson syndrome, potential risks for hepatic impairment or multi-organ hypersensitivity, and reported psychiatric and other side effects in children.[41243]

    Classifications

    • Central Nervous System
      • Psychoanaleptics Excluding Anti-obesity Agents
        • ADHD Agents
          • ADHD Agents, Stimulant, and other Psychostimulants
            • Psychostimulants, Amphetamines
            • Psychostimulants, Methylphenidate Derivatives
        • Narcolepsy Agents
          • Miscellaneous Neurotransmitter Modulators
    Revision Date: 03/28/2024, 01:48:00 AM

    References

    25609 - Broughton RJ, Fleming JA, George CF. Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy. Neurology 1997;49:444-51.26718 - Kingshott RN, Vennelle M, Coleman EL, et al. Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of residual excessive daytime sleepiness in the sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med 2001;163:918-923.26719 - Happe S, Pirker W, Sauter C, et al. Successful treatment of excessive daytime sleepiness in Parkinson's disease with modafinil. J Neurol 2001;248:632-634.41243 - Provigil (modafinil) package insert. Frazer, PA: Cephalon; 2015 Jan.

    Administration Information

    General Administration Information

    For storage information, see the specific product information within the How Supplied section.

     

    A MedGuide that provides information about the proper use and risks of modafinil should be dispensed with each new prescription and refill.[41243]

    Route-Specific Administration

    Oral Administration

    • Administer modafinil in the morning to get maximal effects during waking hours and to avoid possible interference with nocturnal sleep.
    • May be administered with food. The presence of food will delay maximal modafinil absorption by approximately one hour but does not affect the extent of absorption.

    Clinical Pharmaceutics Information

    From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database
      Revision Date: 03/28/2024, 01:48:00 AM

      References

      41243 - Provigil (modafinil) package insert. Frazer, PA: Cephalon; 2015 Jan.

      Adverse Reactions

      Mild

      • agitation
      • anorexia
      • anxiety
      • back pain
      • chills
      • diarrhea
      • dizziness
      • drowsiness
      • dysgeusia
      • dysmenorrhea
      • dyspepsia
      • emotional lability
      • epistaxis
      • fever
      • flatulence
      • headache
      • hyperhidrosis
      • hyperkinesis
      • insomnia
      • irritability
      • nausea
      • paresthesias
      • pharyngitis
      • polydipsia
      • pruritus
      • rash
      • rhinitis
      • tremor
      • vertigo
      • xerostomia

      Moderate

      • chest pain (unspecified)
      • confusion
      • constipation
      • depression
      • dyskinesia
      • dyspnea
      • edema
      • elevated hepatic enzymes
      • eosinophilia
      • euphoria
      • hallucinations
      • hostility
      • hypertension
      • hypertonia
      • leukopenia
      • mania
      • oral ulceration
      • palpitations
      • peripheral vasodilation
      • psychological dependence
      • psychosis
      • sinus tachycardia

      Severe

      • agranulocytosis
      • anaphylactoid reactions
      • angioedema
      • asystole
      • bronchospasm
      • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
      • erythema multiforme
      • Stevens-Johnson syndrome
      • suicidal ideation
      • Tourette's syndrome
      • toxic epidermal necrolysis
      • visual impairment

      During clinical trials of modafinil for narcolepsy, obstructive sleep apnea (OSA), and shift work disorder (SWD) in adults, the following centrally-mediated adverse effects were reported more frequently in patients receiving modafinil than placebo: insomnia (5% vs 1%), dizziness (5% vs 4%), paresthesias (2% vs 0%), drowsiness (2% vs 1%), hypertonia (1% vs 0%), dyskinesia (1% vs 0%), hyperkinesis (1% vs 0%), tremor (1% vs 0%), vertigo (1% vs 0%), and headache (34% vs 23%). Adverse reactions occurring more frequently than placebo and resulting in treatment discontinuation included headache (2%), insomnia (< 1%), and dizziness (< 1%). Insomnia was also reported in clinical trials of pediatric patients; however, the incidence is unknown. Headache is considered a dose-related effect of the drug. Compared to other prescribed, controlled CNS stimulants (i.e., methylphenidate and the amphetamines), modafinil appears to produce few serious adverse side effects in most narcoleptic patients at normally prescribed doses. Pharmacodynamic studies of modafinil indicate that certain systemic adverse effects may occur more frequently with modafinil dosages above 400 mg PO per day.[41243]

      Psychological dependence may occur with modafinil therapy. Clinical study data indicate that modafinil produces psychoactive effects and euphoria, alterations in mood, perception, thinking, and feelings similar to that of other controlled CNS stimulants.[41243] Misuse or abuse may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with stimulant abuse or misuse.[41243] [68987]

      During clinical trials of modafinil for narcolepsy, obstructive sleep apnea (OSA), and shift work disorder (SWD) in adults, the following psychiatric adverse effects were reported more frequently in patients receiving modafinil than placebo: nervousness (7% vs 3%), anxiety (5% vs 1%), depression (2% vs 1%), agitation (1% vs 0%), confusion (1% vs 0%), and emotional lability (1% vs 0%). Adverse reactions occurring more frequently than placebo and resulting in treatment discontinuation included anxiety (1%), nervousness (1%), confusion (<1%), agitation (<1%), and depression (<1%). Anxiety was considered a dose-related effect. In controlled and open-label clinical studies of pediatric patients, Tourette's syndrome, hostility, increased cataplexy, increased hypnagogic hallucinations, and suicidal ideation were reported; however, the incidences are unknown. In clinical studies of doses ranging from 1000—1600 mg/day and during intentional overdose, agitation, anxiety, aggression, confusion, nervousness, and irritability have been reported. One patient exhibited signs of delusions, psychosis, and hallucinations in association with modafinil use and concomitant conditions of sleep deprivation. Mania, aggression, delusions, hallucinations, depression, and suicidal ideation have been reported during post-marketing use of the drug; some of these events have required hospitalization. Most of the patients had a prior psychiatric history.[41243] Several clinical trials have not noted adverse effects on nocturnal sleep quantity or quality; it should be noted that narcoleptic patients often have interrupted sleep patterns as a feature of their condition. Nervousness, anxiety, and insomnia can be limited by administering modafinil before noon. In some cases a dosage reduction of modafinil may be helpful in limiting CNS side effects.

      During clinical trials of modafinil for narcolepsy, obstructive sleep apnea (OSA), and shift work disorder (SWD) in adults, the following cardiac effects were reported more frequently in patients receiving modafinil than placebo: hypertension (3% vs 1%), sinus tachycardia (2% vs 1%), palpitations (2% vs 1%), chest pain (unspecified) (3% vs 1%), and peripheral vasodilation (2% vs 0%). The requirement for antihypertensive medication was slightly higher in patients receiving modafinil compared to placebo. Chest pain, palpitations, dyspnea, and ECG changes (transient ischemic T-wave changes) were observed in three subjects in association with mitral valve prolapse or left ventricular hypertrophy (LVH). Modafinil is not recommended for use in patients with a history of LVH or in those who have developed mitral valve prolapse syndrome while receiving a CNS stimulant. One patient with a prior history of syncopal episodes experienced a brief episode of asystole after 27 days of modafinil treatment.[41243]

      During clinical trials of modafinil for narcolepsy, obstructive sleep apnea (OSA), and shift work disorder (SWD) in adults, the following gastrointestinal/digestive effects were reported more frequently in patients receiving modafinil than placebo: nausea (11% vs 3%), diarrhea (6% vs 5%), dyspepsia (5% vs 4%), xerostomia (4% vs 2%), anorexia (4% vs 1%), constipation (2% vs 1%), elevated hepatic enzymes (2% vs 1%), flatulence (1% vs 0%), oral ulceration (1% vs 0%), dysgeusia (1% vs 0%), and polydipsia (1% vs 0%). While anorexia was reported in clinical trials, clinically significant weight loss was not noted. Elevations in SGOT and GGT were noted, but rarely were the elevations considered to be significantly abnormal. Hepatic disease has not been reported with modafinil, but it may be prudent to periodically monitor LFTs.[41243]

      Benign rash (unspecified) has occurred during treatment with modafinil; however, life-threatening rashes including Stevens-Johnson syndrome (SJS), erythema multiforme (EM), toxic epidermal necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), also known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have also been reported.[40959] [41243] During clinical trials in adults, eosinophilia was reported in 1% of patients receiving modafinil versus no patients in the placebo group; however, no serious rashes were reported. Transient leukopenia was reported in pediatric clinical trials. Discontinuation due to rash occurred in about 0.8% of pediatric patients during clinical trials, and included 1 case of possible SJS and 1 case of apparent DRESS. The median time to rash that resulted in discontinuation was 13 days. During the first 8 years of modafinil commercial availability, the FDA received 6 reports of severe skin reactions including SJS (n=2), SJS/EM (n=1), TEN (n=1), SJS/TEN (n=1), and DRESS (n=1) involving both adult and pediatric patients (7—49 years of age). The median time to onset was 17.5 days, with a range of 5 days to 5 weeks. All of these patients developed partial or full body rash, and some also experienced eruptions in the mouth, eyes, or genitals, skin pigment changes, pruritus, ulcers, skin burning, skin scaling or sloughing, and/or fever. Multiple organ system involvement (i.e., cardiac, renal, respiratory, and pancreatic systems) occurred in one 15 year old patient with DRESS syndrome. At least one fatality from DRESS has occurred in temporal association to modafinil therapy. The median time to detection of DRESS has been 13 days, with a range of 4 to 33 days after treatment initiation. The typical presentation is 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, and/or asthenia). Although cases of SJS, EM, TEN, and DRESS associated with modafinil have occurred relatively early during treatment, prolonged administration should not preclude the possibility of an association to the drug. There are currently no known factors to predict whether a modafinil-related rash will remain benign. Modafinil should be discontinued if a rash appears at any time if an association to the drug is suspected or confirmed.[41243]

      Angioedema has been reported during post-marketing use of modafinil. One serious case of angioedema and one case of an anaphylactoid reaction characterized by rash, dysphagia, and bronchospasm have occurred during treatment with armodafinil, the enantiomer of modafinil. The drug should be discontinued if angioedema or anaphylactoid reactions appear at any time if an association to the drug is suspected or confirmed.[41243]

      During clinical trials of modafinil for narcolepsy, obstructive sleep apnea (OSA), and shift work disorder (SWD) in adults, visual impairment occurred in 1% of patients receiving modafinil and no patients receiving placebo.[41243]

      During clinical trials of modafinil for narcolepsy, obstructive sleep apnea (OSA), and shift work disorder (SWD) in adults, the following infections or respiratory effects were reported more frequently in patients receiving modafinil than placebo: rhinitis (7% vs 6%), pharyngitis (4% vs 2%), epistaxis (1% vs 0%), and asthma or bronchospasm (1% vs 0%).[41243]

      During clinical trials of modafinil for narcolepsy, obstructive sleep apnea (OSA), and shift work disorder (SWD) in adults, the following general effects were reported more frequently in patients receiving modafinil than placebo: back pain (6% vs 5%), chills (1% vs 0%), edema (1% vs 0%), unspecified urine abnormality (1% vs 0%), and hyperhidrosis (1% vs 0%). Laboratory value changes that occurred in modafinil-treated patients but not placebo-treated patients included gamma glutamyltransferase (GGT) and alkaline phosphatase (AP); however, most GGT and AP elevations remained within the normal range.[41243]

      Agranulocytosis has been reported during post-marketing use of modafinil; however, the frequency is unknown and causality to the drug has not been established.[41243]

      During clinical trials of modafinil for narcolepsy, obstructive sleep apnea (OSA), and shift work disorder (SWD) in adults, dysmenorrhea was reported in at least 1% of modafinil-treated female patients; however, this incidence was less than or equal to placebo. In a small, controlled clinical trial of pediatric patients 12 years of age and older, 3 of 38 girls (7.9%) treated with modafinil experienced dysmenorrhea compared to 0 of 10 girls who received placebo.[41243]

      Revision Date: 03/28/2024, 01:48:00 AM

      References

      40959 - Bachot N, Roujeau JC. Differential diagnosis of severe cutaneous drug eruptions. Am J Clin Dermatol 2003;4:561-72.41243 - Provigil (modafinil) package insert. Frazer, PA: Cephalon; 2015 Jan.68987 - Food and Drug Administration (FDA). FDA Drug Safety Communication: FDA updating warnings to improve safe use of prescription stimulants used to treat ADHD and other conditions. https://www.fda.gov/media/168066/download. Retrieved May 11, 2023.

      Contraindications/Precautions

      Absolute contraindications are italicized.

      • acute myocardial infarction
      • alcoholism
      • angina
      • angioedema
      • bipolar disorder
      • breast-feeding
      • cardiac disease
      • children
      • contraception requirements
      • depression
      • driving or operating machinery
      • ethanol ingestion
      • geriatric
      • heart failure
      • hepatic disease
      • hypertension
      • infants
      • mania
      • myocardial infarction
      • potential for overdose or poisoning
      • pregnancy
      • psychosis
      • schizophrenia
      • serious rash
      • substance abuse
      • suicidal ideation
      • valvular heart disease

      Modafinil is contraindicated in any patient with known hypersensitivity to modafinil, or the related compound armodafinil, or any of their inactive ingredients. Life-threatening serious rash (including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), erythema multiforme, and multi-organ hypersensitivity reaction) have occurred in association with modafinil therapy in adult and pediatric patients. Most rashes have developed within 1—5 weeks of treatment initiation. However, prolonged administration should not preclude the possibility of an association to the drug. Modafinil should be discontinued if rash or other hypersensitivity reaction appears at any time during treatment if an association to the drug is suspected or confirmed. Angioedema has been reported during post-marketing use of the drug. Patients should be instructed to immediately report swelling of the face, eyes, lips, tongue or larynx, difficulty in swallowing or breathing, or hoarseness to their health care provider, and seek emergent medical treatment.[41243]

      Assess patients frequently for their degree of sleepiness. Although modafinil has not been shown to produce functional impairment, any CNS stimulant could potentially alter thinking, judgment, or motor skills. Modafinil may mask signs that a patient is physically in need of sleep. Patients should be cautioned against driving or operating machinery, or performing other tasks that require mental alertness, until they are aware of the effects modafinil treatment has on their ability to perform such tasks.[41243]

      Various adverse psychiatric effects have occurred during administration of modafinil including mania, hallucinations, depression, and suicidal ideation. Caution should be exercised when administering modafinil to patients with a known history of mania or bipolar disorder, depression, psychosis (e.g., schizophrenia), suicidal ideation. Such patients may need behavioral assessments or frequent clinical observation. Consider discontinuing modafinil if psychiatric symptoms develop.[41243]

      Increased monitoring of heart rate and blood pressure may be appropriate in patients on modafinil. Caution should be exercised when prescribing modafinil to patients with known cardiac disease. Modafinil is not recommended in patients with a history of left ventricular hypertrophy or heart failure, and use is not recommended in patients with valvular heart disease (mitral valve prolapse) who have experienced the mitral valve prolapse syndrome when previously receiving CNS stimulants. Consider increased monitoring in patients with a recent history of acute myocardial infarction or unstable angina. Also use caution in patients with pre-existing hypertension. Modafinil has been associated with cardiovascular side effects in clinical trials in some patients with cardiovascular disease. Some of these changes have included palpitations, chest pain, ECG changes, and dyspnea. Findings suggestive of mitral valve prolapse syndrome include but are not limited to ischemic ECG changes, chest pain, or arrhythmia. If new onset of any of these findings occurs, consider cardiac evaluation. A retrospective analysis of the use of antihypertensive medication in clinical studies showed that a greater proportion of patients on modafinil required new or increased use of antihypertensive medications (2.4%) compared to patients on placebo (0.7%). The differential use was slightly larger when only studies in obstructive sleep apnea were included, with 3.4% of patients on modafinil and 1.1% of patients on placebo requiring such alterations.[41243]

      Serum concentrations of modafinil increase by up to 60% in the presence of severe hepatic disease (Child-Pugh grade C), such as cirrhosis, due to decreased hepatic metabolism. Dose reduction is recommended in patients severe hepatic impairment.[41243]

      There are no well-controlled studies of modafinil in pregnant women. However, there is a pregnancy registry for both armodafinil and modafinil. Between February 2010 to February 2019, 148 women were enrolled in the pregnancy registry; 81 patients received modafinil and 66 received armodafinil, and one patient received both drugs. Narcolepsy was the most common reason for drug therapy (70%), and 96% had first trimester exposure. Of these 148 women, 122 were followed prospectively. At the time of publication, 110 prospective pregnancies had known outcomes. The rate of major congenital malformations (MCM)s in prospective live births was 13% (n=13), which is higher than the estimated background risk of 2 to 4%. The MCMs included congenital torticollis (n=4), hypospadias (n=2), congenital heart defects (n=3). When pooling prospective and retrospective data, the rate of MCMs was the same (13%).[41243] [66140] Additionally, both intrauterine growth retardation and spontaneous abortion have occurred in association with armodafinil and modafinil. In animal studies of pregnant rats (armodafinil, modafinil) and rabbits (modafinil) during organogenesis, evidence of developmental toxicity (increased embryofetal and offspring mortality, decreased fetal growth) was observed at clinically relevant plasma exposure. It is unclear what effect, if any, the use of modafinil, a CNS stimulant, would have on the developing fetal brain. Modafinil should be used in pregnancy only under circumstances where the potential benefit to the mother outweighs the potential risk to the fetus. Pregnant patients receiving modafinil are encouraged to enroll in the pregnancy registry to provide information about the effects of in utero exposure to the drug. The effects of modafinil on labor and delivery are unknown. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to modafinil; information about the registry can be obtained at provigilpregnancyregistry.com or womensmentalhealth.org/research/pregnancyregistry or by calling 1-866-404-4106 or 1-866-961-2388.[41243]

      Recommendations regarding contraception requirements are available for modafinil. Clinicians should be aware that modafinil may cause failure of hormonal contraceptives, including oral hormonal contraceptives, as well as hormonal contraceptive depot injections, inserts, rings, patches, implants, and hormonal contraceptive devices (e.g., hormonal intrauterine devices - IUDs). The risk for contraceptive failure may lead to unplanned pregnancies. Caution patients regarding the potential increased risk of pregnancy when using steroidal contraceptives with modafinil and for 1 month after discontinuation of therapy. Patients should discuss birth control options with their health care providers.[41243]

      According to the manufacturer, caution should be exercised when modafinil is administered to a nursing woman.[41243] However, other experts have suggested avoidance of modafinil during lactation if possible or, the use of formula feeding if the breast-feeding female desires to continue modafinil treatment. The low molecular weight and pharmacokinetic profile of modafinil suggest that excretion into human breast milk is likely. Methylphenidate has been a suggested alternative for lactating patients with narcolepsy since transfer to breast milk has not been noted, the use of stimulant medications during lactation not been formally evaluated.[46149] [46150] The AAP has previously considered amphetamines, when used as drugs of abuse, to be contraindicated in breast-feeding due to concerns of irritability and poor sleeping pattern in the infant.[27500] The AAP has also previously cautioned that the long-term adverse event risk of exposure to psychotropic medications in a developing infant is not known.[27500] If maternal use of modafinil is absolutely medically necessary and the patient continues breast-feeding, the nursing infant should be observed for evidence of side effects, such as infection, nausea or decreased appetite, irritability, and insomnia. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

      Central nervous system (CNS) stimulants, such as modafinil, have a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction.[41243] [68987] Caution is recommended in patients with a known history of substance abuse, including alcoholism.[41243] Assess each individual's risk for abuse, misuse, or addiction before prescribing a CNS stimulant, and monitor for the development of these behaviors or conditions throughout treatment.[41243] [68987] CNS stimulants can be diverted for non-medical use into illicit channels or distribution. The most common source of non-medical use is sharing from family or friends with misuse of the patient's own prescription or obtaining from illicit channels occurring less frequently. Sharing of CNS stimulant medications can lead to substance abuse disorder and addiction in those they are shared with. Misuse and abuse of CNS stimulants can result in potential for overdose or poisoning and death; the risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Educate patients and their families about these risks, proper storage, and proper disposal of any unused medication. Misuse or abuse may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with stimulant abuse or misuse.[68987] The use of alcohol in combination with modafinil has not been studied; advise patients to avoid ethanol ingestion with the use of this medication.[41243]

      In the geriatric patient, the elimination of modafinil and its metabolites may be reduced as a consequence of aging. Therefore, lower initial doses and close monitoring are recommended for the geriatric patient. Experience in a limited number of patients who were greater than 65 years of age in clinical trials showed an incidence of adverse experiences similar to other age groups.[41243]

      The safety and effectiveness of modafinil have not been established in pediatric patients (adolescents, children, infants) for any indication; safety and/or efficacy concerns have been noted in pediatric patients.[41243] Serious skin rashes, including erythema multiforme major (EMM) and Stevens-Johnson Syndrome (SJS) have been associated with modafinil use in children and adolescents. In a controlled 6-week study, 165 pediatric patients (aged 5-17 years) with narcolepsy were treated with modafinil (n=123), or placebo (n=42). There were no statistically significant differences favoring modafinil over placebo for narcolepsy. Treatment emergent adverse reactions of the psychiatric and nervous system in children and adolescents included Tourette’s syndrome, insomnia, hostility, increased cataplexy, increased hypnagogic hallucinations, and suicidal ideation. Transient leukopenia, which resolved without medical intervention, was also observed. In the controlled clinical study, 3 adolescent females treated with modafinil experienced dysmenorrhea. There were three 7 to 9 week, double-blind, placebo-controlled, parallel group studies in children and adolescents (aged 6-17 years) with Attention-Deficit Hyperactivity Disorder (ADHD).[31838] Although these studies showed statistically significant differences favoring modafinil over placebo in reducing ADHD symptoms as measured by the ADHD-RS (school version), there were 3 cases of serious rash including one case of possible SJS among 933 patients exposed to modafinil in this program. Modafinil is not approved for use in treating ADHD in any age group.[41243]

      Revision Date: 03/28/2024, 01:48:00 AM

      References

      27500 - American Academy of Pediatrics (AAP) Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108(3):776-789.31838 - Biederman J, Swanson JM, Wigal SB, et al. Efficacy and safety of modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, flexible-dose study. Pediatrics 2005;116:777-8441243 - Provigil (modafinil) package insert. Frazer, PA: Cephalon; 2015 Jan.46149 - Hackett LP, Kristensen JH, Hale TW, et al. Methylphenidate and breast-feeding. Ann Pharmacother 2006;40:1890-1.46150 - Spigset O, Brede WR, Zahlsen K. Excretion of methylphenidate in breast milk. Am J Psychiatry 2007;164:348.66140 - Kaplan S, Braverman DL, Frishman I, Bartov N. Pregnancy and fetal outcomes following exposure to modafinil and armodafinil during pregnancy. JAMA Intern Med 2020; Published online Oct. 19, 2020. doi:10.1001/jamainternmed.2020.4009.68987 - Food and Drug Administration (FDA). FDA Drug Safety Communication: FDA updating warnings to improve safe use of prescription stimulants used to treat ADHD and other conditions. https://www.fda.gov/media/168066/download. Retrieved May 11, 2023.

      Mechanism of Action

      Mechanism of Action: The exact mechanism of modafinil's action in reducing somnolence is not fully understood. The enantiomers of modafinil appear to have similar pharmacologic profiles. Modafinil-induced wakefulness can be attenuated by the alpha-1 adrenergic antagonist, prazosin, which led to the initial conclusion that modafinil stimulates the central alpha-1 adrenergic system. However, in vitro assay systems responsive to alpha-adrenergic stimulation have not shown that modafinil is a direct or indirect alpha-1 adrenergic agonist. The primary sites of modafinil's CNS activity appear to be in the subregions of the hippocampus, the centrolateral nucleus of the thalamus, and the central nucleus of the amygdala. Limited animal studies demonstrate that modafinil may increase excitatory glutaminergic transmission in the thalamus and hippocampus. In contrast to the amphetamines and other CNS stimulants, the effects of modafinil do not appear to be mediated by dopamine or sympathomimetic systems. In vitro and in vivo studies demonstrate that modafinil does not bind to most of the neurochemical receptors involved in sleep-wake cycles, including norepinephrine, serotonin, dopamine, GABA, adenosine, histamine, monoamine oxidase B, and benzodiazepines. Modafinil also does not alter hormones associated with sleep regulation (i.e., melatonin, cortisol, or growth hormone). Modafinil-induced wakefulness does not influence nocturnal sleep patterns or the incidence of cataplexy in narcoleptic patients. In the periphery, the actions of modafinil appear to be minimal at normally prescribed doses. Modafinil doses of > 800 mg per day have produced symptoms of increased blood pressure and heart rate.

      Modafinil produces euphoric and psychoactive effects that are similar to other CNS stimulants, including methylphenidate and the amphetamines. Reinforcing behavior, including incrementation of dose and modafinil-seeking behavior, has been observed in monkeys previously trained to self-administer cocaine. However, modafinil is over 200 times less potent than dextroamphetamine in producing addictive behaviors. In an inpatient study of humans experienced with drugs of abuse, modafinil produced psychoactive behavior, feelings, and euphoric effects comparable to methylphenidate; modafinil was partially discriminated as 'stimulant-like'. Modafinil may potentially lead to habitual psychological dependence in some individuals. No specific withdrawal symptoms have been reported upon modafinil discontinuation in clinical studies. Unlike the amphetamines, modafinil has not been demonstrated to promote weight loss.

      Revision Date: 03/28/2024, 01:48:00 AM

      References

      Pharmacokinetics

      Modafinil is administered orally. Modafinil is administered orally as a racemic compound whose enantiomers (armodafinil and S-modafinil) have different pharmacokinetic properties and do not interconvert. At steady state, total exposure to the l-isomer of modafinil is three times that of the d-isomer; the trough (Cmin) of circulating modafinil after once daily dosing consists of 90% of the l-isomer and 10% of the d-isomer. The d-isomer is known to be eliminated three-fold faster than the l-isomer at steady state. Both enantiomers exhibit linear kinetics with multiple dosing; steady state levels of total modafinil and l-modafinil are reached in 2—4 days of daily dosing.

       

      Modafinil is well distributed in body tissues and is moderately bound to plasma proteins (~60%, mainly to albumin). The major route of elimination of modafinil is liver metabolism, with subsequent renal elimination of the metabolites. Liver metabolism occurs via hydrolytic deamination, S-oxidation, hydroxylation, and glucuronide conjugation. Only two modafinil metabolites are present in the plasma in significant concentrations (i.e., modafinil acid and modafinil sulfone). Both appear to have no pharmacologic activity. Modafinil acid is the major urinary metabolite. Less than 10% of modafinil is eliminated as the parent compound. The elimination half-life of modafinil is roughly 15 hours.

       

      Affected Cytochrome P450 (CYP450) enzymes and drug transporters: CYP3A4, CYP2C19, CYP2C9, CYP2B6, P-glycoprotein (P-gp)

      In humans, modafinil appears to induce its own metabolism through weak induction of the CYP3A4 isoenzyme. This weak induction can increase the elimination of drugs metabolized via CYP3A4, including oral contraceptives. Modafinil is also a weak inducer of CYP2B6 activity in vitro. In vitro data demonstrated that modafinil is a weak inducer of CYP1A2 in a concentration-related manner. However, in a clinical study with armodafinil using caffeine as a probe substrate, no significant effect on CYP1A2 activity was observed. In vitro data show that modafinil and one of its metabolites are inhibitors of CYP2C19, and may inhibit CYP2C9. Armodafinil is a substrate of P-gp but it is not clear if P-gp inhibitors affect its pharmacokinetics.[41243]

      Route-Specific Pharmacokinetics

      Oral Route

      Absorption of modafinil occurs rapidly after oral administration; peak plasma concentrations occur within 2 to 4 hours. The absolute bioavailability of modafinil tablets is not known due to insolubility factors that preclude the formulation of an intravenous dosage form. The presence of food delays the rate, but not the extent, of modafinil absorption.

      Special Populations

      Hepatic Impairment

      Patients with hepatic impairment exhibit reduced modafinil clearance; significant reductions in hepatic clearance result in a doubling of modafinil serum concentrations compared to normal subjects.[41243]

      Renal Impairment

      Renal failure (CrCl <= 20 ml/min) does not influence the pharmacokinetics of modafinil but does cause the accumulation of the inactive metabolite, modafinil acid.

      Pediatrics

      Data for pharmacokinetic studies of modafinil in children have not yet been reported.

      Geriatric

      The oral clearance of modafinil appears to be reduced in the elderly (20—50%).

      Gender Differences

      The pharmacokinetics of modafinil are not affected by gender.

      Revision Date: 03/28/2024, 01:48:00 AM

      References

      41243 - Provigil (modafinil) package insert. Frazer, PA: Cephalon; 2015 Jan.

      Pregnancy/Breast-feeding

      pregnancy

      There are no well-controlled studies of modafinil in pregnant women. However, there is a pregnancy registry for both armodafinil and modafinil. Between February 2010 to February 2019, 148 women were enrolled in the pregnancy registry; 81 patients received modafinil and 66 received armodafinil, and one patient received both drugs. Narcolepsy was the most common reason for drug therapy (70%), and 96% had first trimester exposure. Of these 148 women, 122 were followed prospectively. At the time of publication, 110 prospective pregnancies had known outcomes. The rate of major congenital malformations (MCM)s in prospective live births was 13% (n=13), which is higher than the estimated background risk of 2 to 4%. The MCMs included congenital torticollis (n=4), hypospadias (n=2), congenital heart defects (n=3). When pooling prospective and retrospective data, the rate of MCMs was the same (13%).[41243] [66140] Additionally, both intrauterine growth retardation and spontaneous abortion have occurred in association with armodafinil and modafinil. In animal studies of pregnant rats (armodafinil, modafinil) and rabbits (modafinil) during organogenesis, evidence of developmental toxicity (increased embryofetal and offspring mortality, decreased fetal growth) was observed at clinically relevant plasma exposure. It is unclear what effect, if any, the use of modafinil, a CNS stimulant, would have on the developing fetal brain. Modafinil should be used in pregnancy only under circumstances where the potential benefit to the mother outweighs the potential risk to the fetus. Pregnant patients receiving modafinil are encouraged to enroll in the pregnancy registry to provide information about the effects of in utero exposure to the drug. The effects of modafinil on labor and delivery are unknown. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to modafinil; information about the registry can be obtained at provigilpregnancyregistry.com or womensmentalhealth.org/research/pregnancyregistry or by calling 1-866-404-4106 or 1-866-961-2388.[41243]

      breast-feeding

      According to the manufacturer, caution should be exercised when modafinil is administered to a nursing woman.[41243] However, other experts have suggested avoidance of modafinil during lactation if possible or, the use of formula feeding if the breast-feeding female desires to continue modafinil treatment. The low molecular weight and pharmacokinetic profile of modafinil suggest that excretion into human breast milk is likely. Methylphenidate has been a suggested alternative for lactating patients with narcolepsy since transfer to breast milk has not been noted, the use of stimulant medications during lactation not been formally evaluated.[46149] [46150] The AAP has previously considered amphetamines, when used as drugs of abuse, to be contraindicated in breast-feeding due to concerns of irritability and poor sleeping pattern in the infant.[27500] The AAP has also previously cautioned that the long-term adverse event risk of exposure to psychotropic medications in a developing infant is not known.[27500] If maternal use of modafinil is absolutely medically necessary and the patient continues breast-feeding, the nursing infant should be observed for evidence of side effects, such as infection, nausea or decreased appetite, irritability, and insomnia. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

      Revision Date: 03/28/2024, 01:48:00 AM

      References

      27500 - American Academy of Pediatrics (AAP) Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108(3):776-789.41243 - Provigil (modafinil) package insert. Frazer, PA: Cephalon; 2015 Jan.46149 - Hackett LP, Kristensen JH, Hale TW, et al. Methylphenidate and breast-feeding. Ann Pharmacother 2006;40:1890-1.46150 - Spigset O, Brede WR, Zahlsen K. Excretion of methylphenidate in breast milk. Am J Psychiatry 2007;164:348.66140 - Kaplan S, Braverman DL, Frishman I, Bartov N. Pregnancy and fetal outcomes following exposure to modafinil and armodafinil during pregnancy. JAMA Intern Med 2020; Published online Oct. 19, 2020. doi:10.1001/jamainternmed.2020.4009.

      Interactions

      Level 1 (Severe)

      • Mavacamten

      Level 2 (Major)

      • Abemaciclib
      • Amobarbital
      • Amoxicillin; Clarithromycin; Omeprazole
      • Aprepitant, Fosaprepitant
      • Artemether; Lumefantrine
      • Aspirin, ASA; Butalbital; Caffeine
      • Atazanavir
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      • Atogepant
      • Avapritinib
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      • Barbiturates
      • Bedaquiline
      • Bupropion
      • Bupropion; Naltrexone
      • Butalbital; Acetaminophen
      • Butalbital; Acetaminophen; Caffeine
      • Butalbital; Acetaminophen; Caffeine; Codeine
      • Butalbital; Aspirin; Caffeine; Codeine
      • Cariprazine
      • Clarithromycin
      • Clopidogrel
      • Cobicistat
      • Cobimetinib
      • Conjugated Estrogens; Medroxyprogesterone
      • Daclatasvir
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      • Darunavir; Cobicistat
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      • Deflazacort
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      • Dienogest; Estradiol valerate
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      • Drospirenone
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      • Drospirenone; Ethinyl Estradiol
      • Drospirenone; Ethinyl Estradiol; Levomefolate
      • Elagolix; Estradiol; Norethindrone acetate
      • Elbasvir; Grazoprevir
      • Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide
      • Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate
      • Entrectinib
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      • Erlotinib
      • Esketamine
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      • Estradiol; Norethindrone
      • Estradiol; Norgestimate
      • Estradiol; Progesterone
      • Ethanol
      • Ethinyl Estradiol; Norelgestromin
      • Ethinyl Estradiol; Norethindrone Acetate
      • Ethinyl Estradiol; Norgestrel
      • Ethynodiol Diacetate; Ethinyl Estradiol
      • Etonogestrel
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      • Fedratinib
      • Flibanserin
      • Fosamprenavir
      • Glasdegib
      • Green Tea
      • Idelalisib
      • Ioflupane I 123
      • Isavuconazonium
      • Isocarboxazid
      • Isoniazid, INH; Pyrazinamide, PZA; Rifampin
      • Isoniazid, INH; Rifampin
      • Lansoprazole; Amoxicillin; Clarithromycin
      • Lefamulin
      • Lemborexant
      • Letermovir
      • Leuprolide; Norethindrone
      • Levonorgestrel
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      • Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate
      • Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate
      • Lonafarnib
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      • Norgestimate; Ethinyl Estradiol
      • Norgestrel
      • Olaparib
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      • Phenelzine
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      • Phenobarbital; Hyoscyamine; Atropine; Scopolamine
      • Pimavanserin
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      • Rifampin
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      • Sofosbuvir; Velpatasvir
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      • Sonidegib
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      • Tolvaptan
      • Tranylcypromine
      • Ubrogepant
      • Ulipristal
      • Vemurafenib
      • Venetoclax
      • Vonoprazan; Amoxicillin; Clarithromycin

      Level 3 (Moderate)

      • Abacavir; Dolutegravir; Lamivudine
      • Acetaminophen; Aspirin, ASA; Caffeine
      • Acetaminophen; Caffeine
      • Acetaminophen; Caffeine; Dihydrocodeine
      • Acetaminophen; Caffeine; Pyrilamine
      • Acetaminophen; Codeine
      • Acetaminophen; Hydrocodone
      • Acetaminophen; Oxycodone
      • Adagrasib
      • Albuterol; Budesonide
      • Amantadine
      • Amphetamine
      • Amphetamine; Dextroamphetamine
      • Amphetamines
      • Apalutamide
      • Aripiprazole
      • Aspirin, ASA; Caffeine
      • Aspirin, ASA; Caffeine; Orphenadrine
      • Aspirin, ASA; Carisoprodol; Codeine
      • Aspirin, ASA; Oxycodone
      • Belzutifan
      • Benzhydrocodone; Acetaminophen
      • Benzphetamine
      • Brexpiprazole
      • Bromocriptine
      • Budesonide
      • Budesonide; Formoterol
      • Budesonide; Glycopyrrolate; Formoterol
      • Bupivacaine; Lidocaine
      • Bupivacaine; Meloxicam
      • Cabotegravir; Rilpivirine
      • Caffeine
      • Caffeine; Sodium Benzoate
      • Carbamazepine
      • Ceritinib
      • Chlorpheniramine; Codeine
      • Chlorpheniramine; Hydrocodone
      • Cimetidine
      • Cisapride
      • Citalopram
      • Clobazam
      • Clomipramine
      • Clozapine
      • Codeine
      • Codeine; Guaifenesin
      • Codeine; Guaifenesin; Pseudoephedrine
      • Codeine; Phenylephrine; Promethazine
      • Codeine; Promethazine
      • Conjugated Estrogens
      • Conjugated Estrogens; Bazedoxifene
      • Cyclosporine
      • Dapsone
      • Desipramine
      • Dextroamphetamine
      • Diazepam
      • Diclofenac
      • Diclofenac; Misoprostol
      • Dolutegravir
      • Dolutegravir; Lamivudine
      • Dolutegravir; Rilpivirine
      • Doravirine
      • Doravirine; Lamivudine; Tenofovir disoproxil fumarate
      • Doxepin
      • Doxercalciferol
      • Dronabinol
      • Empagliflozin; Linagliptin
      • Empagliflozin; Linagliptin; Metformin
      • Emtricitabine; Rilpivirine; Tenofovir alafenamide
      • Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate
      • Encorafenib
      • Enzalutamide
      • Ergotamine; Caffeine
      • Erythromycin
      • Escitalopram
      • Esterified Estrogens
      • Esterified Estrogens; Methyltestosterone
      • Estradiol
      • Estropipate
      • Ethotoin
      • Fentanyl
      • Fluconazole
      • Fluoxetine
      • food
      • Fosphenytoin
      • grapefruit juice
      • Homatropine; Hydrocodone
      • Hydantoins
      • Hydrocodone
      • Hydrocodone; Ibuprofen
      • Ibrutinib
      • Ibuprofen; Oxycodone
      • Ifosfamide
      • Imipramine
      • Itraconazole
      • Ketoconazole
      • Levoketoconazole
      • Lidocaine
      • Lidocaine; Epinephrine
      • Lidocaine; Prilocaine
      • Linagliptin
      • Linagliptin; Metformin
      • Linezolid
      • Lisdexamfetamine
      • Lurasidone
      • Maraviroc
      • Meloxicam
      • Methamphetamine
      • Nanoparticle Albumin-Bound Paclitaxel
      • Nanoparticle Albumin-Bound Sirolimus
      • Nateglinide
      • Nefazodone
      • Olanzapine; Fluoxetine
      • Omeprazole; Amoxicillin; Rifabutin
      • Oritavancin
      • Oxycodone
      • Pazopanib
      • Phenytoin
      • Posaconazole
      • Propranolol
      • Ribociclib
      • Ribociclib; Letrozole
      • Rifabutin
      • Rifapentine
      • Rilpivirine
      • Riluzole
      • Romidepsin
      • Ruxolitinib
      • Selegiline
      • Sertraline
      • Siponimod
      • Sirolimus
      • Solriamfetol
      • Sufentanil
      • Tasimelteon
      • Temsirolimus
      • Terbinafine
      • Theophylline, Aminophylline
      • Triazolam
      • Tucatinib
      • Vincristine
      • Vincristine Liposomal
      • Vorapaxar
      • Warfarin
      • Zolpidem

      Level 4 (Minor)

      • Amlodipine
      • Amlodipine; Atorvastatin
      • Amlodipine; Benazepril
      • Amlodipine; Celecoxib
      • Amlodipine; Olmesartan
      • Amlodipine; Valsartan
      • Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ
      • Carisoprodol
      • Donepezil
      • Donepezil; Memantine
      • Levamlodipine
      • Mitotane
      • Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ
      • Perindopril; Amlodipine
      • Rivaroxaban
      • Telmisartan; Amlodipine
      • Voriconazole
      Abacavir; Dolutegravir; Lamivudine: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with modafinil; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Modafinil is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme. [41243] [55594] Abemaciclib: (Major) Avoid coadministration of modafinil with abemaciclib due to decreased exposure to abemaciclib and its active metabolites, which may lead to reduced efficacy. Abemaciclib is a CYP3A substrate and modafinil is a CYP3A inducer. Coadministration is predicted to decrease the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 29%. [62393] Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Caffeine should be used cautiously with modafinil. Excessive intake should be limited. Excessive intake may cause nervousness, irritability, insomnia or other side effects. [41243] [4666] Acetaminophen; Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Caffeine should be used cautiously with modafinil. Excessive intake should be limited. Excessive intake may cause nervousness, irritability, insomnia or other side effects. [41243] [4666] Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Caffeine should be used cautiously with modafinil. Excessive intake should be limited. Excessive intake may cause nervousness, irritability, insomnia or other side effects. [41243] [4666] (Moderate) Concomitant use of dihydrocodeine with modafinil can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If modafinil is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Modafinil is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. [30282] [41243] Acetaminophen; Caffeine; Pyrilamine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Caffeine should be used cautiously with modafinil. Excessive intake should be limited. Excessive intake may cause nervousness, irritability, insomnia or other side effects. [41243] [4666] Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with modafinil can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If modafinil is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Modafinil is a moderate CYP3A4 inducer. [33654] [34883] [41243] Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with modafinil can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If modafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. [30379] [41243] [56303] Acetaminophen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with modafinil is necessary; consider increasing the dose of oxycodone as needed. If modafinil is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. [39926] [41243] Adagrasib: (Moderate) Monitor for an increase in modafinil-related adverse reactions if coadministration with adagrasib is necessary. Modafinil has multiple pathways for metabolism including non-CYP-related pathways; however, due to partial involvement of the CYP3A enzymes, concomitant use of strong CYP3A inhibitors such as adagrasib could increase plasma concentrations of modafinil. [41243] [68325] Albuterol; Budesonide: (Moderate) Theoretically, induction of the cytochrome P450 3A4 isoenzyme by modafinil may result in a lowering of budesonide plasma concentrations, reducing the clinical effect. [28001] [28529] Amantadine: (Moderate) Use of amantadine with modafinil, a CNS stimulant, requires careful observation. Coadministration may increase the risk of stimulant effects, such as nervousness, irritability, insomnia, tremor, seizures, or cardiac arrhythmias. [28049] [28529] [46061] Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as modafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased. [35588] [41243] Amlodipine; Atorvastatin: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as modafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased. [35588] [41243] Amlodipine; Benazepril: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as modafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased. [35588] [41243] Amlodipine; Celecoxib: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as modafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased. [35588] [41243] Amlodipine; Olmesartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as modafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased. [35588] [41243] Amlodipine; Valsartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as modafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased. [35588] [41243] Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as modafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased. [35588] [41243] Amobarbital: (Major) It is not clear how modafinil interacts with barbiturates like phenobarbital. Modafinil is partially metabolized by CYP3A4 and combined use with CYP3A4 inducers such as phenobarbital and other barbiturates may result in decreased modafinil efficacy. Barbiturates used for sleep could counteract the effect of modafinil on wakefulness, and would not ordinarily be prescribed. The potential effects of combining modafinil with anticonvulsant barbiturate medications are unclear. Many psychostimulants can reduce the seizure threshold, but it is not clear if modafinil can affect seizure control. [28001] [41243] Amoxicillin; Clarithromycin; Omeprazole: (Major) Coadministration of modafinil and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. Additionally, clarithromycin is a significant inhibitor of CYP3A4, which may increase serum concentrations of modafinil. [28238] [41243] Amphetamine: (Moderate) The use of modafinil with other psychostimulants, including amphetamines (e.g., amphetamine, dextroamphetamine, lisdexamfetamine), has not been extensively studied. Patients receiving combination therapy of modafinil with other psychostimulants should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other CNS stimulant-related side effects. In single-dose studies of dextroamphetamine combined with modafinil, no significant pharmacokinetic interactions occurred, but a slight increase in stimulant-associated side effects was noted. [41243] [54946] Amphetamine; Dextroamphetamine: (Moderate) The use of modafinil with other psychostimulants, including amphetamines (e.g., amphetamine, dextroamphetamine, lisdexamfetamine), has not been extensively studied. Patients receiving combination therapy of modafinil with other psychostimulants should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other CNS stimulant-related side effects. In single-dose studies of dextroamphetamine combined with modafinil, no significant pharmacokinetic interactions occurred, but a slight increase in stimulant-associated side effects was noted. [41243] [54946] Amphetamines: (Moderate) The use of modafinil with other psychostimulants, including amphetamines (e.g., amphetamine, dextroamphetamine, lisdexamfetamine), has not been extensively studied. Patients receiving combination therapy of modafinil with other psychostimulants should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other CNS stimulant-related side effects. In single-dose studies of dextroamphetamine combined with modafinil, no significant pharmacokinetic interactions occurred, but a slight increase in stimulant-associated side effects was noted. [41243] [54946] Apalutamide: (Moderate) Monitor for decreased efficacy of modafinil if coadministration with apalutamide is necessary. Modafinil is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. The probability of effect of apalutamide on modafinil exposure is low due to the existence of multiple pathways for modafinil metabolism, as well as the fact that a non-CYP-related pathway is the most rapid in metabolizing modafinil; however, plasma concentrations of modafinil may be impacted by strong CYP3A4 inducers. [41243] [62874] Aprepitant, Fosaprepitant: (Major) Use caution if modafinil and aprepitant, fosaprepitant are used concurrently, and monitor for a possible decrease in the efficacy of aprepitant as well as an increase in modafinil-related adverse effects for several days after administration of a multi-day aprepitant regimen. Modafinil is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of modafinil. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Additionally, modafinil is a moderate CYP3A4 inducer and aprepitant is a CYP3A4 substrate. When a single dose of aprepitant (375 mg, or 3 times the maximum recommended dose) was administered on day 9 of a 14-day rifampin regimen (a strong CYP3A4 inducer), the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased by 3-fold. The manufacturer of aprepitant recommends avoidance of administration with strong CYP3A4 inducers, but does not provide guidance for low-to-moderate inducers. [30676] [40027] [41243] Aripiprazole: (Moderate) Because aripiprazole is metabolized by CYP3A4, concurrent use of CYP3A4 inducers such as modafinil may result in decreased plasma concentrations of aripiprazole. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. An increase in aripiprazole dosage may be clinically warranted in some patients. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inducer. [42845] [53394] [60196] [63328] Artemether; Lumefantrine: (Major) Modafinil is a substrate/inducer and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity. [35401] [5259] Aspirin, ASA; Butalbital; Caffeine: (Major) It is not clear how modafinil interacts with barbiturates like phenobarbital. Modafinil is partially metabolized by CYP3A4 and combined use with CYP3A4 inducers such as phenobarbital and other barbiturates may result in decreased modafinil efficacy. Barbiturates used for sleep could counteract the effect of modafinil on wakefulness, and would not ordinarily be prescribed. The potential effects of combining modafinil with anticonvulsant barbiturate medications are unclear. Many psychostimulants can reduce the seizure threshold, but it is not clear if modafinil can affect seizure control. [28001] [41243] (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Caffeine should be used cautiously with modafinil. Excessive intake should be limited. Excessive intake may cause nervousness, irritability, insomnia or other side effects. [41243] [4666] Aspirin, ASA; Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Caffeine should be used cautiously with modafinil. Excessive intake should be limited. Excessive intake may cause nervousness, irritability, insomnia or other side effects. [41243] [4666] Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Caffeine should be used cautiously with modafinil. Excessive intake should be limited. Excessive intake may cause nervousness, irritability, insomnia or other side effects. [41243] [4666] Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with modafinil can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If modafinil is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Modafinil is a moderate CYP3A4 inducer. [33654] [34883] [41243] (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as modafinil, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects. [4718] [5113] [7810] Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with modafinil is necessary; consider increasing the dose of oxycodone as needed. If modafinil is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. [39926] [41243] Atazanavir: (Major) Coadministration of atazanavir with modafinil is not recommended as there is a potential for elevated modafinil concentrations and decreased atazanavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Modafinil is a CYP3A4 substrate/inducer. Atazanavir is an inhibitor/substrate of CYP3A4. [28142] [41243] Atazanavir; Cobicistat: (Major) Coadministration of atazanavir with modafinil is not recommended as there is a potential for elevated modafinil concentrations and decreased atazanavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Modafinil is a CYP3A4 substrate/inducer. Atazanavir is an inhibitor/substrate of CYP3A4. [28142] [41243] (Major) Coadministration of cobicistat with modafinil is not recommended as there is a potential for elevated modafinil concentrations and decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Modafinil is a CYP3A4 substrate/inducer. Cobicistat is an inhibitor/substrate of CYP3A4. [41243] [51664] [58000] Atogepant: (Major) Avoid use of atogepant and modafinil when atogepant is used for chronic migraine. Use an atogepant dose of 30 or 60 mg PO once daily for episodic migraine if coadministered with modafinil. Concurrent use may decrease atogepant exposure and reduce efficacy. Atogepant is a CYP3A substrate and modafinil is a weak CYP3A inducer. Coadministration with a weak CYP3A inducer resulted in a 25% reduction in atogepant overall exposure and a 24% reduction in atogepant peak concentration. [41243] [67011] Avapritinib: (Major) Avoid coadministration of avapritinib with modafinil due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively. [41243] [64922] Axitinib: (Major) Avoid coadministration of axitinib with modafinil if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and modafinil is a moderate CYP3A4 inducer. [41243] [48494] Barbiturates: (Major) It is not clear how modafinil interacts with barbiturates like phenobarbital. Modafinil is partially metabolized by CYP3A4 and combined use with CYP3A4 inducers such as phenobarbital and other barbiturates may result in decreased modafinil efficacy. Barbiturates used for sleep could counteract the effect of modafinil on wakefulness, and would not ordinarily be prescribed. The potential effects of combining modafinil with anticonvulsant barbiturate medications are unclear. Many psychostimulants can reduce the seizure threshold, but it is not clear if modafinil can affect seizure control. [28001] [41243] Bedaquiline: (Major) Avoid concurrent use of modafinil with bedaquiline. Modafinil is a CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect. [41243] [52746] Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of modafinil with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and modafinil is a CYP2C19 inhibitor. [41243] [66875] Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with modafinil may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If concomitant use is necessary, consider increasing the benzhydrocodone dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Discontinuation of modafinil may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. If modafinil is discontinued, consider a benzhydrocodone dosage reduction and monitor patients for respiratory depression and sedation at frequent intervals. Benzhydrocodone is a prodrug of hydrocodone. Modafinil is an inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone. [41243] [62889] Benzphetamine: (Moderate) The use of modafinil with other psychostimulants, including amphetamines (e.g., amphetamine, dextroamphetamine, lisdexamfetamine), has not been extensively studied. Patients receiving combination therapy of modafinil with other psychostimulants should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other CNS stimulant-related side effects. In single-dose studies of dextroamphetamine combined with modafinil, no significant pharmacokinetic interactions occurred, but a slight increase in stimulant-associated side effects was noted. [41243] [54946] Brexpiprazole: (Moderate) Because brexpiprazole is partially metabolized by CYP3A4, concurrent use of CYP3A4 inducers such as modafinil or armodafinil may result in decreased plasma concentrations of brexpiprazole. If these agents are used in combination, the patient should be carefully monitored for a decrease in brexpiprazole efficacy. An increase in brexpiprazole dosage may be clinically warranted in some patients. [5259] [59949] Bromocriptine: (Moderate) Caution and close monitoring are advised if bromocriptine and modafinil are used together. Concurrent use may decrease the plasma concentrations of bromocriptine resulting in loss of efficacy. Bromocriptine is extensively metabolized by the liver via CYP3A4; modafinil is a moderate inducer of CYP3A4. [35591] [41243] Budesonide: (Moderate) Theoretically, induction of the cytochrome P450 3A4 isoenzyme by modafinil may result in a lowering of budesonide plasma concentrations, reducing the clinical effect. [28001] [28529] Budesonide; Formoterol: (Moderate) Theoretically, induction of the cytochrome P450 3A4 isoenzyme by modafinil may result in a lowering of budesonide plasma concentrations, reducing the clinical effect. [28001] [28529] Budesonide; Glycopyrrolate; Formoterol: (Moderate) Theoretically, induction of the cytochrome P450 3A4 isoenzyme by modafinil may result in a lowering of budesonide plasma concentrations, reducing the clinical effect. [28001] [28529] Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and modafinil may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; modafinil induces both isoenzymes. [32857] [41243] Bupivacaine; Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with modafinil is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and modafinil is a weak CYP2C9 inhibitor. [41243] [65019] Bupropion: (Major) Bupropion is associated with a dose-related risk of seizures. It is unclear whether modafinil lowers the seizure threshold. Seizures have occurred during post-marketing use of modafinil, although the frequency is unknown. [28058] [40907] Bupropion; Naltrexone: (Major) Bupropion is associated with a dose-related risk of seizures. It is unclear whether modafinil lowers the seizure threshold. Seizures have occurred during post-marketing use of modafinil, although the frequency is unknown. [28058] [40907] Butalbital; Acetaminophen: (Major) It is not clear how modafinil interacts with barbiturates like phenobarbital. Modafinil is partially metabolized by CYP3A4 and combined use with CYP3A4 inducers such as phenobarbital and other barbiturates may result in decreased modafinil efficacy. Barbiturates used for sleep could counteract the effect of modafinil on wakefulness, and would not ordinarily be prescribed. The potential effects of combining modafinil with anticonvulsant barbiturate medications are unclear. Many psychostimulants can reduce the seizure threshold, but it is not clear if modafinil can affect seizure control. [28001] [41243] Butalbital; Acetaminophen; Caffeine: (Major) It is not clear how modafinil interacts with barbiturates like phenobarbital. Modafinil is partially metabolized by CYP3A4 and combined use with CYP3A4 inducers such as phenobarbital and other barbiturates may result in decreased modafinil efficacy. Barbiturates used for sleep could counteract the effect of modafinil on wakefulness, and would not ordinarily be prescribed. The potential effects of combining modafinil with anticonvulsant barbiturate medications are unclear. Many psychostimulants can reduce the seizure threshold, but it is not clear if modafinil can affect seizure control. [28001] [41243] (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Caffeine should be used cautiously with modafinil. Excessive intake should be limited. Excessive intake may cause nervousness, irritability, insomnia or other side effects. [41243] [4666] Butalbital; Acetaminophen; Caffeine; Codeine: (Major) It is not clear how modafinil interacts with barbiturates like phenobarbital. Modafinil is partially metabolized by CYP3A4 and combined use with CYP3A4 inducers such as phenobarbital and other barbiturates may result in decreased modafinil efficacy. Barbiturates used for sleep could counteract the effect of modafinil on wakefulness, and would not ordinarily be prescribed. The potential effects of combining modafinil with anticonvulsant barbiturate medications are unclear. Many psychostimulants can reduce the seizure threshold, but it is not clear if modafinil can affect seizure control. [28001] [41243] (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Caffeine should be used cautiously with modafinil. Excessive intake should be limited. Excessive intake may cause nervousness, irritability, insomnia or other side effects. [41243] [4666] (Moderate) Concomitant use of codeine with modafinil can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If modafinil is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Modafinil is a moderate CYP3A4 inducer. [33654] [34883] [41243] Butalbital; Aspirin; Caffeine; Codeine: (Major) It is not clear how modafinil interacts with barbiturates like phenobarbital. Modafinil is partially metabolized by CYP3A4 and combined use with CYP3A4 inducers such as phenobarbital and other barbiturates may result in decreased modafinil efficacy. Barbiturates used for sleep could counteract the effect of modafinil on wakefulness, and would not ordinarily be prescribed. The potential effects of combining modafinil with anticonvulsant barbiturate medications are unclear. Many psychostimulants can reduce the seizure threshold, but it is not clear if modafinil can affect seizure control. [28001] [41243] (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Caffeine should be used cautiously with modafinil. Excessive intake should be limited. Excessive intake may cause nervousness, irritability, insomnia or other side effects. [41243] [4666] (Moderate) Concomitant use of codeine with modafinil can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If modafinil is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Modafinil is a moderate CYP3A4 inducer. [33654] [34883] [41243] Cabotegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering modafinil with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Modafinil is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. [44376] Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. [41243] [4666] (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Caffeine should be used cautiously with modafinil. Excessive intake should be limited. Excessive intake may cause nervousness, irritability, insomnia or other side effects. [41243] [4666] Caffeine; Sodium Benzoate: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Caffeine should be used cautiously with modafinil. Excessive intake should be limited. Excessive intake may cause nervousness, irritability, insomnia or other side effects. [41243] [4666] Carbamazepine: (Moderate) Modafinil is partially metabolized by CYP3A4 and combined use with CYP3A4 inducers such as carbamazepine may result in decreased modafinil efficacy. In vitro data indicate that modafinil is an inducer of CYP3A4. Therefore, decreased carbamazepine serum levels are possible. Clinically, be alert for increased sleepiness or other indicators of reduced mofafinil efficacy. The potential pharmacodynamic effects of combining modafinil with anticonvulsant medications are unclear; however, should it be noted that other CNS stimulants (e.g., amphetamines) are known to lower the seizure threshold. [41243] [4718] Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Concurrent use of cariprazine with CYP3A4 inducers, such as modafinil or armodafinil, has not been evaluated and is not recommended because the net effect on active drug and metabolites is unclear. [60164] Carisoprodol: (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as modafinil, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects. [4718] [5113] [7810] Ceritinib: (Moderate) Monitor for an increase in modafinil-related adverse reactions if coadministration with ceritinib is necessary. Modafinil has multiple pathways for metabolism including non-CYP-related pathways; however, due to partial involvement of the CYP3A enzymes, concomitant use of strong CYP3A4 inhibitors such as ceritinib could increase plasma concentrations of modafinil. [41243] [57094] Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with modafinil can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If modafinil is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Modafinil is a moderate CYP3A4 inducer. [33654] [34883] [41243] Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with modafinil can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If modafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. [30379] [41243] [56303] Cimetidine: (Moderate) Modafinil is extensively metabolized by the CYP3A4 hepatic isoenzyme. When significant CYP3A4 inhibitors like cimetidine are administered concomitantly with modafinil, the health care professional may need to observe the patient for increased effects from modafinil. [5259] Cisapride: (Moderate) Cisapride is metabolized by the hepatic cytochrome P450 enzyme system, specifically the CYP3A4 isoenzyme. Inducers of CYP3A4, such as modafinil, may increase the clearance of cisapride. [5137] Citalopram: (Moderate) The plasma concentration of citalopram, a CYP2C19 substrate, may be increased when administered concurrently with modafinil, a CYP2C19 inhibitor. Because citalopram causes dose-dependent QT prolongation, the maximum daily dose should not exceed 20 mg per day in patients receiving CYP2C19 inhibitors. [28269] [41243] Clarithromycin: (Major) Coadministration of modafinil and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. Additionally, clarithromycin is a significant inhibitor of CYP3A4, which may increase serum concentrations of modafinil. [28238] [41243] Clobazam: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of modafinil or armodafinil. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and modafinil and armodafinil are inhibitors of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated. [33467] [46370] [5259] Clomipramine: (Moderate) Modafinil inhibits CYP2C19 at pharmacologically relevant concentrations. In patients deficient in the CYP2D6 enzyme (poor metabolizers, 7% to 10% of the Caucasian population), the metabolism of certain tricyclics (i.e., clomipramine, desipramine, doxepin, imipramine) may be largely dependent on CYP2C19. One case of a narcoleptic patient is available in which the patient experienced increased side effects and increased serum levels of clomipramine and its active metabolite, desmethylclomipramine, during modafinil treatment. Because tricyclic antidepressants may be given to the narcoleptic patient for the treatment of cataplexy, the health care professional should be aware of the potential for interactions with modafinil. Patients on tricyclic antidepressants may require antidepressant dose reductions. [33467] [41243] [5525] Clopidogrel: (Major) Modafinil may reduce the antiplatelet activity of clopidogrel by inhibiting clopidogrel's metabolism to its active metabolite. Use clopidogrel and modafinil together with caution and monitor for reduced efficacy of clopidogrel. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps; the CYP2C19 isoenzyme is involved in both steps. Modafinil is an inhibitor of CYP2C19. [28435] [41243] Clozapine: (Moderate) Caution is advisable during concurrent use of modafinil or armodafinil with clozapine. Modanil and armodafinil have potential to induce CYP1A2, one of the isoenzymes responsible for the metabolism of clozapine. Patients receiving clozapine in combination with a CYP1A2 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. An interaction between modafinil and clozapine has been reported in a case report that resulted in clinical side effects. After the addition of modafinil to the drug regimen of a patient stabilized on clozapine, the patient became symptomatic with dizziness, problems with gait, and sinus tachycardia. Clozapine serum concentrations were found to be elevated. All symptoms resolved and the patient's clozapine levels returned to normal on modafinil discontinuation. The mechanism of the interaction is unclear, but may be related to changes in clozapine metabolism by modafinil. Concomitant therapy of modafinil and clozapine should be approached with close monitoring of the patient's clinical status. [28262] [33467] [41243] [5042] Cobicistat: (Major) Coadministration of cobicistat with modafinil is not recommended as there is a potential for elevated modafinil concentrations and decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Modafinil is a CYP3A4 substrate/inducer. Cobicistat is an inhibitor/substrate of CYP3A4. [41243] [51664] [58000] Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with modafinil due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and modafinil is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer. [41243] [60281] Codeine: (Moderate) Concomitant use of codeine with modafinil can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If modafinil is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Modafinil is a moderate CYP3A4 inducer. [33654] [34883] [41243] Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with modafinil can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If modafinil is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Modafinil is a moderate CYP3A4 inducer. [33654] [34883] [41243] Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with modafinil can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If modafinil is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Modafinil is a moderate CYP3A4 inducer. [33654] [34883] [41243] Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with modafinil can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If modafinil is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Modafinil is a moderate CYP3A4 inducer. [33654] [34883] [41243] Codeine; Promethazine: (Moderate) Concomitant use of codeine with modafinil can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If modafinil is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Modafinil is a moderate CYP3A4 inducer. [33654] [34883] [41243] Conjugated Estrogens: (Moderate) Modafinil is an inducer of CYP3A hepatic enzymes. Estrogens are metabolized by CYP3A4. A decrease in estrogen concentrations, and thus efficacy, may occur in patients taking estrogens for hormone replacement therapy. If these drugs are used together, monitor patients for a decrease in clinical effects. Dosage adjustments may be necessary. [41243] [4718] [4744] Conjugated Estrogens; Bazedoxifene: (Moderate) Modafinil is an inducer of CYP3A hepatic enzymes. Estrogens are metabolized by CYP3A4. A decrease in estrogen concentrations, and thus efficacy, may occur in patients taking estrogens for hormone replacement therapy. If these drugs are used together, monitor patients for a decrease in clinical effects. Dosage adjustments may be necessary. [41243] [4718] [4744] Conjugated Estrogens; Medroxyprogesterone: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] (Moderate) Modafinil is an inducer of CYP3A hepatic enzymes. Estrogens are metabolized by CYP3A4. A decrease in estrogen concentrations, and thus efficacy, may occur in patients taking estrogens for hormone replacement therapy. If these drugs are used together, monitor patients for a decrease in clinical effects. Dosage adjustments may be necessary. [41243] [4718] [4744] Cyclosporine: (Moderate) Modafinil can increase the clearance of cyclosporine by inducing cyclosporine metabolism. Increased cyclosporine clearance and decreased cyclosporine concentrations can lead to loss of therapeutic effect or organ rejection. Cyclosporine concentrations should be monitored closely after the addition of modafinil until a new steady-state level is achieved. [4718] Daclatasvir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as modafinil. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance. [41243] [60001] Dapsone: (Moderate) Closely monitor for a reduction in dapsone efficacy and signs of hemolytic anemia if coadministration with modafinil is necessary. Dapsone is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. Coadministration may decrease plasma concentrations of dapsone and increase the formation of dapsone hydroxylamine (a metabolite associated with hemolysis). [34335] [34470] [60612] Darunavir: (Major) Coadministration of darunavir with modafinil is not recommended as there is a potential for elevated modafinil concentrations and decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Modafinil is a CYP3A4 substrate/inducer. Darunavir is an inhibitor/substrate of CYP3A4. [32432] [41243] Darunavir; Cobicistat: (Major) Coadministration of cobicistat with modafinil is not recommended as there is a potential for elevated modafinil concentrations and decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Modafinil is a CYP3A4 substrate/inducer. Cobicistat is an inhibitor/substrate of CYP3A4. [41243] [51664] [58000] (Major) Coadministration of darunavir with modafinil is not recommended as there is a potential for elevated modafinil concentrations and decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Modafinil is a CYP3A4 substrate/inducer. Darunavir is an inhibitor/substrate of CYP3A4. [32432] [41243] Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Coadministration of cobicistat with modafinil is not recommended as there is a potential for elevated modafinil concentrations and decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Modafinil is a CYP3A4 substrate/inducer. Cobicistat is an inhibitor/substrate of CYP3A4. [41243] [51664] [58000] (Major) Coadministration of darunavir with modafinil is not recommended as there is a potential for elevated modafinil concentrations and decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Modafinil is a CYP3A4 substrate/inducer. Darunavir is an inhibitor/substrate of CYP3A4. [32432] [41243] Deflazacort: (Major) Avoid concomitant use of deflazacort and modafinil. Concurrent use may significantly decrease concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in loss of efficacy. Deflazacort is a CYP3A4 substrate; modafinil is a moderate inducer of CYP3A4. Administration of deflazacort with multiple doses of rifampin (a strong CYP3A4 inducer) resulted in geometric mean exposures that were approximately 95% lower compared to administration alone. [41243] [61750] Desipramine: (Moderate) Modafinil inhibits CYP2C19 at pharmacologically relevant concentrations. In patients deficient in the CYP2D6 enzyme (poor metabolizers, 7% to 10% of the Caucasian population), the metabolism of certain tricyclics (i.e., clomipramine, desipramine, doxepin, imipramine) may be largely dependent on CYP2C19. One case of a narcoleptic patient is available in which the patient experienced increased side effects and increased serum levels of clomipramine and its active metabolite, desmethylclomipramine, during modafinil treatment. Because tricyclic antidepressants may be given to the narcoleptic patient for the treatment of cataplexy, the health care professional should be aware of the potential for interactions with modafinil. Patients on tricyclic antidepressants may require antidepressant dose reductions. [41243] Desogestrel; Ethinyl Estradiol: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of ethinyl estradiol in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. [41243] (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Dexmethylphenidate: (Major) The use of modafinil with other psychostimulants, including methylphenidate or its derivatives, has not been extensively studied. Patients receiving combination therapy of modafinil with other psychostimulants should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other CNS stimulant-related side effects. Single dose studies of methylphenidate combined with modafinil noted that the rate of absorption of modafinil was delayed up to one hour by the presence of methylphenidate; no changes occurred in the metabolism and extent of absorption of either medication. [41243] Dextroamphetamine: (Moderate) The use of modafinil with other psychostimulants, including amphetamines (e.g., amphetamine, dextroamphetamine, lisdexamfetamine), has not been extensively studied. Patients receiving combination therapy of modafinil with other psychostimulants should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other CNS stimulant-related side effects. In single-dose studies of dextroamphetamine combined with modafinil, no significant pharmacokinetic interactions occurred, but a slight increase in stimulant-associated side effects was noted. [41243] [54946] Dextromethorphan; Bupropion: (Major) Bupropion is associated with a dose-related risk of seizures. It is unclear whether modafinil lowers the seizure threshold. Seizures have occurred during post-marketing use of modafinil, although the frequency is unknown. [28058] [40907] Diazepam: (Moderate) Modafinil has demonstrated an inhibition of the CYP2C19 hepatic microsomal isoenzyme at pharmacologically relevant concentrations. Drugs that are largely eliminated via CYP2C19 metabolism, such as diazepam, may have prolonged elimination upon co-administration of modafinil. [5259] Diclofenac: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as modafinil; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events. [31949] Diclofenac; Misoprostol: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as modafinil; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events. [31949] Dienogest; Estradiol valerate: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] (Moderate) Modafinil is an inducer of CYP3A hepatic enzymes. Estrogens are metabolized by CYP3A4. A decrease in estrogen concentrations, and thus efficacy, may occur in patients taking estrogens for hormone replacement therapy. If these drugs are used together, monitor patients for a decrease in clinical effects. Dosage adjustments may be necessary. [41243] [4718] [4744] Dolutegravir: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with modafinil; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Modafinil is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme. [41243] [55594] Dolutegravir; Lamivudine: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with modafinil; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Modafinil is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme. [41243] [55594] Dolutegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering modafinil with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Modafinil is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. [44376] (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with modafinil; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Modafinil is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme. [41243] [55594] Donepezil: (Minor) The elimination of donepezil may be increased by concurrent administration of certain in vitro inducers of the hepatic isoenzymes CYP2D6 and CYP3A4 including modafinil. [29640] Donepezil; Memantine: (Minor) The elimination of donepezil may be increased by concurrent administration of certain in vitro inducers of the hepatic isoenzymes CYP2D6 and CYP3A4 including modafinil. [29640] Doravirine: (Moderate) Concurrent administration of doravirine and modafinil may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; modafinil is a moderate CYP3A4 inducer. [41243] [63484] Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Concurrent administration of doravirine and modafinil may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; modafinil is a moderate CYP3A4 inducer. [41243] [63484] Doxepin: (Moderate) Modafinil inhibits CYP2C19 at pharmacologically relevant concentrations. In patients deficient in the CYP2D6 enzyme (poor metabolizers, 7% to 10% of the Caucasian population), the metabolism of certain tricyclics (i.e., clomipramine, desipramine, doxepin, imipramine) may be largely dependent on CYP2C19. One case of a narcoleptic patient is available in which the patient experienced increased side effects and increased serum levels of clomipramine and its active metabolite, desmethylclomipramine, during modafinil treatment. Because tricyclic antidepressants may be given to the narcoleptic patient for the treatment of cataplexy, the health care professional should be aware of the potential for interactions with modafinil. Patients on tricyclic antidepressants may require antidepressant dose reductions. [39684] [41243] Doxercalciferol: (Moderate) Cytochrome P450 enzyme inhibitors, such as modafinil, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. [30802] [51248] Doxorubicin Liposomal: (Major) Modafinil is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of modafinil and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy. [41243] [56361] Doxorubicin: (Major) Modafinil is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of modafinil and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy. [41243] [56361] Dronabinol: (Moderate) Use caution if coadministration of dronabinol with modafinil is necessary, and monitor for changes in the efficacy or adverse effect profile of dronabinol (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate. Modafinil is a weak inhibitor of CYP2C9 and moderate CYP3A4 inducer. Concomitant use may result in altered plasma concentrations of dronabinol. [30431] [41243] [60951] Drospirenone: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Drospirenone; Estetrol: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Drospirenone; Estradiol: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] (Moderate) Modafinil is an inducer of CYP3A hepatic enzymes. Estrogens are metabolized by CYP3A4. A decrease in estrogen concentrations, and thus efficacy, may occur in patients taking estrogens for hormone replacement therapy. If these drugs are used together, monitor patients for a decrease in clinical effects. Dosage adjustments may be necessary. [41243] [4718] [4744] Drospirenone; Ethinyl Estradiol: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of ethinyl estradiol in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. [41243] (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of ethinyl estradiol in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. [41243] (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Elagolix; Estradiol; Norethindrone acetate: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] (Moderate) Modafinil is an inducer of CYP3A hepatic enzymes. Estrogens are metabolized by CYP3A4. A decrease in estrogen concentrations, and thus efficacy, may occur in patients taking estrogens for hormone replacement therapy. If these drugs are used together, monitor patients for a decrease in clinical effects. Dosage adjustments may be necessary. [41243] [4718] [4744] Elbasvir; Grazoprevir: (Major) Concurrent administration of elbasvir with modafinil should be avoided if possible. Modafinil is a moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. [41243] [60523] (Major) Concurrent administration of grazoprevir with modafinil should be avoided if possible. Modafinil is a moderate CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response. [41243] [60523] Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Coadministration of cobicistat with modafinil is not recommended as there is a potential for elevated modafinil concentrations and decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Modafinil is a CYP3A4 substrate/inducer. Cobicistat is an inhibitor/substrate of CYP3A4. [41243] [51664] [58000] (Major) Coadministration of elvitegravir with modafinil is not recommended as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Modafinil is a CYP3A4 inducer, while elvitegravir is a substrate of CYP3A4. [41243] [58001] Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of cobicistat with modafinil is not recommended as there is a potential for elevated modafinil concentrations and decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Modafinil is a CYP3A4 substrate/inducer. Cobicistat is an inhibitor/substrate of CYP3A4. [41243] [51664] [58000] (Major) Coadministration of elvitegravir with modafinil is not recommended as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Modafinil is a CYP3A4 inducer, while elvitegravir is a substrate of CYP3A4. [41243] [58001] Empagliflozin; Linagliptin: (Moderate) Concomitant use of linagliptin with modafinil may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; modafinil is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together. [41243] [51559] Empagliflozin; Linagliptin; Metformin: (Moderate) Concomitant use of linagliptin with modafinil may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; modafinil is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together. [41243] [51559] Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Close clinical monitoring is advised when administering modafinil with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Modafinil is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. [44376] Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Close clinical monitoring is advised when administering modafinil with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Modafinil is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. [44376] Encorafenib: (Moderate) Monitor for decreased efficacy of modafinil if coadministration with encorafenib is necessary. Modafinil is a CYP3A substrate and encorafenib is a strong CYP3A inducer. The probability of effect of encorafenib on modafinil exposure is low due to the existence of multiple pathways for modafinil metabolism, as well as the fact that a non-CYP-related pathway is the most rapid in metabolizing modafinil; however, plasma concentrations of modafinil may be impacted by strong CYP3A inducers. [41243] [63317] Entrectinib: (Major) Avoid coadministration of entrectinib with modafinil due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; modafinil is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%. [41243] [64567] Enzalutamide: (Moderate) Monitor for decreased efficacy of modafinil if coadministration with enzalutamide is necessary. Modafinil is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. The probability of effect of enzalutamide on modafinil exposure is low due to the existence of multiple pathways for modafinil metabolism, as well as the fact that a non-CYP-related pathway is the most rapid in metabolizing modafinil; however, plasma concentrations of modafinil may be impacted by strong CYP3A4 inducers. [41243] [51727] Erdafitinib: (Major) If coadministration of erdafitinib and modafinil is necessary at the initiation of erdafitinib therapy, administer the dose of erdafitinib as recommended (8 mg once daily with potential to increase the dose to 9 mg on days 14 to 21 based on phosphate levels and tolerability). If modafinil must be added to erdafitinib therapy after the initial dose increase period (days 14 to 21), increase the dose of erdafitinib up to 9 mg. If modafinil is discontinued, continue erdafitinib at the same dose in the absence of drug-related toxicity. Erdafitinib is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. [41243] [64064] Ergotamine; Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Caffeine should be used cautiously with modafinil. Excessive intake should be limited. Excessive intake may cause nervousness, irritability, insomnia or other side effects. [41243] [4666] Erlotinib: (Major) Avoid the coadministration of erlotinib with modafinil if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. Coadministration may decrease plasma concentrations of erlotinib. [30555] [41243] Erythromycin: (Moderate) Erythromycin can inhibit the hepatic metabolism of other drugs, such as modafinil, increasing their serum concentrations and potentially causing toxicity. [4978] Escitalopram: (Moderate) The plasma concentration of escitalopram, a CYP2C19 and CYP3A4 substrate, may be altered when administered concurrently with modafinil, a CYP2C19 inhibitor and CYP3A4 inducer. Because escitalopram is extensively metabolized by both CYP2C19 and CYP3A4, the outcome of the interaction is unpredictable. If these drugs are used together, monitor for reduced efficacy of escitalopram as well as escitalopram-associated adverse reactions. [28270] [41243] Esketamine: (Major) Closely monitor blood pressure during concomitant use of esketamine and modafinil. Coadministration of psychostimulants, such as modafinil, with esketamine may increase blood pressure, including the possibility of hypertensive crisis. [63989] Esterified Estrogens: (Moderate) Modafinil is an inducer of CYP3A hepatic enzymes. Estrogens are metabolized by CYP3A4. A decrease in estrogen concentrations, and thus efficacy, may occur in patients taking estrogens for hormone replacement therapy. If these drugs are used together, monitor patients for a decrease in clinical effects. Dosage adjustments may be necessary. [41243] [4718] [4744] Esterified Estrogens; Methyltestosterone: (Moderate) Modafinil is an inducer of CYP3A hepatic enzymes. Estrogens are metabolized by CYP3A4. A decrease in estrogen concentrations, and thus efficacy, may occur in patients taking estrogens for hormone replacement therapy. If these drugs are used together, monitor patients for a decrease in clinical effects. Dosage adjustments may be necessary. [41243] [4718] [4744] Estradiol: (Moderate) Modafinil is an inducer of CYP3A hepatic enzymes. Estrogens are metabolized by CYP3A4. A decrease in estrogen concentrations, and thus efficacy, may occur in patients taking estrogens for hormone replacement therapy. If these drugs are used together, monitor patients for a decrease in clinical effects. Dosage adjustments may be necessary. [41243] [4718] [4744] Estradiol; Levonorgestrel: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] (Moderate) Modafinil is an inducer of CYP3A hepatic enzymes. Estrogens are metabolized by CYP3A4. A decrease in estrogen concentrations, and thus efficacy, may occur in patients taking estrogens for hormone replacement therapy. If these drugs are used together, monitor patients for a decrease in clinical effects. Dosage adjustments may be necessary. [41243] [4718] [4744] Estradiol; Norethindrone: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] (Moderate) Modafinil is an inducer of CYP3A hepatic enzymes. Estrogens are metabolized by CYP3A4. A decrease in estrogen concentrations, and thus efficacy, may occur in patients taking estrogens for hormone replacement therapy. If these drugs are used together, monitor patients for a decrease in clinical effects. Dosage adjustments may be necessary. [41243] [4718] [4744] Estradiol; Norgestimate: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] (Moderate) Modafinil is an inducer of CYP3A hepatic enzymes. Estrogens are metabolized by CYP3A4. A decrease in estrogen concentrations, and thus efficacy, may occur in patients taking estrogens for hormone replacement therapy. If these drugs are used together, monitor patients for a decrease in clinical effects. Dosage adjustments may be necessary. [41243] [4718] [4744] Estradiol; Progesterone: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] (Moderate) Modafinil is an inducer of CYP3A hepatic enzymes. Estrogens are metabolized by CYP3A4. A decrease in estrogen concentrations, and thus efficacy, may occur in patients taking estrogens for hormone replacement therapy. If these drugs are used together, monitor patients for a decrease in clinical effects. Dosage adjustments may be necessary. [41243] [4718] [4744] Estropipate: (Moderate) Modafinil is an inducer of CYP3A hepatic enzymes. Estrogens are metabolized by CYP3A4. A decrease in estrogen concentrations, and thus efficacy, may occur in patients taking estrogens for hormone replacement therapy. If these drugs are used together, monitor patients for a decrease in clinical effects. Dosage adjustments may be necessary. [41243] [4718] [4744] Ethanol: (Major) Advise patients to avoid alcohol-containing beverages while taking modafinil. There is no information on the effects of concurrent administration of ethanol or alcohol-containing medications with modafinil; the CNS depressant effect of alcohol may reduce the response to modafinil. [41243] Ethinyl Estradiol; Norelgestromin: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of ethinyl estradiol in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. [41243] (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Ethinyl Estradiol; Norethindrone Acetate: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of ethinyl estradiol in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. [41243] (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Ethinyl Estradiol; Norgestrel: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of ethinyl estradiol in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. [41243] (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Ethotoin: (Moderate) Since modafinil is metabolized by the CYP3A4 isoenzyme, and hydantoins (e.g., phenytoin, fosphenytoin) are CYP3A4 inducers, decreased modafinil efficacy may result from increased modafinil metabolism. In addition, modafinil is an inhibitor of the CYP2C19 and CYP2C9 isoenzymes. Hydantoins are substrates of CYP2C19, and phenytoin is a substrate of CYP2C9. Hydantoin concentrations may increase. Monitor carefully for signs of toxicity; phenytoin concentration monitoring may be helpful. [41243] [4718] Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of ethinyl estradiol in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. [41243] (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Etonogestrel: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Etonogestrel; Ethinyl Estradiol: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of ethinyl estradiol in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. [41243] (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Fedratinib: (Major) Avoid coadministration of fedratinib with modafinil as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; modafinil is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated. [64568] Fentanyl: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of modafinil is necessary. If modafinil is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like modafinil with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression. [29623] [29763] [32731] [40943] [41243] Flibanserin: (Major) The concomitant use of flibanserin with CYP3A4 inducers significantly decreases flibanserin exposure compared to the use of flibanserin alone. Therefore, concurrent use of flibanserin and CYP3A4 inducers, such as modafinil or armodafinil, is not recommended. In addition, modafinil and armodafinil are inhibitors of CYP2C19, a minor metabolic pathway of flibanserin. [5259] [60099] Fluconazole: (Moderate) Modafinil is significantly metabolized by the CYP3A4 hepatic microsomal enzyme system. Azole antifungals, such as fluconazole, are significant inhibitors of this isoenzyme and may reduce the clearance of modafinil. [4718] [5259] Fluoxetine: (Moderate) Although no clinical data are available, fluoxetine may inhibit the clearance and potentiate the actions of modafinil. Modafinil is metabolized by CYP3A4 isozyme, a pathway that fluoxetine is known to inhibit. [4718] Food: (Moderate) Food delays the rate, but not the extent, of modafinil absorption by approximately one hour. A delayed onset of action of a modafinil dose may result from this interaction, but this may not be clinically significant to the patient. Patients may take modafinil with or without food. [41243] Fosamprenavir: (Major) Caution is advised when administering modafinil with fosamprenavir, as concurrent use may reduce the plasma concentrations of fosamprenavir. Modafinil is an inducer of the hepatic isoenzyme CYP3A4. Amprenavir, the active metabolite of fosamprenavir, is a substrate of CYP3A4. [29012] [41243] Fosphenytoin: (Moderate) Since modafinil is metabolized by the CYP3A4 isoenzyme, and hydantoins (e.g., phenytoin, fosphenytoin) are CYP3A4 inducers, decreased modafinil efficacy may result from increased modafinil metabolism. In addition, modafinil is an inhibitor of the CYP2C19 and CYP2C9 isoenzymes. Hydantoins are substrates of CYP2C19, and phenytoin is a substrate of CYP2C9. Hydantoin concentrations may increase. Monitor carefully for signs of toxicity; phenytoin concentration monitoring may be helpful. [41243] [4718] Glasdegib: (Major) Avoid coadministration of glasdegib and modafinil due to the potential for decreased glasdegib exposure and risk of decreased efficacy. If concurrent use cannot be avoided, increase the glasdegib dosage (i.e., from 100 mg PO daily to 200 mg PO daily; or from 50 mg PO daily to 100 mg PO daily). Resume the previous dose of glasdegib after modafinil has been discontinued for 7 days. Glasdegib is a CYP3A4 substrate; modafinil is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer was predicted to decrease the glasdegib AUC value by 55%. [41243] [63777] Grapefruit juice: (Moderate) Grapefruit juice has been reported to decrease the metabolism of drugs that are metabolized via the CYP3A4 isoenzyme; grapefruit juice inhibits CYP3A4 in enterocytes. Because modafinil is significantly metabolized through CYP3A4, patients should be advised to not significantly alter their grapefruit juice ingestion. [41243] [4718] Green Tea: (Major) Some, but not all, green tea products contain caffeine. Additive CNS stimulant effects are likely to occur when caffeine is coadministered with other CNS stimulants or psychostimulants. Caffeine should be avoided or used cautiously with modafinil. [4666] [4671] Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with modafinil can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If modafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. [30379] [41243] [56303] Hydantoins: (Moderate) Since modafinil is metabolized by the CYP3A4 isoenzyme, and hydantoins (e.g., phenytoin, fosphenytoin) are CYP3A4 inducers, decreased modafinil efficacy may result from increased modafinil metabolism. In addition, modafinil is an inhibitor of the CYP2C19 and CYP2C9 isoenzymes. Hydantoins are substrates of CYP2C19, and phenytoin is a substrate of CYP2C9. Hydantoin concentrations may increase. Monitor carefully for signs of toxicity; phenytoin concentration monitoring may be helpful. [41243] [4718] Hydrocodone: (Moderate) Concomitant use of hydrocodone with modafinil can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If modafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. [30379] [41243] [56303] Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with modafinil can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If modafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. [30379] [41243] [56303] Ibrutinib: (Moderate) Use ibrutinib and modafinil together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; modafinil is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold. [41243] [56410] Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with modafinil is necessary; consider increasing the dose of oxycodone as needed. If modafinil is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. [39926] [41243] Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with modafinil, a CYP3A substrate, as modafinil toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib. [41243] [57675] Ifosfamide: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with modafinil is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; modafinil is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde. [41243] [51027] Imipramine: (Moderate) Modafinil inhibits CYP2C19 at pharmacologically relevant concentrations. In patients deficient in the CYP2D6 enzyme (poor metabolizers, 7% to 10% of the Caucasian population), the metabolism of certain tricyclics (i.e., clomipramine, desipramine, doxepin, imipramine) may be largely dependent on CYP2C19. One case of a narcoleptic patient is available in which the patient experienced increased side effects and increased serum levels of clomipramine and its active metabolite, desmethylclomipramine, during modafinil treatment. Because tricyclic antidepressants may be given to the narcoleptic patient for the treatment of cataplexy, the health care professional should be aware of the potential for interactions with modafinil. Patients on tricyclic antidepressants may require antidepressant dose reductions. [41243] Ioflupane I 123: (Major) Hold modafinil for 3 days, or at least 5 medication half-lives, prior to performing dopamine transporter (DAT) imaging with radiolabeled ioflupane. Modafinil binds to the dopamine transporter which may interfere with striatal tracer binding and increase the risk for a false-positive scan. [60155] [69569] [69570] Isavuconazonium: (Major) Coadministration of isavuconazonium with modafinil is not recommended as there is a potential for elevated modafinil concentrations and decreased isavuconazonium concentrations. Decreased isavuconazonium concentrations may lead to a reduction of antifungal efficacy and the potential for treatment failure. Modafinil is a CYP3A4 substrate/inducer. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and inhibitor of CYP3A4. [34710] [59042] Isocarboxazid: (Major) Modafinil has not been evaluated for drug interactions with monoamine oxidase inhibitors (MAOIs). It is known that many other CNS stimulants may induce severe cardiovascular and cerebrovascular responses if administered in combination with drugs with non-selective MAO inhibitor activity. Until more is known regarding the pharmacology of modafinil, it is prudent avoid the use of modafinil in the presence of an MAO inhibitor. Due to the prolonged duration of action of MAOIs, a period of at least 14 days between the last dose of the MAOI and the first dose of modafinil should elapse. [33467] Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Rifampin exhibits significant induction of the hepatic microsomal CYP3A4 isoenzyme and may potentially increase the metabolism of modafinil. Decreased serum levels of modafinil could potentially result in decreased efficacy of modafinil. [5259] Isoniazid, INH; Rifampin: (Major) Rifampin exhibits significant induction of the hepatic microsomal CYP3A4 isoenzyme and may potentially increase the metabolism of modafinil. Decreased serum levels of modafinil could potentially result in decreased efficacy of modafinil. [5259] Itraconazole: (Moderate) Modafinil is extensively metabolized by the CYP3A4 hepatic isoenzyme and inhibitors of CYP3A4, such as itraconazole, may decrease modafinil clearance. Observation of the patient for increased effects from modafinil may be needed. [4718] [5259] Ketoconazole: (Moderate) Monitor for an increase in modafinil-related adverse reactions if coadministration with ketoconazole is necessary. Modafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as ketoconazole are possible. However, because modafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. [27982] [41243] [67231] Lansoprazole; Amoxicillin; Clarithromycin: (Major) Coadministration of modafinil and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. Additionally, clarithromycin is a significant inhibitor of CYP3A4, which may increase serum concentrations of modafinil. [28238] [41243] Lefamulin: (Major) Avoid coadministration of lefamulin with modafinil unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; modafinil is a moderate CYP3A4 inducer. [41243] [64576] Lemborexant: (Major) Avoid coadministration of lemborexant and modafinil as concurrent use may decrease lemborexant exposure which may reduce efficacy. Lemborexant is a CYP3A4 substrate; modafinil is a moderate CYP3A4 inducer. [41243] [64870] Letermovir: (Major) Concurrent administration of letermovir and modafinil is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. [41243] [62611] Leuprolide; Norethindrone: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Levamlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as modafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased. [35588] [41243] Levoketoconazole: (Moderate) Monitor for an increase in modafinil-related adverse reactions if coadministration with ketoconazole is necessary. Modafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as ketoconazole are possible. However, because modafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. [27982] [41243] [67231] Levonorgestrel: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Levonorgestrel; Ethinyl Estradiol: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of ethinyl estradiol in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. [41243] (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of ethinyl estradiol in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. [41243] (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of ethinyl estradiol in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. [41243] (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Lidocaine: (Moderate) Concomitant use of systemic lidocaine and modafinil may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; modafinil induces both isoenzymes. [32857] [41243] Lidocaine; Epinephrine: (Moderate) Concomitant use of systemic lidocaine and modafinil may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; modafinil induces both isoenzymes. [32857] [41243] Lidocaine; Prilocaine: (Moderate) Concomitant use of systemic lidocaine and modafinil may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; modafinil induces both isoenzymes. [32857] [41243] Linagliptin: (Moderate) Concomitant use of linagliptin with modafinil may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; modafinil is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together. [41243] [51559] Linagliptin; Metformin: (Moderate) Concomitant use of linagliptin with modafinil may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; modafinil is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together. [41243] [51559] Linezolid: (Moderate) Linezolid is an antibiotic which is a reversible, non-selective inhibitor of MAO. Administration of modafinil to patients receiving linezolid may invoke a hypertensive reaction. Such drugs should be avoided during and for up to 2 weeks following the discontinuation of linezolid. [5330] Lisdexamfetamine: (Moderate) The use of modafinil with other psychostimulants, including amphetamines (e.g., amphetamine, dextroamphetamine, lisdexamfetamine), has not been extensively studied. Patients receiving combination therapy of modafinil with other psychostimulants should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other CNS stimulant-related side effects. In single-dose studies of dextroamphetamine combined with modafinil, no significant pharmacokinetic interactions occurred, but a slight increase in stimulant-associated side effects was noted. [41243] [54946] Lonafarnib: (Major) Avoid coadministration of lonafarnib and modafinil; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. The exposure of modafinil may also be increased. If coadministration is unavoidable, closely monitor patients for adverse reactions from both drugs. Lonafarnib is a CYP2C9 substrate and strong CYP3A4 inhibitor; modafinil is a CYP3A4 substrate and CYP2C9 inhibitor. [41243] [66129] Lopinavir; Ritonavir: (Major) Concurrent administration of modafinil with ritonavir may result in elevated plasma concentrations of modafinil and decreased concentrations of ritonavir. Modafinil is a substrate and inducer of the hepatic isoenzyme CYP3A4; ritonavir is a CYP3A4 substrate. In addition, ritonavir is a potent CYP3A4 inhibitor. Because the resultant effect of coadministration of a CYP3A4 inducer (modafinil) and inhibitor (ritonavir) on the plasma concentrations of these drugs is not defined, caution and close monitoring are advised if these drugs are administered together. [41243] [58664] Lorlatinib: (Major) Avoid concomitant use of lorlatinib and modafinil due to decreased plasma concentrations of lorlatinib, which may reduce its efficacy. If concomitant use is necessary, increase the dose of lorlatinib to 125 mg PO once daily. Lorlatinib is a CYP3A substrate and modafinil is a moderate CYP3A inducer. Administration with modafinil decreased lorlatinib exposure by 23%. [41243] [63732] Lumateperone: (Major) Avoid coadministration of lumateperone and modafinil as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A4 substrate; modafinil is a moderate CYP3A4 inducer. [41243] [56579] [64885] Lurasidone: (Moderate) Because lurasidone is primarily metabolized by CYP3A4, decreased plasma concentrations of lurasidone may occur when the drug is co-administered with inducers of CYP3A4. Concurrent use of lurasidone and CYP3A4 inducers, such as modafinil, may lead to a decrease in efficacy of lurasidone. If lurasidone is used with a moderate CYP3A4 inducer, it may be necessary to increase the lurasidone dose after chronic treatment (7 days or more). [28529] [42227] Macimorelin: (Major) Discontinue modafinil and allow a sufficient washout period to pass before administering macimorelin. Use of these drugs together can significantly decrease macimorelin plasma concentrations, and may result in a false positive test for growth hormone deficiency. No drug-drug interaction studies have been conducted; however, macimorelin is primarily metabolized by CYP3A4 and modafinil is a CYP3A4 inducer. [41243] [62723] Maraviroc: (Moderate) Use caution if coadministration of maraviroc with modafinil is necessary, due to a possible decrease in maraviroc exposure. Maraviroc is a CYP3A substrate and modafinil is a CYP3A4 inducer. Monitor for a decrease in maraviroc efficacy with concomitant use. [33473] [41243] Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with modafinil due to risk of heart failure due to systolic dysfunction. Concomitant use increases mavacamten exposure. Mavacamten is a CYP2C19 substrate and modafinil is a moderate CYP2C19 inhibitor. [41243] [67543] Medroxyprogesterone: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with modafinil is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and modafinil is a weak CYP2C9 inhibitor. [41243] [65019] Methamphetamine: (Moderate) The use of modafinil with other psychostimulants, including amphetamines (e.g., amphetamine, dextroamphetamine, lisdexamfetamine), has not been extensively studied. Patients receiving combination therapy of modafinil with other psychostimulants should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other CNS stimulant-related side effects. In single-dose studies of dextroamphetamine combined with modafinil, no significant pharmacokinetic interactions occurred, but a slight increase in stimulant-associated side effects was noted. [41243] [54946] Methohexital: (Major) It is not clear how modafinil interacts with barbiturates like phenobarbital. Modafinil is partially metabolized by CYP3A4 and combined use with CYP3A4 inducers such as phenobarbital and other barbiturates may result in decreased modafinil efficacy. Barbiturates used for sleep could counteract the effect of modafinil on wakefulness, and would not ordinarily be prescribed. The potential effects of combining modafinil with anticonvulsant barbiturate medications are unclear. Many psychostimulants can reduce the seizure threshold, but it is not clear if modafinil can affect seizure control. [28001] [41243] Methylphenidate Derivatives: (Major) The use of modafinil with other psychostimulants, including methylphenidate or its derivatives, has not been extensively studied. Patients receiving combination therapy of modafinil with other psychostimulants should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other CNS stimulant-related side effects. Single dose studies of methylphenidate combined with modafinil noted that the rate of absorption of modafinil was delayed up to one hour by the presence of methylphenidate; no changes occurred in the metabolism and extent of absorption of either medication. [41243] Methylphenidate: (Major) The use of modafinil with other psychostimulants, including methylphenidate or its derivatives, has not been extensively studied. Patients receiving combination therapy of modafinil with other psychostimulants should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other CNS stimulant-related side effects. Single dose studies of methylphenidate combined with modafinil noted that the rate of absorption of modafinil was delayed up to one hour by the presence of methylphenidate; no changes occurred in the metabolism and extent of absorption of either medication. [41243] Mitotane: (Minor) Avoid the concomitant use of mitotane with modafinil; if coadministration cannot be avoided, monitor for decreased efficacy of modafinil. Mitotane is a strong CYP3A4 inducer. A non-CYP related pathway is the most rapid in metabolizing modafinil, suggesting that there is a low probability of substantive effects on the overall pharmacokinetic profile of modafinil due to CYP inhibition by concomitant medications; however, due to the partial involvement of CYP3A in modafinil metabolism, there is a potential for decreased plasma concentrations with strong CYP3A inducers such as mitotane. [41243] [41934] Monoamine oxidase inhibitors: (Major) Modafinil has not been evaluated for drug interactions with monoamine oxidase inhibitors (MAOIs). It is known that many other CNS stimulants may induce severe cardiovascular and cerebrovascular responses if administered in combination with drugs with non-selective MAO inhibitor activity. Until more is known regarding the pharmacology of modafinil, it is prudent avoid the use of modafinil in the presence of an MAO inhibitor. Due to the prolonged duration of action of MAOIs, a period of at least 14 days between the last dose of the MAOI and the first dose of modafinil should elapse. [33467] Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with modafinil is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. [30742] [41243] Nanoparticle Albumin-Bound Sirolimus: (Moderate) Monitor for reduced sirolimus efficacy if sirolimus is coadministered with modafinil. Concomitant use may decrease sirolimus exposure. Sirolimus is a CYP3A substrate and modafinil is a weak CYP3A inducer. [41243] [67136] Nateglinide: (Moderate) Monitor for an increase in nateglinide-related adverse effects, such as hypoglycemia, if concomitant use with modafinil is necessary; a nateglinide dosage reduction may be required. Concomitant use may increase nateglinide exposure. Nateglinide is a CYP2C9 substrate and modafinil is a CYP2C9 inhibitor. [41243] [45644] Nefazodone: (Moderate) Modafinil is extensively metabolized by the CYP3A4 hepatic isoenzyme, which nefazodone inhibits. Modafinil concentrations may increase with concurrent nefazodone use. Because modafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 enzyme inhibition by other medications may be complex and difficult to predict. [4718] Neratinib: (Major) Avoid concomitant use of modafinil with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%. [41243] [62127] Nirmatrelvir; Ritonavir: (Major) Concurrent administration of modafinil with ritonavir may result in elevated plasma concentrations of modafinil and decreased concentrations of ritonavir. Modafinil is a substrate and inducer of the hepatic isoenzyme CYP3A4; ritonavir is a CYP3A4 substrate. In addition, ritonavir is a potent CYP3A4 inhibitor. Because the resultant effect of coadministration of a CYP3A4 inducer (modafinil) and inhibitor (ritonavir) on the plasma concentrations of these drugs is not defined, caution and close monitoring are advised if these drugs are administered together. [41243] [58664] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of modafinil is necessary. Concomitant use of nirmatrelvir and modafinil may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and modafinil is a weak CYP3A inducer. [41243] [67203] Nisoldipine: (Major) Avoid coadministration of nisoldipine with modafinil due to decreased plasma concentrations of nisoldipine. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A4 substrate and modafinil is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels. [29088] [41243] Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of ethinyl estradiol in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. [41243] (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Norethindrone: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Norethindrone; Ethinyl Estradiol: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of ethinyl estradiol in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. [41243] (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of ethinyl estradiol in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. [41243] (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Norgestimate; Ethinyl Estradiol: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of ethinyl estradiol in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. [41243] (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Norgestrel: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Olanzapine; Fluoxetine: (Moderate) Although no clinical data are available, fluoxetine may inhibit the clearance and potentiate the actions of modafinil. Modafinil is metabolized by CYP3A4 isozyme, a pathway that fluoxetine is known to inhibit. [4718] Olaparib: (Major) Avoid coadministration of olaparib with modafinil due to the risk of decreasing the efficacy of olaparib. Olaparib is a CYP3A substrate and modafinil is a moderate CYP3A4 inducer; concomitant use may decrease olaparib exposure. Coadministration with a moderate CYP3A inducer is predicted to decrease the olaparib Cmax by 31% and the AUC by 60%. [41243] [58662] Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as modafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased. [35588] [41243] Omeprazole; Amoxicillin; Rifabutin: (Moderate) Drugs that exhibit significant induction of the hepatic microsomal CYP3A4 isoenzyme may potentially increase the metabolism of modafinil. These medications include rifabutin. Decreased serum levels of modafinil could potentially result in decreased efficacy of modafinil. [5259] Oritavancin: (Moderate) Modafinil is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of modafinil may be reduced if these drugs are administered concurrently. [41243] [57741] Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with modafinil is necessary; consider increasing the dose of oxycodone as needed. If modafinil is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. [39926] [41243] Pazopanib: (Moderate) Pazopanib is a substrate for and a weak inhibitor of CYP3A4. Coadministration of pazopanib and modafinil, a CYP3A4 substrate, may cause an increase in systemic concentrations of modafinil. In addition, modafinil is an inducer of CYP3A4 and may cause a decrease in systemic concentrations of pazopanib. Use caution when administering these drugs concomitantly. [37098] Pemigatinib: (Major) Avoid coadministration of pemigatinib and modafinil due to the risk of decreased pemigatinib exposure which may reduce its efficacy. Pemigatinib is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease pemigatinib exposure by more than 50%. [41243] [65307] Pentobarbital: (Major) It is not clear how modafinil interacts with barbiturates like phenobarbital. Modafinil is partially metabolized by CYP3A4 and combined use with CYP3A4 inducers such as phenobarbital and other barbiturates may result in decreased modafinil efficacy. Barbiturates used for sleep could counteract the effect of modafinil on wakefulness, and would not ordinarily be prescribed. The potential effects of combining modafinil with anticonvulsant barbiturate medications are unclear. Many psychostimulants can reduce the seizure threshold, but it is not clear if modafinil can affect seizure control. [28001] [41243] Perampanel: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with modafinil due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of modafinil occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Modafinil is a moderate CYP3A4 inducer, and perampanel is a CYP3A4 substrate. [41243] [52140] Perindopril; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as modafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased. [35588] [41243] Phenelzine: (Major) Modafinil has not been evaluated for drug interactions with monoamine oxidase inhibitors (MAOIs). It is known that many other CNS stimulants may induce severe cardiovascular and cerebrovascular responses if administered in combination with drugs with non-selective MAO inhibitor activity. Until more is known regarding the pharmacology of modafinil, it is prudent avoid the use of modafinil in the presence of an MAO inhibitor. Due to the prolonged duration of action of MAOIs, a period of at least 14 days between the last dose of the MAOI and the first dose of modafinil should elapse. [33467] Phenobarbital: (Major) It is not clear how modafinil interacts with barbiturates like phenobarbital. Modafinil is partially metabolized by CYP3A4 and combined use with CYP3A4 inducers such as phenobarbital and other barbiturates may result in decreased modafinil efficacy. Barbiturates used for sleep could counteract the effect of modafinil on wakefulness, and would not ordinarily be prescribed. The potential effects of combining modafinil with anticonvulsant barbiturate medications are unclear. Many psychostimulants can reduce the seizure threshold, but it is not clear if modafinil can affect seizure control. [28001] [41243] Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) It is not clear how modafinil interacts with barbiturates like phenobarbital. Modafinil is partially metabolized by CYP3A4 and combined use with CYP3A4 inducers such as phenobarbital and other barbiturates may result in decreased modafinil efficacy. Barbiturates used for sleep could counteract the effect of modafinil on wakefulness, and would not ordinarily be prescribed. The potential effects of combining modafinil with anticonvulsant barbiturate medications are unclear. Many psychostimulants can reduce the seizure threshold, but it is not clear if modafinil can affect seizure control. [28001] [41243] Phenytoin: (Moderate) Since modafinil is metabolized by the CYP3A4 isoenzyme, and hydantoins (e.g., phenytoin, fosphenytoin) are CYP3A4 inducers, decreased modafinil efficacy may result from increased modafinil metabolism. In addition, modafinil is an inhibitor of the CYP2C19 and CYP2C9 isoenzymes. Hydantoins are substrates of CYP2C19, and phenytoin is a substrate of CYP2C9. Hydantoin concentrations may increase. Monitor carefully for signs of toxicity; phenytoin concentration monitoring may be helpful. [41243] [4718] Pimavanserin: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as modafinil. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin. [60748] Posaconazole: (Moderate) Posaconazole and modafinil should be coadministered with caution due to an increased potential for modafinil-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of modafinil. These drugs used in combination may result in elevated modafinil plasma concentrations, causing an increased risk for modafinil-related adverse events. [32723] [5259] Pretomanid: (Major) Avoid coadministration of pretomanid with modafinil as concurrent use may decrease pretomanid exposure which may lead to decreased efficacy. Pretomanid is a CYP3A4 substrate; modafinil is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased pretomanid exposure by 35%. [41243] [64561] Primidone: (Major) It is not clear how modafinil interacts with barbiturates like phenobarbital. Modafinil is partially metabolized by CYP3A4 and combined use with CYP3A4 inducers such as phenobarbital and other barbiturates may result in decreased modafinil efficacy. Barbiturates used for sleep could counteract the effect of modafinil on wakefulness, and would not ordinarily be prescribed. The potential effects of combining modafinil with anticonvulsant barbiturate medications are unclear. Many psychostimulants can reduce the seizure threshold, but it is not clear if modafinil can affect seizure control. [28001] [41243] Progesterone: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Progestins: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Propranolol: (Moderate) In vitro data indicate that modafinil is an inhibitor of CYP2C19. In theory, dosage reductions may be required for drugs that are largely eliminated via CYP2C19 metabolism such as propranolol during coadministration with modafinil. [41243] Relugolix; Estradiol; Norethindrone acetate: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] (Moderate) Modafinil is an inducer of CYP3A hepatic enzymes. Estrogens are metabolized by CYP3A4. A decrease in estrogen concentrations, and thus efficacy, may occur in patients taking estrogens for hormone replacement therapy. If these drugs are used together, monitor patients for a decrease in clinical effects. Dosage adjustments may be necessary. [41243] [4718] [4744] Ribociclib: (Moderate) Monitor for an increase in modafinil-related adverse reactions if coadministration with ribociclib is necessary. Modafinil has multiple pathways for metabolism including non-CYP-related pathways; however, due to partial involvement of the CYP3A enzymes, concomitant use of strong CYP3A4 inhibitors such as ribociclib could increase plasma concentrations of modafinil. [41243] [61816] Ribociclib; Letrozole: (Moderate) Monitor for an increase in modafinil-related adverse reactions if coadministration with ribociclib is necessary. Modafinil has multiple pathways for metabolism including non-CYP-related pathways; however, due to partial involvement of the CYP3A enzymes, concomitant use of strong CYP3A4 inhibitors such as ribociclib could increase plasma concentrations of modafinil. [41243] [61816] Rifabutin: (Moderate) Drugs that exhibit significant induction of the hepatic microsomal CYP3A4 isoenzyme may potentially increase the metabolism of modafinil. These medications include rifabutin. Decreased serum levels of modafinil could potentially result in decreased efficacy of modafinil. [5259] Rifampin: (Major) Rifampin exhibits significant induction of the hepatic microsomal CYP3A4 isoenzyme and may potentially increase the metabolism of modafinil. Decreased serum levels of modafinil could potentially result in decreased efficacy of modafinil. [5259] Rifapentine: (Moderate) Monitor for decreased efficacy of modafinil if coadministration with rifapentine is necessary. Modafinil is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. The probability of effect of rifapentine on modafinil exposure is low due to the existence of multiple pathways for modafinil metabolism, as well as the fact that a non-CYP-related pathway is the most rapid in metabolizing modafinil; however, plasma concentrations of modafinil may be impacted by strong CYP3A4 inducers. [41243] [65685] Rilpivirine: (Moderate) Close clinical monitoring is advised when administering modafinil with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Modafinil is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. [44376] Riluzole: (Moderate) Coadministration of riluzole with modafinil may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and modafinil is a CYP1A2 inducer. [29747] [41243] Rimegepant: (Major) Avoid coadministration of rimegepant with modafinil; concurrent use may significantly decrease rimegepant exposure which may result in loss of efficacy. Rimegepant is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. [41243] [65052] Ritonavir: (Major) Concurrent administration of modafinil with ritonavir may result in elevated plasma concentrations of modafinil and decreased concentrations of ritonavir. Modafinil is a substrate and inducer of the hepatic isoenzyme CYP3A4; ritonavir is a CYP3A4 substrate. In addition, ritonavir is a potent CYP3A4 inhibitor. Because the resultant effect of coadministration of a CYP3A4 inducer (modafinil) and inhibitor (ritonavir) on the plasma concentrations of these drugs is not defined, caution and close monitoring are advised if these drugs are administered together. [41243] [58664] Rivaroxaban: (Minor) Coadministration of rivaroxaban and modafinil may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Modafinil is an inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs of lack of efficacy of rivaroxaban. [41243] [44854] Roflumilast: (Major) Coadminister modafinil and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Modafinil induces CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide. [43551] [5259] Romidepsin: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of a CYP3A4 inducer, like modafinil, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary. [37292] Ruxolitinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as modafinil, a dose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety and efficacy. The Cmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin 600 mg once daily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about 100%, which may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition. [46782] Secobarbital: (Major) It is not clear how modafinil interacts with barbiturates like phenobarbital. Modafinil is partially metabolized by CYP3A4 and combined use with CYP3A4 inducers such as phenobarbital and other barbiturates may result in decreased modafinil efficacy. Barbiturates used for sleep could counteract the effect of modafinil on wakefulness, and would not ordinarily be prescribed. The potential effects of combining modafinil with anticonvulsant barbiturate medications are unclear. Many psychostimulants can reduce the seizure threshold, but it is not clear if modafinil can affect seizure control. [28001] [41243] Segesterone Acetate; Ethinyl Estradiol: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of ethinyl estradiol in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. [41243] (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] Selegiline: (Moderate) Use caution during concomitant use of selegiline and modafinil. Modafinil has not been evaluated for drug interactions with monoamine oxidase inhibitors (MAOIs); however, it is known that many other CNS stimulants may induce severe cardiovascular reactions, such as hypertensive crisis, if administered in combination with drugs with non-selective MAO inhibitor activity. [32026] [32436] [41243] Selpercatinib: (Major) Avoid coadministration of selpercatinib and modafinil due to the risk of decreased selpercatinib exposure which may reduce its efficacy. Selpercatinib is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. Coadministration with other moderate CYP3A4 inducers is predicted to decrease selpercatinib exposure by 40% to 70%. [63732] [65387] Selumetinib: (Major) Avoid coadministration of selumetinib and modafinil due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%. [41243] [65246] Serdexmethylphenidate; Dexmethylphenidate: (Major) The use of modafinil with other psychostimulants, including methylphenidate or its derivatives, has not been extensively studied. Patients receiving combination therapy of modafinil with other psychostimulants should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other CNS stimulant-related side effects. Single dose studies of methylphenidate combined with modafinil noted that the rate of absorption of modafinil was delayed up to one hour by the presence of methylphenidate; no changes occurred in the metabolism and extent of absorption of either medication. [41243] Sertraline: (Moderate) Dose adjustments of sertraline, a substrate for CYP2C19, may be necessary when used concomitantly with modafinil. Elimination of sertraline may be prolonged by modafinil via inhibition of CYP2C19, with resultant higher systemic exposure. Monitor for adverse effects, such as serotonin excess, and reduce the sertraline dosage if needed. [28343] [41243] [44454] Siponimod: (Moderate) Concomitant use of siponimod and modafinil is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; modafinil is a moderate CYP3A4 inducer. Across CYP2C9 genotypes, coadministration of a moderate CYP3A4 inducer reduced siponimod exposure by up to 52%, according to in silico evaluation. [41243] [64031] Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of modafinil. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and modafinil is a weak CYP3A inducer. [28610] [41243] Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of velpatasvir with inducers of CYP3A4 and CYP2B6, such as modafinil. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 and CYP2B6 substrate. [41243] [60911] Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of velpatasvir with inducers of CYP3A4 and CYP2B6, such as modafinil. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 and CYP2B6 substrate. [41243] [60911] (Major) Avoid coadministration of voxilaprevir (a CYP3A4 substrate) with moderate to strong inducers of CYP3A4, such as modafinil. Taking these drugs together may significantly decrease voxilaprevir plasma concentrations, potentially resulting in loss of antiviral efficacy. [41934] [62131] Solriamfetol: (Moderate) Monitor blood pressure and heart rate during coadministration of solriamfetol, a norepinephrine and dopamine reuptake inhibitor, and modafinil, a CNS stimulant. Concurrent use of solriamfetol and other medications that increase blood pressure and/or heart rate may increase the risk of such effects. Coadministration of solriamfetol with other drugs that increase blood pressure or heart rate has not been evaluated. [64026] Sonidegib: (Major) Avoid the concomitant use of sonidegib and modafinil; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that the coadministration of a moderate CYP3A4 inducer for 14 days would decrease the sonidegib AUC by 56% and by 69% if the moderate CYP3A inducer is coadministered for 4 months. [41243] [60000] Sorafenib: (Major) Sorafenib is a CYP3A4 substrate, and concomitant use with a strong CYP3A4 inducer such as modafinil may lead to reduced sorafenib concentrations. For example, concurrent use of sorafenib and the CYP3A4 inducer rifampicin resulted in an average 37% reduction in the sorafenib AUC. Avoid the use of sorafenib with a strong CYP3A4 inducer. If a strong CYP3A4 inducer must be coadministered with sorafenib, consider a sorafenib dose increase. [4718] [8637] St. John's Wort, Hypericum perforatum: (Major) St. John's wort, Hypericum Perforatum may reduce the neuronal uptake of monoamines and should be used cautiously with sympathomimetics. [28211] [28529] Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if modafinil must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with modafinil is necessary; consider increasing the dose of sufentanil injection as needed. If modafinil is discontinued, consider a dose reduction of sufentanil injection and frequently monitor for signs or respiratory depression and sedation. Sufentanil is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease sufentanil concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. [30966] [41243] [63731] Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and modafinil or armodafinil. Because tasimelteon is metabolized via CYP3A4 and CYP1A2, inducers of these isoenzymes, such as modafinil and armodafinil, may reduce the efficacy of tasimelteon. [41243] [56665] Tazemetostat: (Major) Avoid coadministration of tazemetostat with modafinil as concurrent use may decrease tazemetostat exposure, which may reduce its efficacy. Tazemetostat is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. [41243] [64952] Telmisartan; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as modafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased. [35588] [41243] Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with modafinil is necessary, and monitor for decreased efficacy of temsirolimus. Temsirolimus is a CYP3A4 substrate, and modafinil is a moderate inducer of CYP3A4. The manufacturer of temsirolimus recommends a dose increase if coadministered with a strong CYP3A4 inducer, but recommendations are not available for concomitant use of moderate CYP3A4 inducers. Co-administration of temsirolimus with rifampin, a strong CYP3A4/5 inducer, had no significant effect on the AUC or Cmax of temsirolimus, but decreased sirolimus AUC by 56% and Cmax by 65%. [41243] [50586] Terbinafine: (Moderate) Caution is advised when administering terbinafine with modafinil. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may alter the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C9, CYP2C19, and CYP3A4; modafinil is an inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19. Monitor patients for adverse reactions and breakthrough fungal infections if these drugs are coadministered. [37590] [43880] [43881] [56538] Theophylline, Aminophylline: (Moderate) Modafinil induces induces CYP3A4 and has the potential to induce other hepatic microsomal enzymes such as CYP1A2. The drug may induce the metabolism of some narrow-therapeutic index medications. Theophylline is primarily metabolized by CYP1A2 isoenzymes, with secondary pathways by CYP2E1 and CYP3A4 (minor). Patients on theophylline or aminophylline may need to be monitored for reduced methylxanthine efficacy when modafinil is added to therapy. In some cases, monitoring of theophylline concentrations may be helpful. When modafinil is discontinued, monitor the patient for potential increases in theophylline concentrations. [11531] [11532] [33467] (Moderate) Monitor theophylline concentrations and watch for decreased efficacy of theophylline if coadministration with modafinil is necessary; a theophylline dose increase may be necessary. Theophylline is a CYP1A2 substrate with a narrow therapeutic index and modafinil is a CYP1A2 inducer. [41243] [50760] Tolvaptan: (Major) Tolvaptan is metabolized by CYP3A4. Modafinil is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan. [35780] Tranylcypromine: (Major) Modafinil has not been evaluated for drug interactions with monoamine oxidase inhibitors (MAOIs). It is known that many other CNS stimulants may induce severe cardiovascular and cerebrovascular responses if administered in combination with drugs with non-selective MAO inhibitor activity. Until more is known regarding the pharmacology of modafinil, it is prudent avoid the use of modafinil in the presence of an MAO inhibitor. Due to the prolonged duration of action of MAOIs, a period of at least 14 days between the last dose of the MAOI and the first dose of modafinil should elapse. [33467] Triazolam: (Moderate) Modafinil has been reported to induce the metabolism of triazolam via induction of the hepatic microsomal CYP3A4 isoenzyme. If a patient is receiving triazolam and modafinil is introduced, monitor the patient for decreased clinical response to the benzodiazepine. Conversely, if modafinil is discontinued in such a patient, the triazolam dosage may need to be adjusted downward after modafinil cessation. [4718] [5259] Tucatinib: (Moderate) Monitor for an increase in modafinil-related adverse reactions if coadministration with tucatinib is necessary. Modafinil has multiple pathways for metabolism including non-CYP-related pathways; however, due to partial involvement of the CYP3A enzymes, concomitant use of strong CYP3A4 inhibitors such as tucatinib could increase plasma concentrations of modafinil. [41243] [65295] Ubrogepant: (Major) Increase the initial and second dose of ubrogepant to 100 mg if coadministered with modafinil as concurrent use may decrease ubrogepant exposure and reduce its efficacy. Ubrogepant is a CYP3A4 substrate; modafinil is a moderate CYP3A4 inducer. [41243] [64874] Ulipristal: (Major) Avoid administration of ulipristal with drugs that induce CYP3A4. Ulipristal is a substrate of CYP3A4 and modafinil is a CYP3A4 inducer. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal. [41569] [48201] [50623] Vemurafenib: (Major) Concomitant use of vemurafenib and modafinil may result in decreased concentrations of both agents. Both are CYP3A4 substrates and inducers. Use caution and monitor patients for therapeutic effects. [45335] [4718] Venetoclax: (Major) Avoid the concomitant use of venetoclax and modafinil; venetoclax levels may be decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. Consider alternative agents. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. Use of venetoclax with a moderate CYP3A4 inducer has not been evaluated. [41243] [60706] Vincristine Liposomal: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including modafinil. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy. [29472] [41243] Vincristine: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including modafinil. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy. [29472] [41243] Vonoprazan; Amoxicillin; Clarithromycin: (Major) Coadministration of modafinil and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. Additionally, clarithromycin is a significant inhibitor of CYP3A4, which may increase serum concentrations of modafinil. [28238] [41243] Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and modafinil. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with modafinil, a CYP3A inducer. [41243] [57151] Voriconazole: (Minor) Modafinil is significantly metabolized by the CYP3A4 hepatic microsomal enzyme system. Voriconazole is a significant inhibitor of this isoenzyme and may reduce the clearance of modafinil. Headache, nausea and vomiting, nervousness, anxiety, and insomnia may worsen due to increased serum concentrations of modafinil. [4718] [5259] Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with modafinil is necessary as concurrent use may increase or decrease the exposure of warfarin leading to increased bleeding risk or reduced efficacy. Modafinil is a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. Additionally, modafinil is a CYP1A2 inducer and warfarin is a CYP1A2 substrate. [28549] [41243] Zolpidem: (Moderate) It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as modafinil. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamics effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer. [48902] [57789]
      Revision Date: 03/28/2024, 01:48:00 AM

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      Monitoring Parameters

      • blood pressure
      • heart rate
      • LFTs

      US Drug Names

      • Provigil
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