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Modafinil: Pediatric drug information

Modafinil: Pediatric drug information
(For additional information see "Modafinil: Drug information" and see "Modafinil: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Provigil
Brand Names: Canada
  • Alertec;
  • APO-Modafinil;
  • Auro-Modafinil;
  • BIO-Modafinil;
  • JAMP Modafinil;
  • Mar-Modafinil;
  • TEVA-Modafinil
Therapeutic Category
  • Central Nervous System Stimulant
Dosing: Pediatric

Attention deficit hyperactivity disorder (ADHD); refractory: Limited data available: Note: Due to reports of serious dermatologic adverse effects and psychiatric events in children, modafinil should only be used if first- and second-line treatments have failed and the benefits outweigh the risks.

Children ≥6 years and Adolescents ≤13 years:

Patient weight <30 kg: Oral: 200 to 340 mg once daily (Biederman 2006)

Patient weight >30 kg: Oral: 300 to 425 mg once daily (Biederman 2006)

Dosing: Kidney Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution.

Dosing: Hepatic Impairment: Pediatric

There are no pediatric-specific recommendations; based on experience in adult patients, dosing adjustment is suggested.

Dosing: Adult

(For additional information see "Modafinil: Drug information")

Cancer-related fatigue, severe (in patients receiving active treatment) (off-label use): Oral: Initial: 100 mg once daily for 3 days, followed by 200 mg once daily during active treatment; refer to protocol for further details (Jean-Pierre 2010).

Major depressive disorder (antidepressant augmentation) (off-label use): Oral: Initial: 100 mg/day for 3 to 7 days, then increase to 200 mg/day; further adjust dose based on response and tolerability up to 400 mg/day (Abolfazli 2011; DeBattista 2003; Dunlop 2007; Fava 2005).

Multiple sclerosis–related fatigue (off-label use): Oral: Initial: 100 mg/day; may increase daily dose based on response and tolerability in 100 mg increments at intervals ≥1 week up to 200 mg/day in 1 or 2 divided doses (morning and noon). Doses up to 400 mg/day have been evaluated; however, doses >200 mg/day have not demonstrated greater efficacy (Brown 2010; Lange 2009; Rammohan 2002; Zifko 2002).

Narcolepsy-related or obstructive sleep apnea–related excessive daytime sleepiness: Oral: Initial: 200 mg as a single daily dose in the morning. Note: Doses up to 400 mg once daily have been well tolerated, but there is no consistent evidence that this dose confers additional benefit.

Parkinson disease–related excessive daytime sleepiness (off-label use): Oral: Initial: 100 mg once daily; may increase dose after 1 week to 200 mg/day (Högl 2002).

Shift work sleep disorder–related excessive daytime sleepiness: Oral: Initial: 200 mg as a single dose ~1 hour prior to start of work shift.

Dosing: Kidney Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic Impairment: Adult

Mild to moderate hepatic impairment: There are no dosage adjustments provided in the manufacturer's labeling.

Severe hepatic impairment: Reduce dose to one-half of that recommended for patients with normal liver function.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Provigil: 100 mg

Provigil: 200 mg [scored]

Generic: 100 mg, 200 mg

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Alertec: 100 mg

Generic: 100 mg

Controlled Substance

C-IV

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020717s037s038lbl.pdf, must be dispensed with this medication.

Administration: Pediatric

Oral: May be administered without regard to food. For the treatment of ADHD, narcolepsy, and obstructive sleep apnea/hypopnea syndrome, administer dose in the morning. For the treatment of shift work sleep disorder, administer dose ~1 hour prior to start of work shift.

Administration: Adult

Oral: In general, administer in dose in the morning.

Multiple sclerosis–related fatigue: With multiple sclerosis–related fatigue, may consider dividing doses between morning and noon in patients experiencing post-noon fatigue (Brown 2010).

Shift work sleep disorder: Administer dose ~1 hour prior to start of work shift.

Storage/Stability

Store at 20°C to 25°C (68°F to 77°F).

Use

To improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy and shift work sleep disorder (SWSD), as adjunctive therapy for obstructive sleep apnea/hypopnea syndrome (OSAHS) (FDA approved in adults); has also been used for attention-deficit/hyperactivity disorder (ADHD)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Central nervous system: Headache (adults: 34%; children: 20% [Biederman 2005])

Gastrointestinal: Decreased appetite (children: 16% [Biederman 2005]), abdominal pain (children: 12% [Greenhill 2006]), nausea (11%)

1% to 10%:

Cardiovascular: Chest pain (3%), hypertension (3%), palpitations (2%), tachycardia (2%), vasodilation (2%), edema (1%)

Central nervous system: Nervousness (7%), anxiety (5%), dizziness (5%), insomnia (5%), depression (2%), drowsiness (2%), paresthesia (2%), agitation (1%), chills (1%), confusion (1%), emotional lability (1%), hypertonia (1%), vertigo (1%)

Dermatologic: Diaphoresis (1%)

Endocrine & metabolic: Weight loss (children 5% [Greenhill 2006]), increased thirst (1%)

Gastrointestinal: Diarrhea (6%), dyspepsia (5%), xerostomia (4%), anorexia (4%), constipation (2%), dysgeusia (1%), flatulence (1%), oral mucosa ulcer (1%)

Genitourinary: Urine abnormality (1%)

Hematologic & oncologic: Eosinophilia (1%)

Hepatic: Hepatic insufficiency (2%)

Neuromuscular & skeletal: Back pain (6%), dyskinesia (1%), hyperkinesia (1%), tremor (1%)

Ophthalmic: Visual disturbance (1%)

Respiratory: Rhinitis (7%), pharyngitis (4%), asthma (1%), epistaxis (1%)

Frequency not defined:

Endocrine & metabolic: Increased gamma-glutamyl transferase

Hepatic: Increased serum alkaline phosphatase

<1%, postmarketing, and/or case reports: Aggressive behavior, agranulocytosis, anaphylaxis, angioedema, asystole, cerebrovascular accident, delusions, DRESS syndrome, erythema multiforme (pediatric patients), hallucination, hypersensitivity reaction, mania, multiorgan hypersensitivity, psychomotor agitation, psychosis, skin rash, Stevens-Johnson syndrome, suicidal ideation, toxic epidermal necrolysis

Contraindications

Known hypersensitivity to modafinil, armodafinil, or any component of the formulation.

Canadian labeling: Additional contraindications (not in the US labeling): Patients in agitated states or with severe anxiety; pregnancy; females who may become pregnant.

Warnings/Precautions

Concerns related to adverse effects:

• CNS effects: May impair the ability to engage in potentially hazardous activities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Dermatologic effects (severe): Serious and life-threatening rashes, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms (DRESS) have been reported. Although initially reported in children during clinical trials, postmarketing cases have occurred in both children and adults. Most cases have occurred within the first 5 weeks of therapy; however, rare cases have occurred after long-term use (eg, 3 months). No risk factors have been identified to predict occurrence or severity. Patients should be advised to discontinue at first sign of rash (unless the rash is clearly not drug-related). As a result of these serious dermatologic adverse events, approval for the use of modafinil in children for ADHD was denied by the FDA.

• Hypersensitivity reactions: Rare cases of multiorgan hypersensitivity reactions (with fatality) in association with modafinil use; lone cases of angioedema and anaphylactoid reactions with armodafinil have been reported (angioedema has been noted in postmarketing reports with modafinil). Signs and symptoms are diverse, reflecting the involvement of specific organs; patients typically present with fever and rash associated with organ-system dysfunction. No risk factors have been identified to predict occurrence or severity of multiorgan hypersensitivity reactions. Patients should be advised to report any signs and symptoms related to these effects; discontinuation of therapy is recommended.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiovascular disease; increased blood pressure and heart rate monitoring may be required. Use is not recommended in patients with a history of left ventricular hypertrophy or patients with mitral valve prolapse who have developed mitral valve prolapse syndrome with previous CNS stimulant use. Increased monitoring should be considered in patients with a recent history of myocardial infarction or unstable angina.

• Hepatic impairment: Use with caution in patients with hepatic impairment. Dosage reduction is recommended in patients with severe hepatic impairment.

• Psychiatric disorders: Use with caution in patients with a history of psychosis, depression, or mania. Use may result in emergence of or exacerbation of psychiatric symptoms. Observe for symptoms of aggression, hallucinations, mania, delusions, or suicidal ideation. Consider discontinuing therapy if psychiatric symptoms develop.

• Renal impairment: Use with caution in patients with renal impairment.

• Seizure disorder: Limited information exists regarding the use of modafinil or other stimulants in patients with concomitant ADHD and seizure disorder. Whereas patients with ADHD are at an increased risk for seizure activity compared to the general population, a retrospective study using drug claims data showed that the use of stimulant medications was associated with a lower risk (Cortese 2013; Wiggs 2018). Manufacturers of some stimulants recommend discontinuing therapy if seizures occur.

• Sleep disorders: Appropriate use: The degree of sleepiness should be reassessed frequently; some patients may not return to a normal level of wakefulness. In obstructive sleep apnea, modafinil is indicated as treatment for excessive sleepiness and not 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 and during treatment with modafinil for excessive sleepiness.

• Tourette syndrome/tics: Use with caution in patients with Tourette syndrome or other tic disorders. Stimulants may exacerbate tics (motor and phonic) and Tourette syndrome; however, evidence demonstrating increased tics is limited. Evaluate for tics and Tourette syndrome prior to therapy initiation (AACAP [Murphy 2013]; Pliszka 2007).

Special populations:

• Pediatric: Modafinil is not FDA-approved for use in pediatrics for any indication. Serious skin reactions and psychiatric events have been observed in pediatric patients treated with modafinil. The serious nature of these adverse effects resulted in the FDA’s Pediatric Advisory Committee unanimously recommending that a specific warning against the use of modafinil in children be added to the manufacturer's labeling.

Warnings: Additional Pediatric Considerations

Serious cardiovascular adverse events (including sudden death) in patients (both children and adults) taking usual doses of stimulant medications has been reported. Most of these patients were found to have underlying structural heart disease (eg, hypertrophic obstructive cardiomyopathy). The American Heart Association recommends that all children diagnosed with ADHD who may be candidates for stimulant medication, such as modafinil, should have a thorough cardiovascular assessment prior to initiation of therapy. This assessment should include a combination of thorough medical history, family history, and physical examination. An ECG is not mandatory but should be considered.

Use with caution in patients with Tourette syndrome; stimulants may unmask tics. Children may experience a higher frequency of some adverse effects than adults including the following: Insomnia (29% vs 5%), decreased appetite (16% vs 4%), weight loss, and abdominal pain. The following were reported in controlled, open-label clinical studies in children: Cataplexy increased, hostility, hypnagogic hallucinations, suicidal ideation, and Tourette syndrome.

Metabolism/Transport Effects

Substrate of CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2C19 (weak); Induces CYP3A4 (moderate)

Drug Interactions

Abemaciclib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Abemaciclib. Risk X: Avoid combination

Abiraterone Acetate: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Abiraterone Acetate. Risk C: Monitor therapy

Acalabrutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Acalabrutinib. Risk C: Monitor therapy

Acebrophylline: May enhance the stimulatory effect of CNS Stimulants. Risk X: Avoid combination

Alcohol (Ethyl): May diminish the therapeutic effect of Modafinil. Risk X: Avoid combination

Alfentanil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Alfentanil. Management: If concomitant use of alfentanil and moderate CYP3A4 inducers is necessary, consider dosage increase of alfentanil until stable drug effects are achieved. Monitor patients for signs of opioid withdrawal. Risk D: Consider therapy modification

ALPRAZolam: CYP3A4 Inducers (Moderate) may decrease the serum concentration of ALPRAZolam. Risk C: Monitor therapy

AmLODIPine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of AmLODIPine. Risk C: Monitor therapy

Antihepaciviral Combination Products: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Antihepaciviral Combination Products. Risk X: Avoid combination

Apremilast: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Apremilast. Risk C: Monitor therapy

Aprepitant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Aprepitant. Risk C: Monitor therapy

ARIPiprazole: CYP3A4 Inducers (Moderate) may decrease the serum concentration of ARIPiprazole. Risk C: Monitor therapy

ARIPiprazole Lauroxil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of ARIPiprazole Lauroxil. Risk C: Monitor therapy

Artemether and Lumefantrine: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Artemether and Lumefantrine. Specifically, concentrations of dihydroartemisinin (DHA), the active metabolite of artemether may be decreased. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Artemether and Lumefantrine. Risk C: Monitor therapy

Asunaprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Asunaprevir. Risk X: Avoid combination

Atazanavir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Atazanavir. Risk C: Monitor therapy

Atogepant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Atogepant. Management: The recommended dose of atogepant is 30 mg once daily or 60 mg once daily when combined with strong or moderate CYP3A4 inducers. Risk D: Consider therapy modification

Atomoxetine: May enhance the hypertensive effect of Sympathomimetics. Atomoxetine may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy

Atorvastatin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Atorvastatin. Risk C: Monitor therapy

Avacopan: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Avacopan. Risk X: Avoid combination

Avanafil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Avanafil. Risk X: Avoid combination

Avapritinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Avapritinib. Risk X: Avoid combination

Axitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Axitinib. Risk X: Avoid combination

Bedaquiline: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Bedaquiline. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bedaquiline. Risk X: Avoid combination

Belumosudil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Belumosudil. Risk C: Monitor therapy

Benzhydrocodone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Benzhydrocodone. Specifically, the serum concentrations of hydrocodone may be reduced. Risk C: Monitor therapy

Bortezomib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bortezomib. Risk C: Monitor therapy

Bosutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bosutinib. Risk X: Avoid combination

Brexpiprazole: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Brexpiprazole. Risk C: Monitor therapy

Brigatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with moderate CYP3A4 inducers when possible. If combined, increase the daily dose of brigatinib in 30 mg increments after 7 days of treatment with the current brigatinib dose, up to maximum of twice the dose. Risk D: Consider therapy modification

Buprenorphine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Buprenorphine. Risk C: Monitor therapy

BusPIRone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of BusPIRone. Risk C: Monitor therapy

Cabozantinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cabozantinib. Risk C: Monitor therapy

Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy

Cannabis: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be decreased. Risk C: Monitor therapy

Capmatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Capmatinib. Risk X: Avoid combination

CarBAMazepine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of CarBAMazepine. Risk C: Monitor therapy

Ceritinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ceritinib. Risk C: Monitor therapy

Clarithromycin: CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Clarithromycin. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Clarithromycin. Management: Consider alternative antimicrobial therapy for patients receiving a CYP3A4 inducer. Drugs that enhance the metabolism of clarithromycin into 14-hydroxyclarithromycin may alter the clinical activity of clarithromycin and impair its efficacy. Risk D: Consider therapy modification

Clindamycin (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Clindamycin (Systemic). Risk C: Monitor therapy

CloBAZam: CYP2C19 Inhibitors (Weak) may increase serum concentrations of the active metabolite(s) of CloBAZam. CYP2C19 Inhibitors (Weak) may increase the serum concentration of CloBAZam. Risk C: Monitor therapy

CloZAPine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of CloZAPine. Risk C: Monitor therapy

Cobicistat: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cobicistat. Risk C: Monitor therapy

Cobimetinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cobimetinib. Risk X: Avoid combination

Codeine: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Codeine. Risk C: Monitor therapy

Copanlisib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Copanlisib. Risk C: Monitor therapy

Crizotinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Crizotinib. Risk C: Monitor therapy

CycloSPORINE (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy

Daclatasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Daclatasvir. Management: Increase the daclatasvir dose to 90 mg once daily if used with a moderate CYP3A4 inducer. Risk D: Consider therapy modification

Dapsone (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Dapsone (Systemic). Risk C: Monitor therapy

Daridorexant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Daridorexant. Risk X: Avoid combination

Dasabuvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Dasabuvir. Risk X: Avoid combination

Deflazacort: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Deflazacort. Risk X: Avoid combination

Delavirdine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Delavirdine. Risk C: Monitor therapy

DexAMETHasone (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of DexAMETHasone (Systemic). Risk C: Monitor therapy

DiazePAM: CYP3A4 Inducers (Moderate) may decrease the serum concentration of DiazePAM. Risk C: Monitor therapy

DilTIAZem: CYP3A4 Inducers (Moderate) may decrease the serum concentration of DilTIAZem. Risk C: Monitor therapy

Disopyramide: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Disopyramide. Risk C: Monitor therapy

Doravirine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Doravirine. Risk C: Monitor therapy

Doxofylline: Sympathomimetics may enhance the adverse/toxic effect of Doxofylline. Risk C: Monitor therapy

DOXOrubicin (Conventional): CYP3A4 Inducers (Moderate) may decrease the serum concentration of DOXOrubicin (Conventional). Risk X: Avoid combination

Dronabinol: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Dronabinol. Risk C: Monitor therapy

Dronedarone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Dronedarone. Risk C: Monitor therapy

Duvelisib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Duvelisib. Management: Avoid if possible. If used, on day 12 of combination increase duvelisib from 25 mg twice daily to 40 mg twice daily or from 15 mg twice daily to 25 mg twice daily. Resume prior duvelisib dose 14 days after stopping moderate CYP3A4 inducer. Risk D: Consider therapy modification

Dydrogesterone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Dydrogesterone. Risk C: Monitor therapy

Efavirenz: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Efavirenz. Risk C: Monitor therapy

Elbasvir and Grazoprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid combination

Elexacaftor, Tezacaftor, and Ivacaftor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor. Risk C: Monitor therapy

Eliglustat: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Eliglustat. Risk C: Monitor therapy

Elvitegravir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Elvitegravir. Risk C: Monitor therapy

Encorafenib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Encorafenib. Risk X: Avoid combination

Entrectinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Entrectinib. Risk X: Avoid combination

Enzalutamide: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Enzalutamide. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Enzalutamide. Risk C: Monitor therapy

Erdafitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Erdafitinib. Management: Dose modifications of erdafitinib may be required. See full monograph for details. Risk D: Consider therapy modification

Erlotinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Erlotinib. Risk C: Monitor therapy

Esketamine: May enhance the hypertensive effect of CNS Stimulants. Risk C: Monitor therapy

Estrogen Derivatives: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy

Etoposide: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Etoposide. Risk C: Monitor therapy

Etoposide Phosphate: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Etoposide Phosphate. Risk C: Monitor therapy

Etravirine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Etravirine. Risk C: Monitor therapy

Everolimus: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Everolimus. Risk C: Monitor therapy

Exemestane: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Exemestane. Risk C: Monitor therapy

Fedratinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Fedratinib. Risk X: Avoid combination

Felodipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Felodipine. Risk C: Monitor therapy

FentaNYL: CYP3A4 Inducers (Moderate) may decrease the serum concentration of FentaNYL. Risk C: Monitor therapy

Fexinidazole: CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Fexinidazole. Risk X: Avoid combination

Finerenone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Finerenone. Risk X: Avoid combination

Flibanserin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Flibanserin. Risk X: Avoid combination

Fosamprenavir: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Fosamprenavir. Risk C: Monitor therapy

Fosaprepitant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Fosaprepitant. Specifically, CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite aprepitant. Risk C: Monitor therapy

Fosnetupitant: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Fosnetupitant. Risk C: Monitor therapy

Fosphenytoin-Phenytoin: CYP2C19 Inhibitors (Weak) may increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

Fostamatinib: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Fostamatinib. Risk C: Monitor therapy

Gefitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Gefitinib. Risk C: Monitor therapy

Gemigliptin: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Gemigliptin. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Gemigliptin. Risk C: Monitor therapy

Glasdegib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Glasdegib. Management: Avoid use of glasdegib and moderate CYP3A4 inducers whenever possible. If combined, increase glasdegib dose from 100 mg daily to 200 mg daily or from 50 mg daily to 100 mg daily. Resume previous glasdegib dose 7 days after discontinuation of the inducer. Risk D: Consider therapy modification

Glecaprevir and Pibrentasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Glecaprevir and Pibrentasvir. Risk C: Monitor therapy

Guanethidine: May enhance the arrhythmogenic effect of Sympathomimetics. Guanethidine may enhance the hypertensive effect of Sympathomimetics. Risk C: Monitor therapy

GuanFACINE: CYP3A4 Inducers (Moderate) may decrease the serum concentration of GuanFACINE. Management: Increase extended-release guanfacine dose by up to double when initiating guanfacine in patients taking CYP3A4 inducers or if initiating a CYP3A4 inducer in a patient already taking extended-release guanfacine. Monitor for reduced guanfacine efficacy. Risk D: Consider therapy modification

Hormonal Contraceptives: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a moderate CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider therapy modification

HYDROcodone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of HYDROcodone. Risk C: Monitor therapy

Hydrocortisone (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Hydrocortisone (Systemic). Risk C: Monitor therapy

Ibrexafungerp: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ibrexafungerp. Risk X: Avoid combination

Ibrutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ibrutinib. Risk C: Monitor therapy

Idelalisib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Idelalisib. Risk C: Monitor therapy

Ifosfamide: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Ifosfamide. Risk C: Monitor therapy

Imatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Imatinib. Risk C: Monitor therapy

Indinavir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Indinavir. Management: Consider avoiding the combination of indinavir and moderate CYP3A4 inducers whenever possible due to the risk for decreased indinavir concentrations, reduced efficacy, and development of resistance. If combined, monitor for indinavir treatment failure. Risk D: Consider therapy modification

Infigratinib: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Infigratinib. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Infigratinib. Risk X: Avoid combination

Iobenguane Radiopharmaceutical Products: CNS Stimulants may diminish the therapeutic effect of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer these drugs until at least 7 days after each iobenguane dose. Risk X: Avoid combination

Irinotecan Products: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, concentrations of SN-38 may be reduced. Risk C: Monitor therapy

Isavuconazonium Sulfate: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inducers (Moderate) may decrease isavuconazole serum concentrations. Risk C: Monitor therapy

Isradipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Isradipine. Risk C: Monitor therapy

Istradefylline: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Istradefylline. Risk C: Monitor therapy

Itraconazole: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Itraconazole. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Itraconazole. Risk C: Monitor therapy

Ivabradine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ivabradine. Risk X: Avoid combination

Ivacaftor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ivacaftor. Risk C: Monitor therapy

Ixabepilone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ixabepilone. Risk C: Monitor therapy

Ixazomib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ixazomib. Risk C: Monitor therapy

Ketamine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ketamine. Risk C: Monitor therapy

Ketoconazole (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ketoconazole (Systemic). Risk C: Monitor therapy

Kratom: May enhance the adverse/toxic effect of Sympathomimetics. Risk X: Avoid combination

Lapatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lapatinib. Risk C: Monitor therapy

Larotrectinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Larotrectinib. Risk C: Monitor therapy

Lefamulin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with moderate CYP3A4 inducers unless the benefits outweigh the risks. Risk D: Consider therapy modification

Lefamulin (Intravenous): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lefamulin (Intravenous). Management: Avoid concomitant use of lefamulin (intravenous) with moderate CYP3A4 inducers unless the benefits outweigh the risks. Risk D: Consider therapy modification

Lemborexant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lemborexant. Risk X: Avoid combination

Lercanidipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lercanidipine. Risk C: Monitor therapy

Letermovir: Modafinil may decrease the serum concentration of Letermovir. Risk X: Avoid combination

Levamlodipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Levamlodipine. Risk C: Monitor therapy

Levoketoconazole: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Levoketoconazole. Risk C: Monitor therapy

Levomethadone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Levomethadone. Risk C: Monitor therapy

LinaGLIPtin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of LinaGLIPtin. Risk C: Monitor therapy

Linezolid: May enhance the hypertensive effect of Sympathomimetics. Management: Reduce initial doses of sympathomimetic agents, and closely monitor for enhanced pressor response, in patients receiving linezolid. Specific dose adjustment recommendations are not presently available. Risk D: Consider therapy modification

Lonafarnib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lonafarnib. Risk X: Avoid combination

Lopinavir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lopinavir. Risk C: Monitor therapy

Lorlatinib: CYP3A4 Inducers (Moderate) may enhance the hepatotoxic effect of Lorlatinib. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lorlatinib. Management: Avoid use of lorlatinib with moderate CYP3A4 inducers. If such a combination must be used, increase lorlatinib to 125 mg daily. Monitor for reduced lorlatinib efficacy and consider closer monitoring of AST, ALT, and bilirubin. Risk D: Consider therapy modification

Lumacaftor and Ivacaftor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lumacaftor and Ivacaftor. Risk C: Monitor therapy

Lumateperone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lumateperone. Risk X: Avoid combination

Lurasidone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lurasidone. Management: Monitor for decreased lurasidone effects if combined with moderate CYP3A4 inducers and consider increasing the lurasidone dose if coadministered with a moderate CYP3A4 inducer for 7 or more days. Risk D: Consider therapy modification

Lurbinectedin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lurbinectedin. Risk X: Avoid combination

Macimorelin: Modafinil may diminish the diagnostic effect of Macimorelin. Risk C: Monitor therapy

Macitentan: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Macitentan. Risk C: Monitor therapy

Maraviroc: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Maraviroc. Management: Increase maraviroc adult dose to 600 mg twice/day, but only if not receiving a strong CYP3A4 inhibitor. Not recommended for pediatric patients not also receiving a strong CYP3A4 inhibitor. Contraindicated in patients with CrCl less than 30 mL/min. Risk D: Consider therapy modification

Maribavir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Maribavir. Risk C: Monitor therapy

Mefloquine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Mefloquine. Risk C: Monitor therapy

Meperidine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Meperidine. Risk C: Monitor therapy

Methadone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Methadone. Risk C: Monitor therapy

MethylPREDNISolone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of MethylPREDNISolone. Risk C: Monitor therapy

Mianserin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Mianserin. Risk C: Monitor therapy

Midazolam: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Midazolam. Risk C: Monitor therapy

Midostaurin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Midostaurin. Risk C: Monitor therapy

Mirodenafil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Mirodenafil. Risk C: Monitor therapy

Mitapivat: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Mitapivat. Management: Consider alternatives to this combination when possible. If combined, monitor hemoglobin and titrate mitapivat beyond 50 mg twice daily, if needed, but do not exceed doses of 100 mg twice daily. Risk D: Consider therapy modification

Mobocertinib: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Mobocertinib. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Mobocertinib. Risk X: Avoid combination

Naldemedine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Naldemedine. Risk C: Monitor therapy

Naloxegol: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Naloxegol. Risk C: Monitor therapy

Nelfinavir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nelfinavir. Risk C: Monitor therapy

Neratinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Neratinib. Risk X: Avoid combination

Netupitant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Netupitant. Risk C: Monitor therapy

Nevirapine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nevirapine. Risk C: Monitor therapy

NIFEdipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of NIFEdipine. Risk C: Monitor therapy

Nilotinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nilotinib. Risk C: Monitor therapy

Nilvadipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nilvadipine. Risk C: Monitor therapy

NiMODipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of NiMODipine. Risk C: Monitor therapy

Nirmatrelvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nirmatrelvir. Risk C: Monitor therapy

Nisoldipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nisoldipine. Risk X: Avoid combination

Olaparib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Olaparib. Risk X: Avoid combination

Oliceridine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Oliceridine. Risk C: Monitor therapy

Olmutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Olmutinib. Risk C: Monitor therapy

Osimertinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Osimertinib. Risk C: Monitor therapy

OxyCODONE: CYP3A4 Inducers (Moderate) may decrease the serum concentration of OxyCODONE. Risk C: Monitor therapy

Ozanimod: May enhance the hypertensive effect of Sympathomimetics. Risk C: Monitor therapy

PACLitaxel (Conventional): CYP3A4 Inducers (Moderate) may decrease the serum concentration of PACLitaxel (Conventional). Risk C: Monitor therapy

PACLitaxel (Protein Bound): CYP3A4 Inducers (Moderate) may decrease the serum concentration of PACLitaxel (Protein Bound). Risk C: Monitor therapy

Palbociclib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Palbociclib. Risk C: Monitor therapy

PAZOPanib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of PAZOPanib. Risk C: Monitor therapy

Pemigatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pemigatinib. Risk X: Avoid combination

Perampanel: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Perampanel. Management: Increase perampanel starting dose to 4 mg/day if used with moderate CYP3A4 inducers. Increase perampanel dose by 2 mg/day no more than once weekly based on response and tolerability. Dose adjustments may be needed if the inducer is discontinued. Risk D: Consider therapy modification

Pexidartinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pexidartinib. Risk C: Monitor therapy

Pimavanserin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pimavanserin. Risk X: Avoid combination

Piperaquine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Piperaquine. Risk C: Monitor therapy

PONATinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of PONATinib. Risk C: Monitor therapy

Pralsetinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pralsetinib. Risk C: Monitor therapy

Praziquantel: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Praziquantel. Management: Consider alternatives to this combination when possible. If combined, monitor for reduced praziquantel efficacy if combined with moderate CYP3A4 inducers. Risk D: Consider therapy modification

PrednisoLONE (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of PrednisoLONE (Systemic). Risk C: Monitor therapy

PredniSONE: CYP3A4 Inducers (Moderate) may decrease the serum concentration of PredniSONE. Risk C: Monitor therapy

Pretomanid: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pretomanid. Risk X: Avoid combination

QUEtiapine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of QUEtiapine. Risk C: Monitor therapy

QuiNIDine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of QuiNIDine. Risk C: Monitor therapy

QuiNINE: CYP3A4 Inducers (Moderate) may decrease the serum concentration of QuiNINE. Risk C: Monitor therapy

Ranolazine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ranolazine. Risk X: Avoid combination

Regorafenib: CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Regorafenib. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Regorafenib. Risk C: Monitor therapy

Repaglinide: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Repaglinide. Risk C: Monitor therapy

Ribociclib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ribociclib. Risk C: Monitor therapy

Rilpivirine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Rilpivirine. Risk C: Monitor therapy

Rimegepant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Rimegepant. Risk X: Avoid combination

Ripretinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ripretinib. Management: Avoid this combination if possible. If concomitant use is required, increase ripretinib to 150 mg twice daily. Decrease ripretinib to 150 mg once daily 14 days after stopping a moderate CYP3A4 inducer. Monitor patients for ripretinib response and toxicity Risk D: Consider therapy modification

RisperiDONE: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of RisperiDONE. CYP3A4 Inducers (Moderate) may decrease the serum concentration of RisperiDONE. Risk C: Monitor therapy

Ritonavir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ritonavir. Risk C: Monitor therapy

Roflumilast: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Roflumilast. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Roflumilast. Risk C: Monitor therapy

Rolapitant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Rolapitant. Risk C: Monitor therapy

Samidorphan: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Samidorphan. Risk C: Monitor therapy

Saquinavir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Saquinavir. Risk C: Monitor therapy

Selpercatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Selpercatinib. Risk X: Avoid combination

Selumetinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Selumetinib. Risk X: Avoid combination

Sertraline: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sertraline. Risk C: Monitor therapy

Sildenafil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sildenafil. Risk C: Monitor therapy

Simeprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Simeprevir. Risk X: Avoid combination

Sirolimus (Conventional): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy

Sirolimus (Protein Bound): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sirolimus (Protein Bound). Risk C: Monitor therapy

Sofosbuvir: Modafinil may decrease the serum concentration of Sofosbuvir. Risk X: Avoid combination

Solriamfetol: Sympathomimetics may enhance the hypertensive effect of Solriamfetol. Sympathomimetics may enhance the tachycardic effect of Solriamfetol. Risk C: Monitor therapy

Solriamfetol: CNS Stimulants may enhance the hypertensive effect of Solriamfetol. CNS Stimulants may enhance the tachycardic effect of Solriamfetol. Risk C: Monitor therapy

Sonidegib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sonidegib. Risk X: Avoid combination

SORAfenib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of SORAfenib. Risk C: Monitor therapy

Sotorasib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sotorasib. Risk C: Monitor therapy

SUNItinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of SUNItinib. Risk C: Monitor therapy

Suvorexant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Suvorexant. Risk C: Monitor therapy

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapy

Tacrolimus (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy

Tadalafil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tadalafil. Risk C: Monitor therapy

Tamoxifen: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tamoxifen. Risk C: Monitor therapy

Tasimelteon: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tasimelteon. Risk C: Monitor therapy

Tazemetostat: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tazemetostat. Risk X: Avoid combination

Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy

Telithromycin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Telithromycin. Risk C: Monitor therapy

Temsirolimus: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Temsirolimus. Specifically, sirolimus concentrations may be decreased. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Temsirolimus. Risk C: Monitor therapy

Tetrahydrocannabinol: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tetrahydrocannabinol. Risk C: Monitor therapy

Tetrahydrocannabinol and Cannabidiol: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tetrahydrocannabinol and Cannabidiol. Risk C: Monitor therapy

Tezacaftor and Ivacaftor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tezacaftor and Ivacaftor. Risk C: Monitor therapy

Thiotepa: CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Thiotepa. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Thiotepa. Risk C: Monitor therapy

Ticagrelor: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ticagrelor. Risk C: Monitor therapy

Tivozanib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tivozanib. Risk C: Monitor therapy

Tofacitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tofacitinib. Risk C: Monitor therapy

Tolvaptan: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tolvaptan. Risk C: Monitor therapy

Toremifene: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Toremifene. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Toremifene. Risk C: Monitor therapy

Trabectedin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Trabectedin. Risk C: Monitor therapy

TraMADol: CYP3A4 Inducers (Moderate) may decrease the serum concentration of TraMADol. Risk C: Monitor therapy

TraZODone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of TraZODone. Risk C: Monitor therapy

Triazolam: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Triazolam. Risk C: Monitor therapy

Ubrogepant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 100 mg and second dose (if needed) of 100 mg when used with a moderate CYP3A4 inducer. Risk D: Consider therapy modification

Ulipristal: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ulipristal. Risk X: Avoid combination

Upadacitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Upadacitinib. Risk C: Monitor therapy

Valbenazine: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Valbenazine. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Valbenazine. Risk C: Monitor therapy

Vandetanib: CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Vandetanib. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Vandetanib. Risk C: Monitor therapy

Velpatasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Velpatasvir. Risk X: Avoid combination

Vemurafenib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Vemurafenib. Risk C: Monitor therapy

Venetoclax: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Venetoclax. Risk X: Avoid combination

Verapamil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Verapamil. Risk C: Monitor therapy

Vilazodone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Vilazodone. Risk C: Monitor therapy

Voclosporin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Voclosporin. Risk X: Avoid combination

Vorapaxar: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Vorapaxar. Risk X: Avoid combination

Voriconazole: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Voriconazole. Risk C: Monitor therapy

Vortioxetine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Vortioxetine. Risk C: Monitor therapy

Voxelotor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Voxelotor. Management: Avoid concomitant use of voxelotor and moderate CYP3A4 inducers. If unavoidable, increase the voxelotor dose to 2,000 mg once daily. For children ages 4 to less than 12 years, weight-based dose adjustments are required. See full monograph for details. Risk D: Consider therapy modification

Voxilaprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Voxilaprevir. Risk X: Avoid combination

Zaleplon: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Zaleplon. Risk C: Monitor therapy

Zanubrutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Zanubrutinib. Risk X: Avoid combination

Zolpidem: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Zolpidem. Risk C: Monitor therapy

Zopiclone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Zopiclone. Risk C: Monitor therapy

Food Interactions

Food delays absorption, but does not affect bioavailability. Management: Administer without regard to meals.

Reproductive Considerations

Evaluate pregnancy status prior to modafinil initiation; patients who may become pregnant should avoid modafinil use or use effective contraception during modafinil therapy (Ghaffari 2021).

Modafinil induces cytochrome P450 enzymes, decreasing systemic exposure to drugs metabolized via CYP3A4/5. Efficacy of steroidal contraceptives (including depot and implantable contraceptives) may be decreased; alternate means of effective contraception should be used during modafinil therapy and for ≥1 month after modafinil is discontinued. Consult drug interactions database for more detailed information specific to use of modafinil and contraceptives.

Pregnancy Considerations

Outcome information following modafinil use in pregnancy is limited (Calvo-Ferrandiz 2018; Cesta 2020; Damkier 2020; Haervig 2014). Data collected from the Nuvigil/Provigil pregnancy registry suggest an increased risk of major fetal congenital malformations following in utero exposure to modafinil. Outcome information is based on 148 pregnancies reported to the registry between February 2010 and February 2019 (modafinil n=81; armodafinil n=65; both n=1). Data collected prospectively for 122 pregnancies (102 live births with known outcomes) indicated a 13% rate of major congenital malformations. When including data from retrospective live births (n=26), the malformation rate remained the same. No specific pattern of malformations was observed (Kaplan 2021). An increased risk of spontaneous abortion and intrauterine growth restriction has been reported with modafinil.

Data collection to monitor pregnancy and infant outcomes following exposure to modafinil is ongoing. Health care providers are encouraged to enroll patients exposed to modafinil during pregnancy in the registry (1-866-404-4106); pregnant patients may also enroll themselves.

Monitoring Parameters

Levels of sleepiness; blood pressure; heart rate; increased monitoring in patients with recent MI or unstable angina; development of severe skin reactions; development or exacerbation of psychiatric symptoms (eg, agitation, anxiety, depression)

When used for the treatment of ADHD, thoroughly evaluate for cardiovascular risk. Monitor heart rate, blood pressure, and consider obtaining ECG prior to initiation (AHA [Vetter 2008]).

Mechanism of Action

The exact mechanism of action is unclear. Modafinil has been shown to significantly increase dopamine in the brain by blocking dopamine transporters; however, has a lower affinity for dopamine receptors compared to amphetamines (Volkow 2009). EEG studies have shown modafinil increases high-frequency alpha waves while decreasing both delta and theta wave activity, effects consistent with generalized increases in mental alertness (James 2011). Studies also have demonstrated decreased GABA-mediated neurotransmission through increased turnover of serotonin and enhanced activity of 5-HT2 receptors and that an intact central alpha-adrenergic system is required for modafinil's activity (Kumar 2008; Schwartz 2008).

Pharmacokinetics (Adult data unless noted)

Modafinil is a racemic compound (10% S-isomer and 90% R-isomer at steady state) whose enantiomers have different pharmacokinetics

Distribution: Vd: 0.9 L/kg

Protein binding: ~60%, primarily to albumin

Metabolism: Hepatic; multiple pathways including CYP3A4

Half-life elimination: Effective half-life: 15 hours

Time to peak, serum: 2 to 4 hours; may be delayed ~1 hour with food.

Excretion: Urine (80% as metabolites, <10% as unchanged drug); feces (1%)

Pharmacokinetics: Additional Considerations

Renal function impairment: In severe, chronic renal failure (CrCl ≤20 mL/minute), exposure to modafinil acid (inactive metabolite) was increased 9-fold.

Hepatic function impairment: In patients with cirrhosis of the liver, clearance is decreased ~60% and steady-state concentrations are doubled.

Geriatric: Oral clearance decreased ~20% in patients with a mean age of 63 years of age.

Pricing: US

Tablets (Modafinil Oral)

100 mg (per each): $11.19 - $26.40

200 mg (per each): $16.93 - $39.94

Tablets (Provigil Oral)

100 mg (per each): $56.73

200 mg (per each): $85.72

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Activigil (UY);
  • Alertex (CL, EC);
  • Aspendos (NL, RO);
  • Carim (EC, UY);
  • Intensit (AR);
  • Mentix (CL);
  • Modafin (AU);
  • Modalert (IN);
  • Modanil (KR);
  • Modasomil (AT, CH);
  • Modavigil (AU, NZ);
  • Modfil (IN);
  • Modiodal (AE, CR, DK, DO, ES, FR, GR, GT, HN, IS, JP, LB, MX, NI, NL, NO, PA, PT, SV, TR);
  • Movigil (CL);
  • Nopral (AR);
  • Prosentio (IE);
  • Provigil (BB, BE, GB, IE, IL, IT, KR, LU, MT, PY, SG, TW, ZA);
  • Resotyl (CL, PE);
  • Stavigile (BR);
  • Vigia (CO);
  • Vigicer (AR);
  • Vigifinil (HR);
  • Vigil (CZ, DE);
  • Zalox (CL)


For country abbreviations used in Lexicomp (show table)

REFERENCES

  1. Abolfazli R, Hosseini M, Ghanizadeh A, et al. Double-blind randomized parallel-group clinical trial of efficacy of the combination fluoxetine plus modafinil versus fluoxetine plus placebo in the treatment of major depression. Depress Anxiety. 2011;28(4):297-302. doi:10.1002/da.20801 [PubMed 21456039]
  2. Adler CH, Caviness JN, Hentz JG, Lind M, Tiede J. Randomized trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson's disease. Mov Disord. 2003;18(3):287-293. doi:10.1002/mds.10390 [PubMed 12621632]
  3. Alertec (modafinil) [product monograph]. Toronto, Ontario, Canada: Teva Canada Limited; November 2021.
  4. Aurora S, Aurora N, Datta P, Rewers-Felkins K, Baker T, Hale TW. Evaluating transfer of modafinil into human milk during lactation: a case report. J Clin Sleep Med. 2018;14(12):2087-2089. doi:10.5664/jcsm.7546 [PubMed 30518447]
  5. 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(6):e777-784. [PubMed 16322134]
  6. Biederman J, Swanson JM, Wigal SB, et al. A comparison of once-daily and divided doses of modafinil in children with attention-deficit/hyperactivity disorder: a randomized, double-blind, and placebo-controlled study. J Clin Psychiatry. 2006;67(5):727-735. [PubMed 16841622]
  7. Blackhall L, Petroni G, Shu J, Baum L, Farace E. A pilot study evaluating the safety and efficacy of modafinil for cancer-related fatigue. J Palliat Med. 2009;12(5):433-439. doi:10.1089/jpm.2008.0230 [PubMed 19416039]
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