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  • CLASSES

    Miscellaneous Neurotransmitter Modulators

    DEA CLASS

    Rx, schedule IV

    DESCRIPTION

    CNS stimulant unrelated to amphetamines; the R-enantiomer of modafinil; increases mental alertness and decreases fatigue.
    Used in adults for excessive daytime sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift-work sleep disorder.

    COMMON BRAND NAMES

    Nuvigil

    HOW SUPPLIED

    Armodafinil/Nuvigil Oral Tab: 50mg, 150mg, 200mg, 250mg

    DOSAGE & INDICATIONS

    For the treatment of narcolepsy to improve wakefulness in patients with excessive sleepiness.
    Oral dosage
    Adults, including Geriatric Adults

    150 mg to 250 mg PO once daily as a single dose in the morning. In geriatric adults, use lowest effective dose due to the possibility of adverse effects from decreased drug elimination.

    Adolescents 17 years and older

    150 mg to 250 mg PO once daily as a single dose in the morning.

    For the treatment of shift work sleep disorder to improve wakefulness in patients with excessive sleepiness.
    Oral dosage
    Adults, including Geriatric Adults

    150 mg PO once daily, given approximately 1 hour prior to the start of work shift. In geriatric adults, use lowest effective dose due to the possibility of adverse effects from decreased drug elimination.

    Adolescents 17 years and older

    150 mg PO once daily, given approximately 1 hour prior to the start of work shift.

    For the treatment of obstructive sleep apnea to improve wakefulness in patients with excessive sleepiness.
    Oral dosage
    Adults, including Geriatric Adults

    150 mg to 250 mg PO once daily as a single dose in the morning. Doses of 250 mg/day have been well tolerated; however, there is no consistent evidence indicating that this dose provides additional therapeutic benefits. In geriatric adults, use lowest effective dose due to the possibility of adverse effects from decreased drug elimination. In obstructive sleep apnea, armodafinil 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, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating armodafinil for excessive sleepiness.

    Adolescents 17 years and older

    150 mg to 250 mg PO once daily as a single dose in the morning. Doses of 250 mg/day have been well tolerated; however, there is no consistent evidence indicating that this dose provides additional therapeutic benefits. In obstructive sleep apnea, armodafinil 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, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating armodafinil for excessive sleepiness.

    MAXIMUM DOSAGE

    Adults

    250 mg/day PO for narcolepsy and OSA/HS; 150 mg/day PO for circadian rhythm disruption.

    Geriatric

    250 mg/day PO for narcolepsy and OSA/HS; 150 mg/day PO for circadian rhythm disruption.

    Adolescents

    >= 17 years: 250 mg/day PO for narcolepsy and OSA/HS; 150 mg/day PO for circadian rhythm disruption.
    < 17 years: Safety and efficacy have not been established.

    Children

    Safe and effective use has not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for quantitative dosage reductions are not available; however, the manufacturer recommends that the dose of armodafinil be reduced in the presence of severe hepatic impairment.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available. The safety of armodafinil in patients with severe renal impairment is unknown. Exposure to the inactive metabolite modafinil acid was increased 9-fold in patients with chronic renal failure (creatinine clearance <= 20 mL/min) receiving modafinil, a racemic compound containing armodafinil. The clinical significance is unknown.

    ADMINISTRATION

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

    Oral Administration

    •Administer in the morning to get maximal effects during waking hours and to avoid possible interference with nocturnal sleep.
    •May be given without regard to meals. The presence of food will delay maximum peak concentrations by approximately 2—4 hours; however, effects on overall bioavailability are minimal.

    STORAGE

    Nuvigil:
    - Store between 68 to 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Armodafinil should be used only in patients with an indicated sleep disorder and a completed history, physical examination, and/or sleep disorder laboratory testing, if needed. In obstructive sleep apnea, armodafinil is indicated as an adjunct to standard 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 should be made prior to initiating armodafinil. If used adjunctively with CPAP, periodic assessment of CPAP compliance is necessary.

    Angioedema, serious rash

    Armodafinil is contraindicated in patients with known hypersensitivity to the drug, or with a history of hypersensitivity to modafinil, a racemic compound containing armodafinil. Angioedema and hypersensitivity with serious rash, dysphagia, and bronchospasm have been observed during use of armodafinil. Various life-threatening rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), and multi-organ hypersensitivity reaction have occurred in worldwide postmarketing experience in adults and pediatrics. In cases where time to onset was reported, serious rashes generally occurred 1 day to 2 months after treatment initiation; however, there have been isolated cases after more prolonged therapy (e.g., 3 months). Therefore, prolonged administration should not preclude the possibility of an association to drug therapy. Armodafinil should be discontinued if rash appears at any time during treatment if an association to the drug is suspected or confirmed.

    Bipolar disorder, depression, mania, psychosis, schizophrenia, suicidal ideation

    Various adverse psychiatric effects (e.g., mania, delusions, hallucinations, suicidal ideation, aggression) have occurred during administration of armodafinil. Caution should be exercised when administering armodafinil to patients with a known history of psychosis (e.g., schizophrenia), depression, suicidal ideation, mania, or bipolar disorder. Many patients who have developed psychiatric adverse reactions had a prior psychiatric history; therefore, such patients may need behavioral assessments or frequent clinical observation. If psychiatric symptoms develop during treatment with armodafinil, consider discontinuation of the drug.

    Neurological disease

    Armodafinil should be used with caution in patients with neurological disease, as these patients have not been adequately studied. Seizures have occurred with other classes of CNS stimulants (i.e., the amphetamines), particularly in overdose; however, there is currently a lack of evidence substantiating an association between armodafinil and seizure risk or development. It should be noted that safety during concomitant use of armodafinil and anticonvulsants has not been established.

    Acute myocardial infarction, angina, cardiac arrhythmias, cardiac disease, heart failure, hypertension, myocardial infarction, valvular heart disease, ventricular dysfunction

    The safety of armodafinil in those with cardiac disease has not been established. Modafinil, a racemic compound containing armodafinil, has been associated with cardiovascular side effects in clinical trials in some patients with cardiac disease. Some of these changes have included palpitations, chest pain, ischemic ECG changes, and dyspnea, particularly in patients with valvular heart disease (mitral valve prolapse) or left ventricular dysfunction. It is recommended that armodafinil not be prescribed to patients with chest pain, heart failure, cardiac arrhythmias, left ventricular hypertrophy, ischemic ECG changes, or valvular symptoms associated with CNS stimulants (e.g., mitral valve prolapse syndrome). Patients with a history of unstable angina or recent myocardial infarction should be treated with caution, as there is not extensive experience with armodafinil use in these patients. Armodafinil is not recommended for use in the setting of acute myocardial infarction. A small increase in blood pressure occurred in some patients during clinical trials with armodafinil; it is advisable to evaluate blood pressure periodically in patients with hypertension.

    Pregnancy

    There are no well-controlled studies of armodafinil 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%). Additionally, both intrauterine growth retardation and spontaneous abortion have occurred in association with armodafinil and modafinil. Armodafinil did not demonstrate mutagenic potential during in vitro studies. It is not known if the drug is carcinogenic, impairs fertility, or negatively affects labor and delivery. 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 armodafinil, a CNS stimulant, would have on the developing fetal brain. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to armodafinil; information about the registry can be obtained at www.nuvigilpregnancyregistry.com or by calling 1-866-404-4106.

    Contraception requirements

    Armodafinil may cause failure of hormonal contraceptives in females, including hormonal contraceptive implants and hormone-containing contraceptive devices. Additional contraception requirements are recommended. Alternative contraception methods should be used during armodafinil treatment and for 1 month after discontinuation of the drug.

    Breast-feeding

    According to the manufacturer, the developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for armodafinil and any potential adverse effects on the breastfed child from armodafinil or from the underlying maternal condition. It is unknown if armodafinil or its metabolites are excreted into human breast milk, although the low molecular weight and pharmacokinetic profile of the drug suggest that excretion into breast milk is likely. In addition, results from rat studies showed the presence of armodafinil in maternal milk during the lactation period. If maternal use of armodafinil is necessary, the nursing infant should be observed for evidence of side effects, such as infection, nausea or decreased appetite, irritability, and insomnia. It is not clear if stimulants are safe for use during breast-feeding; amphetamines (e.g., dextroamphetamine), when used as drugs of abuse, are considered to be contraindicated in breast-feeding due to concerns of irritability and poor sleeping pattern in the infant. 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.

    Abrupt discontinuation, alcoholism, substance abuse

    Drug abuse, misuse, diversion, psychological dependence, physiological dependence, and/or tolerance have been reported in some patients treated with armodafinil. Health care professionals should closely monitor patients who take armodafinil, especially those patients with a history of alcoholism, stimulant, or other substance abuse. Patients should be observed for signs of misuse or abuse (i.e., frequent prescription refill requests, or drug-seeking behavior). Abrupt discontinuation or dose reduction following chronic use can result in withdrawal symptoms, including shaking, sweating, chills, nausea, vomiting, confusion, aggression, and atrial fibrillation. Abrupt withdrawal of armodafinil has also been associated with seizures, suicidality, fatigue, insomnia, depression or deterioration of existing depression, and headache. The use of alcohol in combination with armodafinil has not been studied; clinicians should advise patients to avoid alcohol with the use of this medication. Signs and symptoms of overdose following abuse of armodafinil include tachycardia, insomnia, agitation, dizziness, anxiety, nausea, headache, dystonia, tremor, chest pain, hypertension, seizures, delirium, or hallucinations. Other signs and symptoms of stimulant abuse include tachypnea, sweating, dilated pupils, hyperactivity, restlessness, decreased appetite, loss of coordination, flushing, vomiting, and abdominal pain.

    Geriatric

    Armodafinil should be used with caution in geriatric patients. Pharmacokinetic studies indicate that geriatric patients have a higher systemic exposure to armodafinil than younger adults and initial dosage reductions should be considered in 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.

    Hepatic disease, hepatitis

    Data on the use of armodafinil in those with hepatic disease, including cirrhosis and hepatitis, are not available. Serum concentrations of modafinil, a racemic compound containing armodafinil, increase by 50% and oral clearance is decreased by about 60% in the presence of severe hepatic disease due to decreased hepatic metabolism. Therefore, the manufacturer recommends that the dose of armodafinil be reduced in patients with severe hepatic disease.

    Renal disease, renal failure, renal impairment

    Data on the use of armodafinil in those with renal disease are not available. Patients with renal failure (CrCl <= 20 mL/min) receiving modafinil, a racemic compound containing armodafinil, have reduced clearance of modafinil acid, an inactive metabolite of both modafinil and armodafinil. It is unknown if the accumulation of this metabolite would have clinical consequences. There are no dosing guidelines for the use of armodafinil in patients with severe renal impairment; caution is advised.

    Children, infants, neonates

    The safety and effectiveness of armodafinil in neonates, infants, children and adolescents  under the age of 17 years has not been established. The drug has not been studied by the manufacturer in pediatric patients for any indication. It should be noted that serious rashes have been reported in children who have received modafinil, a racemic compound containing armodafinil. The discontinuation rate due to rash development in pediatric patients receiving modafinil was 0.8%; these rashes included 1 case of possible Stevens-Johnson Syndrome (SJS) and 1 case of multi-organ hypersensitivity reaction.

    Driving or operating machinery

    Armodafinil has not been shown to produce functional impairment; however, any CNS stimulant could potentially alter thinking, judgment, or motor skills. Armodafinil may mask signs of sleep deprivation. Patients should be cautioned against driving or operating machinery, or performing other tasks that require mental alertness, until they are aware of the effects the drug has on their ability to perform such tasks.

    ADVERSE REACTIONS

    Severe

    Stevens-Johnson syndrome / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    pancytopenia / Delayed / Incidence not known
    suicidal ideation / Delayed / Incidence not known

    Moderate

    hypertension / Early / 0-2.9
    depression / Delayed / 2.0-2.0
    palpitations / Early / 2.0-2.0
    migraine / Early / 1.0-1.0
    constipation / Delayed / 1.0-1.0
    contact dermatitis / Delayed / 1.0-1.0
    dyspnea / Early / 1.0-1.0
    oral ulceration / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    mania / Early / Incidence not known
    hallucinations / Early / Incidence not known
    psychological dependence / Delayed / Incidence not known
    physiological dependence / Delayed / Incidence not known
    tolerance / Delayed / Incidence not known
    withdrawal / Early / Incidence not known

    Mild

    headache / Early / 17.0-17.0
    nausea / Early / 7.0-7.0
    insomnia / Early / 5.0-5.0
    dizziness / Early / 5.0-5.0
    xerostomia / Early / 4.0-4.0
    diarrhea / Early / 4.0-4.0
    anxiety / Delayed / 4.0-4.0
    dyspepsia / Early / 2.0-2.0
    abdominal pain / Early / 2.0-2.0
    rash / Early / 2.0-2.0
    fatigue / Early / 2.0-2.0
    tremor / Early / 1.0-1.0
    paresthesias / Delayed / 1.0-1.0
    anorexia / Delayed / 1.0-1.0
    vomiting / Early / 1.0-1.0
    hyperhidrosis / Delayed / 1.0-1.0
    agitation / Early / 1.0-1.0
    restlessness / Early / 1.0-1.0
    influenza / Delayed / 1.0-1.0
    fever / Early / 1.0-1.0
    polyuria / Early / 1.0-1.0

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with armodafinil; 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. Armodafinil is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with armodafinil. Caffeine should be used cautiously with armodafinil. Intake of caffeine should be limited. Excessive intake may cause nervousness, irritability, insomnia, or other side effects.
    Acetaminophen; Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with armodafinil. Caffeine should be used cautiously with armodafinil. Intake of caffeine should be limited. Excessive intake may cause nervousness, irritability, insomnia, or other side effects.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with armodafinil. Caffeine should be used cautiously with armodafinil. Intake of caffeine should be limited. Excessive intake may cause nervousness, irritability, insomnia, or other side effects. (Moderate) Concomitant use of dihydrocodeine with armodafinil 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 armodafinil is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Armodafinil is a weak inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with armodafinil. Caffeine should be used cautiously with armodafinil. Intake of caffeine should be limited. Excessive intake may cause nervousness, irritability, insomnia, or other side effects.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with armodafinil. Caffeine should be used cautiously with armodafinil. Intake of caffeine should be limited. Excessive intake may cause nervousness, irritability, insomnia, or other side effects.
    Acetaminophen; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of hydrocodone as needed. If armodafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Acetaminophen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of oxycodone as needed. If armodafinil is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Aliskiren; 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 armodafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Aliskiren; 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 armodafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    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 armodafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    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 armodafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    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 armodafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    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 armodafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    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 armodafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    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 armodafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    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 armodafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as clarithromycin are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed. (Moderate) In vitro data indicate that armodafinil is an inhibitor of CYP2C19. In theory, dosage reductions may be required for drugs that are largely eliminated via CYP2C19 metabolism such as omeprazole during coadministration with armodafinil. A 40% increase in exposure of omeprazole was observed during coadministration with armodafinil. The clinical significance of this interaction is unknown.
    Amphetamine: (Moderate) The use of armodafinil with other psychostimulants, including amphetamines, (e.g., dextroamphetamine, lisdexamfetamine, amphetamine) has not been studied. In a single-dose study of dextroamphetamine combined with modafinil, a racemic compound containing armodafinil, no pharmacokinetic interactions occurred but a slight increase in stimulant-associated side effects was noted. Patients receiving combination therapy of armodafinil with other psychostimulants should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other stimulant-related side effects.
    Amphetamine; Dextroamphetamine: (Moderate) The use of armodafinil with other psychostimulants, including amphetamines, (e.g., dextroamphetamine, lisdexamfetamine, amphetamine) has not been studied. In a single-dose study of dextroamphetamine combined with modafinil, a racemic compound containing armodafinil, no pharmacokinetic interactions occurred but a slight increase in stimulant-associated side effects was noted. Patients receiving combination therapy of armodafinil with other psychostimulants should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other stimulant-related side effects.
    Amphetamines: (Moderate) The use of armodafinil with other psychostimulants, including amphetamines, (e.g., dextroamphetamine, lisdexamfetamine, amphetamine) has not been studied. In a single-dose study of dextroamphetamine combined with modafinil, a racemic compound containing armodafinil, no pharmacokinetic interactions occurred but a slight increase in stimulant-associated side effects was noted. Patients receiving combination therapy of armodafinil with other psychostimulants should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other stimulant-related side effects.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if armodafinil and aprepitant, fosaprepitant are used concurrently and monitor for a possible decrease in the efficacy of aprepitant, fosaprepitant. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Armodafinil is a weak CYP3A4 inducer; 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 weak-to-moderate inducers.
    Aripiprazole: (Moderate) In vitro data indicate that armodafinil is an inducer of CYP3A4/5 isoenzymes. Decreased blood levels of aripiprazole are expected when the drug is coadministered with inducers of CYP3A4, such as armodafinil. A dosage adjustment of aripiprazole may be necessary when these drugs are used concomitantly, and conversely, when armodafinil is discontinued in a patient taking aripiprazole. 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.
    Artemether; Lumefantrine: (Major) Armodafinil is an inducer of CYP3A4/5, and a reversible inhibitor of CYP2C19. Artemether is predominantly metabolized by the CYP3A4/5 isoenzyme, with lesser contributions from CYP2C19. Coadministration may lead to decreased artemether; lumefantrine concentrations and warrants caution due to a possible reduction in antimalarial activity.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with armodafinil. Caffeine should be used cautiously with armodafinil. Intake of caffeine should be limited. Excessive intake may cause nervousness, irritability, insomnia, or other side effects.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with armodafinil. Caffeine should be used cautiously with armodafinil. Intake of caffeine should be limited. Excessive intake may cause nervousness, irritability, insomnia, or other side effects.
    Aspirin, ASA; Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with armodafinil. Caffeine should be used cautiously with armodafinil. Intake of caffeine should be limited. Excessive intake may cause nervousness, irritability, insomnia, or other side effects.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with armodafinil. Caffeine should be used cautiously with armodafinil. Intake of caffeine should be limited. Excessive intake may cause nervousness, irritability, insomnia, or other side effects. (Moderate) Concomitant use of dihydrocodeine with armodafinil 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 armodafinil is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Armodafinil is a weak inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with armodafinil. Caffeine should be used cautiously with armodafinil. Intake of caffeine should be limited. Excessive intake may cause nervousness, irritability, insomnia, or other side effects.
    Aspirin, ASA; Omeprazole: (Moderate) In vitro data indicate that armodafinil is an inhibitor of CYP2C19. In theory, dosage reductions may be required for drugs that are largely eliminated via CYP2C19 metabolism such as omeprazole during coadministration with armodafinil. A 40% increase in exposure of omeprazole was observed during coadministration with armodafinil. The clinical significance of this interaction is unknown.
    Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of oxycodone as needed. If armodafinil is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Atazanavir; Cobicistat: (Major) Coadministration of cobicistat with armodafinil is not recommended as there is a potential for elevated armodafinil concentrations and decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Armodafinil is a CYP3A4 substrate/inducer and a P-glycoprotein (P-gp) substrate. Cobicistat is an inhibitor of CYP3A4 and P-gp, and a substrate of CYP3A4.
    Barbiturates: (Major) It is not clear how armodafinil interacts with barbiturates like phenobarbital. Armodafinil is partially metabolized by CYP3A4 and combined use with CYP3A4 inducers such as phenobarbital and other barbiturates may result in decreased armodafinil efficacy. Barbiturates used for sleep could counteract the effect of armodafinil on wakefulness, and would not ordinarily be prescribed. The potential effects of combining armodafinil with anticonvulsant barbiturate medications are unclear. Many psychostimulants can reduce the seizure threshold, but it is not clear if armodafinil can affect seizure control.
    Bedaquiline: (Major) Avoid concurrent use of armodafinil with bedaquiline. Armodafinil is a CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
    Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of armodafinil 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 armodafinil is a CYP2C19 inhibitor.
    Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with armodafinil 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 armodafinil may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. If armodafinil is discontinued, consider a benzhydrocodone dosage reduction and monitor patients for respiratory depression and sedation at frequent intervals. Benzhydrocodone is a prodrug of hydrocodone. Armodafinil is a weak in vitro inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone.
    Benzphetamine: (Moderate) The use of armodafinil with other psychostimulants, including amphetamines, (e.g., dextroamphetamine, lisdexamfetamine, amphetamine) has not been studied. In a single-dose study of dextroamphetamine combined with modafinil, a racemic compound containing armodafinil, no pharmacokinetic interactions occurred but a slight increase in stimulant-associated side effects was noted. Patients receiving combination therapy of armodafinil with other psychostimulants should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other stimulant-related side effects.
    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.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of hydrocodone as needed. If armodafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of hydrocodone as needed. If armodafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Bupropion: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Bupropion; Naltrexone: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Butalbital; Acetaminophen; Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with armodafinil. Caffeine should be used cautiously with armodafinil. Intake of caffeine should be limited. Excessive intake may cause nervousness, irritability, insomnia, or other side effects.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with armodafinil. Caffeine should be used cautiously with armodafinil. Intake of caffeine should be limited. Excessive intake may cause nervousness, irritability, insomnia, or other side effects.
    Cabotegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering armodafinil with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of these drugs. Armodafinil 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.
    Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with armodafinil. Caffeine should be used cautiously with armodafinil. Intake of caffeine should be limited. Excessive intake may cause nervousness, irritability, insomnia, or other side effects. (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with psychostimulants such as armodafinil. Patients taking armodafinil may need to be cautioned to avoid excessive intake of caffeine.
    Caffeine; Sodium Benzoate: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with armodafinil. Caffeine should be used cautiously with armodafinil. Intake of caffeine should be limited. Excessive intake may cause nervousness, irritability, insomnia, or other side effects.
    Carbamazepine: (Moderate) Armodafinil is partially metabolized by CYP3A4 and combined use with CYP3A4 inducers such as carbamazepine may result in decreased armodafinil efficacy. In vitro data indicate that armodafinil is an inducer of CYP3A4. Therefore, decreased carbamazepine serum levels are possible during combined use with armodafinil. Clinically, be alert for increased sleepiness or other indicators of reduced armofafinil efficacy. The potential pharmacodynamic effects of combining armodafinil with anticonvulsant medications are unclear; however, should it be noted that other CNS stimulants (e.g., amphetamines) are known to lower the seizure threshold.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of hydrocodone as needed. If armodafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of hydrocodone as needed. If armodafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    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.
    Carvedilol: (Moderate) Concomitant use of carvedilol and armodafinil may result in increased armodafinil concentrations. Carvedilol is a P-glycoprotein (P-gp) inhibitor. An in vitro study indicated that and armodafinil is a P-gp substrate. Observation of the patient for increased effects from armodafinil may be needed.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with armodafinil 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 armodafinil is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Armodafinil is a weak inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with armodafinil 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 armodafinil is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Armodafinil is a weak inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of hydrocodone as needed. If armodafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Chlorpheniramine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of hydrocodone as needed. If armodafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of hydrocodone as needed. If armodafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of hydrocodone as needed. If armodafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Cimetidine: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as cimetidine are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed.
    Citalopram: (Moderate) The plasma concentration of citalopram, a CYP2C19 substrate, may be increased when administered concurrently with armodafinil, 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.
    Clarithromycin: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as clarithromycin are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed.
    Clobazam: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of armodafinil. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and armodafinil is an inhibitor 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.
    Clomipramine: (Moderate) In vitro data indicate that armodafinil is an inhibitor of CYP2C19. In theory, dosage reductions may be required for drugs that are largely eliminated via CYP2C19 metabolism such as clomipramine during coadministration with armodafinil.
    Clopidogrel: (Major) Armodafinil may reduce the antiplatelet activity of clopidogrel by inhibiting clopidogrel's metabolism to its active metabolite. Use clopidogrel and armodafinil 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. Armodafinil is an inhibitor of CYP2C19.
    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.
    Cobicistat: (Major) Coadministration of cobicistat with armodafinil is not recommended as there is a potential for elevated armodafinil concentrations and decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Armodafinil is a CYP3A4 substrate/inducer and a P-glycoprotein (P-gp) substrate. Cobicistat is an inhibitor of CYP3A4 and P-gp, and a substrate of CYP3A4.
    Cobimetinib: (Moderate) If concurrent use of cobimetinib and armodafinil is necessary, use caution and monitor for decreased efficacy of cobimetinib. Cobimetinib is a CYP3A substrate in vitro, and armodafinil is a weak in vitro inducer of CYP3A. The manufacturer of cobimetinib recommends avoiding coadministration of cobimetinib with moderate or strong CYP3A inducers based on simulations demonstrating that cobimetinib exposure would decrease by 73% or 83% when coadministered with a moderate or strong CYP3A inducer, respectively. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inducers.
    Cyclosporine: (Moderate) In vitro data indicate that armodafinil is an inducer of CYP3A4/5 isoenzymes. Therefore, armodafinil may induce the metabolism of medications which are substrates for CYP3A4 such as cyclosporine. Increased cyclosporine clearance and decreased cyclosporine concentrations can lead to loss of therapeutic effect. Cyclosporine concentrations should be monitored closely after the addition or discontinuation of armodafinil until a new steady-state level is achieved.
    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 armodafinil. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance. Conversely, the therapeutic effects of armodafinil, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor.
    Dapsone: (Minor) The metabolism of dapsone may be accelerated when administered concurrently with armodafinil, a known inducer of CYP3A4. Coadministration is expected to decrease the plasma concentration of dapsone and increase the formation of dapsone hydroxylamine (a metabolite associated with hemolysis). If these drugs must be administered together, closely monitor for a reduction in dapsone efficacy and signs of hemolytic anemia.
    Darunavir: (Major) Coadministration of darunavir with armodafinil is not recommended as there is a potential for elevated armodafinil concentrations and decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Armodafinil is a CYP3A4 substrate/inducer. Darunavir is an inhibitor/substrate of CYP3A4.
    Darunavir; Cobicistat: (Major) Coadministration of cobicistat with armodafinil is not recommended as there is a potential for elevated armodafinil concentrations and decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Armodafinil is a CYP3A4 substrate/inducer and a P-glycoprotein (P-gp) substrate. Cobicistat is an inhibitor of CYP3A4 and P-gp, and a substrate of CYP3A4. (Major) Coadministration of darunavir with armodafinil is not recommended as there is a potential for elevated armodafinil concentrations and decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Armodafinil is a CYP3A4 substrate/inducer. Darunavir is an inhibitor/substrate of CYP3A4.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Coadministration of cobicistat with armodafinil is not recommended as there is a potential for elevated armodafinil concentrations and decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Armodafinil is a CYP3A4 substrate/inducer and a P-glycoprotein (P-gp) substrate. Cobicistat is an inhibitor of CYP3A4 and P-gp, and a substrate of CYP3A4. (Major) Coadministration of darunavir with armodafinil is not recommended as there is a potential for elevated armodafinil concentrations and decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Armodafinil is a CYP3A4 substrate/inducer. Darunavir is an inhibitor/substrate of CYP3A4.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) Concurrent administration of armodafinil with dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in decreased plasma concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Armodafinil is an inducer of the hepatic isoenzyme CYP3A4; paritaprevir, ritonavir and dasabuvir (minor) are substrates of this enzyme. (Contraindicated) Concurrent administration of armodafinil with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in decreased plasma concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Armodafinil is an inducer of the hepatic isoenzyme CYP3A4; paritaprevir, ritonavir and dasabuvir (minor) are substrates of this enzyme. (Major) Coadministration of ritonavir with armodafinil may result in elevated armodafinil concentrations and decreased ritonavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Armodafinil is a substrate and inducer of CYP3A4, and a P-glycoprotein (P-gp) substrate. Ritonavir is a substrate of CYP3A4 and an inhibitor of P-gp. Ritonavir is also a potent inhibitor of CYP3A4.
    Desogestrel; Ethinyl Estradiol: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Dexamethasone: (Minor) Armodafinil is partially metabolized via CYP3A4/5 isoenzymes. CYP3A4 inducers, such as dexamethasone, may potentially increase the metabolism of armodafinil. Decreased serum levels of armodafinil could potentially result in decreased efficacy of the drug.
    Dextroamphetamine: (Moderate) The use of armodafinil with other psychostimulants, including amphetamines, (e.g., dextroamphetamine, lisdexamfetamine, amphetamine) has not been studied. In a single-dose study of dextroamphetamine combined with modafinil, a racemic compound containing armodafinil, no pharmacokinetic interactions occurred but a slight increase in stimulant-associated side effects was noted. Patients receiving combination therapy of armodafinil with other psychostimulants should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other stimulant-related side effects.
    Diazepam: (Moderate) In vitro data indicate that armodafinil is an inhibitor of CYP2C19. In theory, dosage reductions may be required for drugs that are largely eliminated via CYP2C19 metabolism such as diazepam during coadministration with armodafinil.
    Dienogest; Estradiol valerate: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with armodafinil 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 armodafinil is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Armodafinil is a weak inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of hydrocodone as needed. If armodafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Dolutegravir: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with armodafinil; 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. Armodafinil is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
    Dolutegravir; Lamivudine: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with armodafinil; 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. Armodafinil is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
    Dolutegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering armodafinil with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of these drugs. Armodafinil 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. (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with armodafinil; 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. Armodafinil is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
    Donepezil: (Minor) The elimination of donepezil may be increased by concurrent administration of moderate inducers of CYP3A4, such as modafinil or armodafinil. The clinical effect of this interaction on the efficacy of donepezil has not been determined. Observe patients for evidence of reduced donepezil efficacy if these agents are prescribed concurrently.
    Donepezil; Memantine: (Minor) The elimination of donepezil may be increased by concurrent administration of moderate inducers of CYP3A4, such as modafinil or armodafinil. The clinical effect of this interaction on the efficacy of donepezil has not been determined. Observe patients for evidence of reduced donepezil efficacy if these agents are prescribed concurrently.
    Doravirine: (Minor) Concurrent administration of doravirine and armodafinil may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; armodafinil is a weak CYP3A4 inducer.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Minor) Concurrent administration of doravirine and armodafinil may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; armodafinil is a weak CYP3A4 inducer.
    Dronabinol: (Moderate) Use caution if coadministration of dronabinol with armodafinil is necessary, and monitor for a decrease in the efficacy of dronabinol. Dronabinol is a CYP2C9 and 3A4 substrate; armodafinil is a weak inducer of CYP3A4 in vitro. Concomitant use may result in decreased plasma concentrations of dronabinol.
    Drospirenone; Estradiol: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Drospirenone; Ethinyl Estradiol: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Elagolix; Estradiol; Norethindrone acetate: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Elbasvir; Grazoprevir: (Major) Concurrent administration of elbasvir with armodafinil should be avoided if possible. Armodafinil 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. (Major) Concurrent administration of grazoprevir with armodafinil should be avoided if possible. Armodafinil 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.
    Elvitegravir: (Major) Coadministration of with armodafinil 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. Armodafinil is a CYP3A4 inducer, while elvitegravir is a substrate of CYP3A4.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Coadministration of cobicistat with armodafinil is not recommended as there is a potential for elevated armodafinil concentrations and decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Armodafinil is a CYP3A4 substrate/inducer and a P-glycoprotein (P-gp) substrate. Cobicistat is an inhibitor of CYP3A4 and P-gp, and a substrate of CYP3A4. (Major) Coadministration of with armodafinil 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. Armodafinil is a CYP3A4 inducer, while elvitegravir is a substrate of CYP3A4.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of cobicistat with armodafinil is not recommended as there is a potential for elevated armodafinil concentrations and decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Armodafinil is a CYP3A4 substrate/inducer and a P-glycoprotein (P-gp) substrate. Cobicistat is an inhibitor of CYP3A4 and P-gp, and a substrate of CYP3A4. (Major) Coadministration of with armodafinil 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. Armodafinil is a CYP3A4 inducer, while elvitegravir is a substrate of CYP3A4.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Close clinical monitoring is advised when administering armodafinil with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of these drugs. Armodafinil 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.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Close clinical monitoring is advised when administering armodafinil with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of these drugs. Armodafinil 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.
    Ergotamine; Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with armodafinil. Caffeine should be used cautiously with armodafinil. Intake of caffeine should be limited. Excessive intake may cause nervousness, irritability, insomnia, or other side effects.
    Erlotinib: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with armodafinil; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate, and armodafinil is a CYP3A4 inducer.
    Erythromycin: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as erythromycin are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed.
    Erythromycin; Sulfisoxazole: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as erythromycin are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed.
    Escitalopram: (Moderate) The plasma concentration of escitalopram, a CYP2C19 substrate, may be increased when administered concurrently with armodafinil, a CYP2C19 inhibitor. If these drugs are used together, monitor for escitalopram-associated adverse reactions.
    Esketamine: (Major) Closely monitor blood pressure during concomitant use of esketamine and armodafinil. Coadministration of psychostimulants, such as armodafinil, with esketamine may increase blood pressure, including the possibility of hypertensive crisis.
    Estradiol Cypionate; Medroxyprogesterone: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Estradiol: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Estradiol; Levonorgestrel: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Estradiol; Norethindrone: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Estradiol; Norgestimate: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Estradiol; Progesterone: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Ethanol: (Major) Advise patients to avoid alcohol-containing beverages while taking armodafinil. There is no information on the effects of concurrent administration of alcohol or alcohol-containing medications with armodafinil; the CNS depressant effect of alcohol may reduce the response to armodafinil.
    Ethinyl Estradiol: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Ethinyl Estradiol; Norelgestromin: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Ethinyl Estradiol; Norgestrel: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Ethotoin: (Moderate) Since armodafinil is metabolized by the CYP3A4 isoenzyme, and hydantoins (e.g., phenytoin, fosphenytoin) are CYP3A4 inducers. decreased armodafinil efficacy may result from increased armodafinil metabolism. In addition, armodafinil 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.
    Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Etonogestrel; Ethinyl Estradiol: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Fentanyl: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if coadministration with armodafinil is necessary. If armodafinil is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like armodafinil 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.
    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.
    Fluconazole: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as fluconazole are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed.
    Fluoxetine: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as fluoxetine are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed.
    Fosamprenavir: (Major) Caution is advised when administering armodafinil with fosamprenavir, as concurrent use may reduce the plasma concentrations of both drugs. Armodafinil is an inducer of the hepatic isoenzyme CYP3A4 and a substrate for the drug transporter P-glycoprotein (P-gp). Amprenavir, the active metabolite of fosamprenavir, is an inducer of P-gp and a substrate of CYP3A4.
    Fosphenytoin: (Moderate) Since armodafinil is metabolized by the CYP3A4 isoenzyme, and hydantoins (e.g., phenytoin, fosphenytoin) are CYP3A4 inducers. decreased armodafinil efficacy may result from increased armodafinil metabolism. In addition, armodafinil 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.
    Green Tea: (Major) Some green tea products contain caffeine. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Patients taking armodafinil may need to be cautioned to avoid excessive intake of caffeine.
    Guaifenesin; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of hydrocodone as needed. If armodafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of hydrocodone as needed. If armodafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Homatropine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of hydrocodone as needed. If armodafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydantoins: (Moderate) Since armodafinil is metabolized by the CYP3A4 isoenzyme, and hydantoins (e.g., phenytoin, fosphenytoin) are CYP3A4 inducers. decreased armodafinil efficacy may result from increased armodafinil metabolism. In addition, armodafinil 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.
    Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of hydrocodone as needed. If armodafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydrocodone; Ibuprofen: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of hydrocodone as needed. If armodafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydrocodone; Phenylephrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of hydrocodone as needed. If armodafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of hydrocodone as needed. If armodafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of hydrocodone as needed. If armodafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of hydrocodone as needed. If armodafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of oxycodone as needed. If armodafinil is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Isavuconazonium: (Major) Coadministration of isavuconazonium with armodafinil is not recommended as there is a potential for elevated armodafinil concentrations and decreased concentrations of isavuconazonium. Decreased isavuconazonium concentrations may lead to a reduction of antifungal efficacy and the potential for treatment failure. Armodafinil is a CYP3A4 substrate/inducer. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of CYP3A4.
    Isocarboxazid: (Major) Armodafinil 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 armodafinil, it is prudent avoid the use of armodafinil 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 armodafinil should elapse.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Armodafinil is partially metabolized via CYP3A4/5 isoenzymes. Drugs that exhibit significant induction of the CYP3A4 isoenzyme, such as rifampin, may potentially increase the metabolism of armodafinil. Decreased serum levels of armodafinil could potentially result in decreased efficacy of the drug.
    Isoniazid, INH; Rifampin: (Major) Armodafinil is partially metabolized via CYP3A4/5 isoenzymes. Drugs that exhibit significant induction of the CYP3A4 isoenzyme, such as rifampin, may potentially increase the metabolism of armodafinil. Decreased serum levels of armodafinil could potentially result in decreased efficacy of the drug.
    Itraconazole: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as itraconazole are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed.
    Ketoconazole: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as ketoconazole are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed.
    Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as clarithromycin are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed.
    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 armodafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Levoketoconazole: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as ketoconazole are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed.
    Levonorgestrel; Ethinyl Estradiol: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Linezolid: (Moderate) Use caution during coadministration of armodafinil with MAO inhibitors. Armodafinil has not been evaluated for drug interactions with monoamine oxidase inhibitors (MAOIs), including drugs with MAO inhibiting activity (e.g., linezolid). Other CNS stimulants may induce severe cardiovascular and cerebrovascular responses if administered in combination with drugs with MAO inhibitor activity.
    Lisdexamfetamine: (Moderate) The use of armodafinil with other psychostimulants, including amphetamines, (e.g., dextroamphetamine, lisdexamfetamine, amphetamine) has not been studied. In a single-dose study of dextroamphetamine combined with modafinil, a racemic compound containing armodafinil, no pharmacokinetic interactions occurred but a slight increase in stimulant-associated side effects was noted. Patients receiving combination therapy of armodafinil with other psychostimulants should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other stimulant-related side effects.
    Loperamide: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with armodafinil. Loperamide is metabolized by the hepatic enzyme CYP3A4; armodafinil is a mild inducer of this enzyme.
    Loperamide; Simethicone: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with armodafinil. Loperamide is metabolized by the hepatic enzyme CYP3A4; armodafinil is a mild inducer of this enzyme.
    Lopinavir; Ritonavir: (Major) Coadministration of ritonavir with armodafinil may result in elevated armodafinil concentrations and decreased ritonavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Armodafinil is a substrate and inducer of CYP3A4, and a P-glycoprotein (P-gp) substrate. Ritonavir is a substrate of CYP3A4 and an inhibitor of P-gp. Ritonavir is also a potent inhibitor of CYP3A4.
    Lumateperone: (Major) Avoid coadministration of lumateperone and armodafinil as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A4 substrate; armodafinil is a weak CYP3A4 inducer.
    Macimorelin: (Major) Discontinue armodafinil and allow a sufficient washout period to pass before administering macimorelin. Use of these drugs together can 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 armodafinil is a weak CYP3A4 inducer.
    Maraviroc: (Minor) Use caution if coadministration of maraviroc with armodafinil is necessary, due to a possible decrease in maraviroc exposure. Maraviroc is a CYP3A substrate and armodafinil is a weak CYP3A4 inducer. Monitor for a decrease in efficacy with concomitant use.
    Mestranol; Norethindrone: (Major) Amodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of ethinyl estradiol and/or the progestins in these products. Mestranol is converted to ethinyl estradiol in the body. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Methamphetamine: (Moderate) The use of armodafinil with other psychostimulants, including amphetamines, (e.g., dextroamphetamine, lisdexamfetamine, amphetamine) has not been studied. In a single-dose study of dextroamphetamine combined with modafinil, a racemic compound containing armodafinil, no pharmacokinetic interactions occurred but a slight increase in stimulant-associated side effects was noted. Patients receiving combination therapy of armodafinil with other psychostimulants should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other stimulant-related side effects.
    Methylphenidate Derivatives: (Major) The use of armodafinil with other psychostimulants, including methylphenidate derivatives, has not been studied. Patients receiving combination therapy of armodafinil with other psychostimulants should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other stimulant-related side effects.
    Midazolam: (Moderate) In vitro data indicate that armodafinil is an inducer of CYP3A4/5 isoenzymes. Therefore, armodafinil may induce the metabolism of benzodiazepines which are substrates for CYP3A, including midazolam. Concurrent administration of armodafinil with midazolam resulted in a 32% reduction in systemic exposure of midazolam. Dosage adjustments of midazolam may be required during initiation or discontinuation of armodafinil.
    Monoamine oxidase inhibitors: (Major) Armodafinil 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 armodafinil, it is prudent avoid the use of armodafinil 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 armodafinil should elapse.
    Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with armodafinil is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer.
    Nanoparticle Albumin-Bound Sirolimus: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of armodafinil; a sirolimus dose adjustment may be necessary. Monitor sirolimus serum concentrations as appropriate. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; armodafinil is a weak CYP3A inducer.
    Nefazodone: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as nefazodone are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed.
    Nirmatrelvir; Ritonavir: (Major) Coadministration of ritonavir with armodafinil may result in elevated armodafinil concentrations and decreased ritonavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Armodafinil is a substrate and inducer of CYP3A4, and a P-glycoprotein (P-gp) substrate. Ritonavir is a substrate of CYP3A4 and an inhibitor of P-gp. Ritonavir is also a potent inhibitor of CYP3A4. (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of armodafinil is necessary. Concomitant use of nirmatrelvir and armodafinil may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and armodafinil is a weak CYP3A inducer.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with armodafinil due to decreased plasma concentrations of nisoldipine. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels.
    Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Norethindrone; Ethinyl Estradiol: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Norgestimate; Ethinyl Estradiol: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Olanzapine; Fluoxetine: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as fluoxetine are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed.
    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 armodafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) Concurrent administration of armodafinil with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in decreased plasma concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Armodafinil is an inducer of the hepatic isoenzyme CYP3A4; paritaprevir, ritonavir and dasabuvir (minor) are substrates of this enzyme. (Major) Coadministration of ritonavir with armodafinil may result in elevated armodafinil concentrations and decreased ritonavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Armodafinil is a substrate and inducer of CYP3A4, and a P-glycoprotein (P-gp) substrate. Ritonavir is a substrate of CYP3A4 and an inhibitor of P-gp. Ritonavir is also a potent inhibitor of CYP3A4.
    Omeprazole: (Moderate) In vitro data indicate that armodafinil is an inhibitor of CYP2C19. In theory, dosage reductions may be required for drugs that are largely eliminated via CYP2C19 metabolism such as omeprazole during coadministration with armodafinil. A 40% increase in exposure of omeprazole was observed during coadministration with armodafinil. The clinical significance of this interaction is unknown.
    Omeprazole; Amoxicillin; Rifabutin: (Moderate) Armodafinil is partially metabolized via CYP3A4/5 isoenzymes. Drugs that exhibit significant induction of the CYP3A4 isoenzyme, such as rifabutin, may potentially increase the metabolism of armodafinil. Decreased serum levels of armodafinil could potentially result in decreased efficacy of the drug. (Moderate) In vitro data indicate that armodafinil is an inhibitor of CYP2C19. In theory, dosage reductions may be required for drugs that are largely eliminated via CYP2C19 metabolism such as omeprazole during coadministration with armodafinil. A 40% increase in exposure of omeprazole was observed during coadministration with armodafinil. The clinical significance of this interaction is unknown.
    Omeprazole; Sodium Bicarbonate: (Moderate) In vitro data indicate that armodafinil is an inhibitor of CYP2C19. In theory, dosage reductions may be required for drugs that are largely eliminated via CYP2C19 metabolism such as omeprazole during coadministration with armodafinil. A 40% increase in exposure of omeprazole was observed during coadministration with armodafinil. The clinical significance of this interaction is unknown.
    Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of oxycodone as needed. If armodafinil is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Pemoline: (Major) The use of armodafinil with other psychostimulants (e.g., pemoline) has not been studied; however, patients receiving combination therapy of armodafinil with other psychostimulants should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other stimulant-related side effects.
    Perampanel: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with armodafinil due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of armodafinil occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Armodafinil is a moderate CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    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 armodafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Phenelzine: (Major) Armodafinil 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 armodafinil, it is prudent avoid the use of armodafinil 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 armodafinil should elapse.
    Phenytoin: (Moderate) Since armodafinil is metabolized by the CYP3A4 isoenzyme, and hydantoins (e.g., phenytoin, fosphenytoin) are CYP3A4 inducers. decreased armodafinil efficacy may result from increased armodafinil metabolism. In addition, armodafinil 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.
    Praziquantel: (Major) In vitro and drug interactions studies suggest that the CYP3A4 isoenzyme is the major enzyme involved in praziquantel metabolism. Therefore, use of praziquantel with armodafinil, a CYP3A4 inducer, should be done with caution as concomitant use may produce therapeutically ineffective concentrations of praziquantel.
    Procarbazine: (Contraindicated) Armodafinil has not been evaluated for drug interactions with drugs with MAO inhibiting activity (e.g., procarbazine). Other CNS stimulants may induce severe cardiovascular and cerebrovascular responses if administered in combination with drugs with MAO inhibitor activity. The manufacturer recommends caution during coadministration of armodafinil with MAO inhibitors.
    Progestins: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estrogens and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Propranolol: (Moderate) In vitro data indicate that armodafinil 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 armodafinil.
    Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) In vitro data indicate that armodafinil 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 armodafinil.
    Relugolix; Estradiol; Norethindrone acetate: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Rifabutin: (Moderate) Armodafinil is partially metabolized via CYP3A4/5 isoenzymes. Drugs that exhibit significant induction of the CYP3A4 isoenzyme, such as rifabutin, may potentially increase the metabolism of armodafinil. Decreased serum levels of armodafinil could potentially result in decreased efficacy of the drug.
    Rifampin: (Major) Armodafinil is partially metabolized via CYP3A4/5 isoenzymes. Drugs that exhibit significant induction of the CYP3A4 isoenzyme, such as rifampin, may potentially increase the metabolism of armodafinil. Decreased serum levels of armodafinil could potentially result in decreased efficacy of the drug.
    Rilpivirine: (Moderate) Close clinical monitoring is advised when administering armodafinil with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of these drugs. Armodafinil 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.
    Ritonavir: (Major) Coadministration of ritonavir with armodafinil may result in elevated armodafinil concentrations and decreased ritonavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Armodafinil is a substrate and inducer of CYP3A4, and a P-glycoprotein (P-gp) substrate. Ritonavir is a substrate of CYP3A4 and an inhibitor of P-gp. Ritonavir is also a potent inhibitor of CYP3A4.
    Rivaroxaban: (Minor) Coadministration of rivaroxaban and armodafinil may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Armodafinil is a mild 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.
    Segesterone Acetate; Ethinyl Estradiol: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Selegiline: (Moderate) Use caution during concomitant use of selegiline and armodafinil. Armodafinil 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.
    Simeprevir: (Major) Avoid concurrent use of simeprevir and armodafinil. Potential induction of CYP3A4 by armodafinil (an in vitro inducer) may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Sirolimus: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of armodafinil; a sirolimus dose adjustment may be necessary. Monitor sirolimus serum concentrations as appropriate. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; armodafinil is a weak CYP3A inducer.
    Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of velpatasvir with armodafinil. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; armodafinil is an in vitro inducer of CYP3A4.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of velpatasvir with armodafinil. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; armodafinil is an in vitro inducer of CYP3A4.
    Solriamfetol: (Moderate) Monitor blood pressure and heart rate during coadministration of solriamfetol, a norepinephrine and dopamine reuptake inhibitor, and armodafinil, 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.
    Sonidegib: (Major) Avoid the concomitant use of sonidegib and armodafinil; sonidegib levels may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and armodafinil is a CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would decrease by 56% in cancer patients who received 14 days of sonidegib 200 mg/day with a moderate CYP3A inducer. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would decrease by 69% in cancer patients who received sonidegib 200 mg/day with a moderate CYP3A inducer for 4 months.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if armodafinil must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of sufentanil injection as needed. If armodafinil 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 armodafinil is a weak 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.
    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.
    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 armodafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Terbinafine: (Moderate) Caution is advised when administering terbinafine with armodafinil. 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 CYP1A2, CYP2C8, CYP2C9, CYP2C19 and CYP3A4; armodafinil is an inhibitor of CYP2C19 and an inducer of CYP1A2 and CYP3A4. Taking these drugs together may increase or decrease the systemic exposure of terbinafine. Monitor patients for breakthrough fungal infections and terbinafine related adverse reactions.
    Theophylline, Aminophylline: (Minor) In vitro data indicate that armodafinil is an inducer of CYP3A4/5 isoenzymes. Although theophylline is only metabolized by CYP3A4 to a minor degree, caution is warranted due to the narrow therapeutic index of the drug. Theophylline concentrations should be monitored closely after the addition or discontinuation of armodafinil until a new steady-state level is achieved. (Minor) In vitro data indicate that armodafinil is an inducer of CYP3A4/5 isoenzymes. Although theophylline/aminophylline is only metabolized by CYP3A4 to a minor degree, caution is warranted due to the narrow therapeutic index of the drug. Theophylline/aminophylline concentrations should be monitored closely after the addition or discontinuation of armodafinil until a new steady-state level is achieved.
    Tranylcypromine: (Major) Armodafinil 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 armodafinil, it is prudent avoid the use of armodafinil 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 armodafinil should elapse.
    Ubrogepant: (Major) Increase the initial and second dose of ubrogepant to 100 mg if coadministered with armodafinil as concurrent use may decrease ubrogepant exposure and reduce its efficacy. Ubrogepant is a CYP3A4 substrate; armodafinil is a weak CYP3A4 inducer.
    Ulipristal: (Major) Avoid administration of ulipristal with drugs that induce CYP3A4. Ulipristal is a substrate of CYP3A4 and armodafinil is a CYP3A4 inducer. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal.
    Vincristine Liposomal: (Minor) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including armodafinil (in vitro). Patients receiving these drugs concurrently should be monitored for possible loss of vincristine efficacy.
    Vincristine: (Minor) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including armodafinil (in vitro). Patients receiving these drugs concurrently should be monitored for possible loss of vincristine efficacy.
    Vorapaxar: (Minor) Use caution during concurrent use of vorapaxar and armodafinil. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with armodafinil, a mild inducer of CYP3A4 in vitro.
    Voriconazole: (Minor) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as voriconazole are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with armodafinil is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Armodafinil is a weak CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no well-controlled studies of armodafinil 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%). Additionally, both intrauterine growth retardation and spontaneous abortion have occurred in association with armodafinil and modafinil. Armodafinil did not demonstrate mutagenic potential during in vitro studies. It is not known if the drug is carcinogenic, impairs fertility, or negatively affects labor and delivery. 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 armodafinil, a CNS stimulant, would have on the developing fetal brain. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to armodafinil; information about the registry can be obtained at www.nuvigilpregnancyregistry.com or by calling 1-866-404-4106.

    According to the manufacturer, the developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for armodafinil and any potential adverse effects on the breastfed child from armodafinil or from the underlying maternal condition. It is unknown if armodafinil or its metabolites are excreted into human breast milk, although the low molecular weight and pharmacokinetic profile of the drug suggest that excretion into breast milk is likely. In addition, results from rat studies showed the presence of armodafinil in maternal milk during the lactation period. If maternal use of armodafinil is necessary, the nursing infant should be observed for evidence of side effects, such as infection, nausea or decreased appetite, irritability, and insomnia. It is not clear if stimulants are safe for use during breast-feeding; amphetamines (e.g., dextroamphetamine), when used as drugs of abuse, are considered to be contraindicated in breast-feeding due to concerns of irritability and poor sleeping pattern in the infant. 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.

    MECHANISM OF ACTION

    Armodafinil is the R-enantiomer of the racemic compound modafinil. The exact mechanism of action is not fully known; however, the enantiomers of modafinil (e.g., armodafinil) have similar pharmacologic profiles. Data obtained from modafinil suggest that the primary sites of activity are in the subregions of the hippocampus, the centrolateral nucleus of the thalamus, and the central nucleus of the amygdala. In vitro and nonclinical animal studies suggest that armodafinil does not bind to or inhibit most of the enzymes, hormones, or neurotransmitters/receptors thought to be involved in sleep-wake cycles including adenosine, benzodiazepines, catechol-O-methyltransferase (COMT), cortisol, galanin, gamma-butyric amino acid (GABA), GABA transaminase, growth hormone, histamine, melanocortin, melatonin, norepinephrine, orphanin, orexin-1, phosphodiesterase VI, pituitary adenylate cyclase-activating polypeptide (PACAP), serotonin, or tyrosine hydroxylase. The related compound modafinil does not inhibit monoamine oxidase B, or phosphodiesterases II—IV. Armodafinil is not a dopamine receptor agonist; however, in vitro data indicate that the drug binds to the dopamine transporter (DAT) and inhibits dopamine reuptake. It is important to note that the wake-promoting effects of modafinil are not diminished by the administration of dopamine receptor antagonists, nor does the dopamine synthesis inhibitor alpha-methyl-p-tyrosine block its locomotor activity in animal models. Modafinil-induced wakefulness can be attenuated by the alpha-1 adrenergic antagonist, prazosin, which initially led to the 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. In addition to wake-promoting actions, other pharmacologic effects of armodafinil may include euphoria, as well as alterations in mood, perception, thinking, and feelings similar to those which occur with other CNS stimulants. Drug seeking behavior occurred in monkeys receiving modafinil who were previously trained to self-administer cocaine. Therefore, it is possible that armodafinil may potentially lead to habitual psychological dependence in some individuals.

    PHARMACOKINETICS

    Armodafinil is administered orally. The protein binding characteristics are unknown. The elimination half-life is roughly 15 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP3A4/5, CYP2C19, P-glycoprotein (P-gp)
    In vitro data indicate that armodafinil is an inducer of CYP1A2 and CYP3A4/5, and a reversible inhibitor of CYP2C19. The major route of elimination is liver metabolism, occurring via hydrolytic deamination, S-oxidation, hydroxylation, and glucuronide conjugation; in vitro data indicate that it is a substrate of P-glycoprotein (P-gp). Sulfone formation occurs via the CYP3A4/5 isoenzymes. Only two metabolites are present in the plasma in significant concentrations (i.e., R-modafinil acid and modafinil sulfone). Neither appear to have pharmacologic activity.

    Oral Route

    Absorption of armodafinil occurs rapidly after oral administration; peak plasma concentrations occur in 2 hours when administered without food. When administered with food, Tmax is delayed by about 2—4 hours.