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Armodafinil: Drug information

Armodafinil: Drug information
(For additional information see "Armodafinil: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Nuvigil
Pharmacologic Category
  • Central Nervous System Stimulant
Dosing: Adult

Narcolepsy: Oral: 150 to 250 mg once daily in the morning

Obstructive sleep apnea (OSA): Oral: 150 to 250 mg once daily in the morning; doses >150 mg have not been shown to have an increased benefit.

Shift-work disorder: Oral: 150 mg given once daily ~1 hour prior to work shift.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

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

Dosing: Hepatic Impairment: Adult

Mild to moderate hepatic impairment: No dosage adjustment necessary.

Severe hepatic impairment: The manufacturer recommends a reduced dose due to decreased clearance and increased steady-state concentration of modafinil in this patient population.

Dosing: Older Adult

Refer to adult dosing. Consider lower initial dosage.

Dosage Forms: US

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

Tablet, Oral:

Nuvigil: 50 mg, 150 mg, 200 mg, 250 mg

Generic: 50 mg, 150 mg, 200 mg, 250 mg

Generic Equivalent Available: US

Yes

Controlled Substance

C-IV

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/UCM231717.pdf, must be dispensed with this medication.

Administration: Adult

May be administered without regard to food.

Use: Labeled Indications

Narcolepsy: To improve wakefulness in patients with excessive sleepiness associated with narcolepsy.

Obstructive sleep apnea: To improve wakefulness in patients with excessive sleepiness associated with obstructive sleep apnea (OSA).

Limitations of use: In OSA, armodafinil is indicated to treat excessive sleepiness and not as treatment for the underlying obstruction. If continuous positive airway pressure (CPAP) is the treatment of choice for a patient, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating armodafinil for excessive sleepiness.

Shift-work disorder: To improve wakefulness in patients with excessive sleepiness associated with shift-work disorder.

Adverse Reactions

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

>10%: Central nervous system: Headache (14% to 23%; dose related)

1% to 10%:

Cardiovascular: Palpitations (2%), increased heart rate (1%)

Central nervous system: Insomnia (4% to 6%; dose related), dizziness (5%), anxiety (4%), depression (1% to 3%; dose related), fatigue (2%), agitation (1%), depressed mood (1%), lack of concentration (1%), migraine (1%), nervousness (1%), pain (1%), paresthesia (1%)

Dermatologic: Skin rash (1% to 4%; dose related), contact dermatitis (1%), diaphoresis (1%)

Endocrine & metabolic: Increased gamma-glutamyl transferase (1%), increased thirst (1%)

Gastrointestinal: Nausea (6% to 9%; dose related), xerostomia (2% to 7%; dose related), diarrhea (4%), dyspepsia (2%), upper abdominal pain (2%), anorexia (1%), constipation (1%), decreased appetite (1%), loose stools (1%), vomiting (1%)

Hypersensitivity: Seasonal allergy (1%)

Neuromuscular & skeletal: Tremor (1%)

Renal: Polyuria (1%)

Respiratory: Dyspnea (1%), flu-like symptoms (1%)

Miscellaneous: Fever (1%)

<1%, postmarketing, and/or case reports: Anaphylaxis, angioedema, DRESS syndrome, hypersensitivity reaction (including bronchospasm, dysphagia), hypouricemia, increased liver enzymes, increased serum alkaline phosphatase, irritability, multi-organ hypersensitivity, oral mucosa changes (including blistering, sores, ulceration), pancytopenia, skin changes (including blistering, sores, ulceration), Stevens-Johnson syndrome, suicidal ideation, systolic hypertension, toxic epidermal necrolysis

Contraindications

Hypersensitivity to armodafinil, modafinil, or any component of the formulation.

Warnings/Precautions

Concerns related to adverse effects:

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

• Dermatologic effects (severe): Serious and life-threatening rashes including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. In modafinil clinical trials, rashes were more likely to occur in children; serious, postmarketing reactions have occurred with modafinil and armodafinil in adults and children. Most cases have been reported within the first 8 weeks of initiating therapy; however, rare cases have occurred after prolonged therapy. No risk factors have been identified to predict occurrence or severity of these reactions. Patients should be advised to discontinue use at first sign of rash, skin or mouth sores or blistering or ulceration (unless the rash is clearly not drug-related).

• Hypersensitivity reactions: Rare cases of drug reaction with eosinophilia and system symptoms (DRESS), also known as multiorgan hypersensitivity, and cases of angioedema and anaphylactoid reactions have been reported. Signs and symptoms of DRESS are diverse. Patients typically present with fever and rash associated with other organ system involvement. Patients should be advised to discontinue therapy and promptly report any signs or symptoms related to these adverse effects.

Disease-related concerns:

• Cardiovascular disease: Use is not recommended in patients with a history of left ventricular hypertrophy or patients with mitral valve prolapse who have developed mitral valve prolapse syndrome with previous CNS stimulant use. Patients with these conditions may also experience chest pain, palpitations, dyspnea, and transient ischemic T-wave changes on ECG. Due to limited experience use caution in patients with history of myocardial infarction (MI) or angina. Increased blood pressure monitoring may be required, and new or additional antihypertensive therapy may be needed.

• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage reduction is recommended with severe dysfunction.

• Psychiatric disorders: Use caution in patients with a history of psychosis, depression, or mania. Armodafinil has been shown to worsen the symptoms of these diseases (eg, mania, hallucinations, suicidal thoughts). Discontinue therapy if psychiatric symptoms develop.

• Sleep disorders: Appropriate use: For use following complete evaluation of sleepiness and in conjunction with other standard treatments (eg, CPAP). The degree of sleepiness should be reassessed frequently; some patients may not return to a normal level of wakefulness. Patients with excessive sleepiness should be advised to avoid driving or any other potentially dangerous activity. Use >12 weeks has not been studied; patient should be reevaluated to determine effectiveness if use exceeds 12 weeks.

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

Special populations:

• Elderly: Use reduced doses in elderly patients; concentrations of armodafinil are significantly higher in patients >65 years of age.

Other warnings/precautions:

• Abuse potential: Use with caution in patients with a history of drug abuse; potential for drug dependency exists.

Metabolism/Transport Effects

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

Drug Interactions

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

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

ARIPiprazole: Armodafinil may decrease the serum concentration of ARIPiprazole. Risk C: Monitor therapy

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

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

CarBAMazepine: May decrease the serum concentration of Armodafinil. Armodafinil may decrease the serum concentration of CarBAMazepine. Risk C: Monitor therapy

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

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

Cocaine (Topical): May enhance the hypertensive effect of Sympathomimetics. Management: Consider alternatives to use of this combination when possible. Monitor closely for substantially increased blood pressure or heart rate and for any evidence of myocardial ischemia with concurrent use. Risk D: Consider therapy modification

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

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

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

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

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

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

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

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

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

Lumateperone: Armodafinil may decrease the serum concentration of Lumateperone. Risk C: Monitor therapy

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

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

QUEtiapine: Armodafinil may decrease the serum concentration of QUEtiapine. Risk C: Monitor therapy

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

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

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

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

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

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

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

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

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

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

Food Interactions

Food delays absorption, but minimal effects on bioavailability. Food may affect the onset and time course of armodafinil. Management: Administer without regard to meals.

Reproductive Considerations

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

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

Pregnancy Considerations

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

Data collection to monitor pregnancy and infant outcomes following exposure to armodafinil is ongoing. Health care providers are encouraged to register pregnant patients or pregnant females may register themselves by calling 1-866-404-4106.

Breastfeeding Considerations

Armodafinil is present in breast milk.

Breast milk was sampled over 24 hours in a female 19 days postpartum following long-term use of modafinil 250 mg daily. The peak breast milk concentration of armodafinil was 2.4 mcg/mL 2 hours after the maternal dose and decreased to 0.43 mcg/mL prior to the next dose. Her infant was not breastfed (Aurora 2018).

According to the manufacturer, the decision to breastfeed during armodafinil therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.

Monitoring Parameters

Signs of hypersensitivity, rash, psychiatric symptoms, levels of sleepiness, blood pressure, and drug abuse

Mechanism of Action

The exact mechanism of action of armodafinil is unknown. It is the R-enantiomer of modafinil. Armodafinil binds to the dopamine transporter and inhibits dopamine reuptake, which may result in increased extracellular dopamine levels in the brain. However, it does not appear to be a dopamine receptor agonist and also does not appear to bind to or inhibit the most common receptors or enzymes that are relevant for sleep/wake regulation.

Pharmacokinetics

Absorption: Readily absorbed

Distribution: Vd: 42 L

Protein binding: ~60% (based on modafinil; primarily albumin)

Metabolism: Hepatic, multiple pathways, including amine hydrolysis and CYP3A4/5; metabolites include R-modafinil acid and modafinil sulfone

Half-life elimination: ~15 hours

Time to peak, plasma: 2 hours (fasted)

Excretion: Urine (based on modafinil: 80% predominantly as metabolites; <10% as unchanged drug)

Pharmacokinetics: Additional Considerations

Renal function impairment: Severe chronic renal failure (CrCl ≤20 mL/minute) did not influence the pharmacokinetics of modafinil, but increased exposure to modafinil acid ninefold.

Hepatic function impairment: In patients with severe hepatic impairment, clearance of modafinil was decreased by ~60% and the steady-state concentration was doubled.

Geriatric: Systemic exposure of armodafinil was ~15% higher and clearance was ~12% lower in patients greater than 65 years of age.

Pricing: US

Tablets (Armodafinil Oral)

50 mg (per each): $7.26 - $7.27

150 mg (per each): $21.86 - $21.89

200 mg (per each): $21.89

250 mg (per each): $21.86 - $21.89

Tablets (Nuvigil Oral)

50 mg (per each): $13.47

150 mg (per each): $40.54

200 mg (per each): $40.54

250 mg (per each): $40.54

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

Brand Names: International
  • Armalert (EG);
  • Armod (IN);
  • Armovigil (EG);
  • Armowake (EG);
  • Arvigil (CL);
  • Modialex (AR);
  • Neoresotyl (CL, PY);
  • Nuvigil (AU, CR, DO, GT, HN, IL, MX, NI, PA, SV);
  • Nuvugil (BB);
  • Wakefinate (EG);
  • Waklert (IN)


For country abbreviations used in Lexicomp (show table)

REFERENCES

  1. Alertec (modafinil) [product monograph]. Toronto, Ontario, Canada: Teva Canada Limited; June 2019.
  2. Aurora S, Aurora N, Datta P, Rewers-Felkins K, Baker T, Hale TW. Evaluating transfer of modafinil into human milk during lactation: A case report. J Clin Sleep Med. 2018;14(12):2087-2089. doi: 10.5664/jcsm.7546. [PubMed 30518447]
  3. Fratto G, Manzon L. Use of psychotropic drugs and associated dental diseases. Int J Psychiatry Med. 2014;48(3):185-197. doi:10.2190/PM.48.3.d [PubMed 25492713]
  4. Ghaffari N, Robertson PA. Caution in prescribing modafinil and armodafinil to individuals who could become pregnant. JAMA Intern Med. 2021;181(2):277-278. doi:10.1001/jamainternmed.2020.4206 [PubMed 33074296]
  5. Hirshkowitz M, Black JE, Wesnes K, et al, “Adjunct Armodafinil Improves Wakefulness and Memory in Obstructive Sleep Apnea/Hypopnea Syndrome,” Respir Med, 2007, 101(3):616-27. [PubMed 16908126]
  6. Kaplan S, Braverman DL, Frishman I, Bartov N. Pregnancy and fetal outcomes following exposure to modafinil and armodafinil during pregnancy. JAMA Intern Med. 2021;181(2):275-277. doi:10.1001/jamainternmed.2020.4009 [PubMed 33074297]
  7. Murphy TK, Lewin AB, Storch EA, Stock S; American Academy of Child and Adolescent Psychiatry (AACAP) Committee on Quality Issues (CQI). Practice parameter for the assessment and treatment of children and adolescents with tic disorders. J Am Acad Child Adolesc Psychiatry. 2013;52(12):1341-1359. [PubMed 24290467]
  8. Nuvigil (armodafinil) [prescribing information]. North Wales, PA: Teva Pharmaceuticals USA, Inc; July 2019.
  9. Pliszka S; AACAP Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2007; 46(7): 894-921. [PubMed 17581453]
  10. Roessner V, Plessen KJ, Rothenberger A; ESSTS Guidelines Group. European clinical guidelines for Tourette syndrome and other tic disorders. Part II: pharmacological treatment [published correction appears in Eur Child Adolesc Psychiatry. 2011;20(7):377]. Eur Child Adolesc Psychiatry. 2011;20(4):173-196. [PubMed 21445724]
  11. Roth T, White D, Schmidt-Nowara W, et al, “Effects of Armodafinil in the Treatment of Residual Excessive Sleepiness Associated With Obstructive Sleep Apnea/Hypopnea Syndrome: A 12-week, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study in nCPAP-Adherent Adults,” Clin Ther, 2006, 28(5): 689-706. [PubMed 16861091]
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