Armodafinil

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Armodafinil
Armodafinil structure.svg
Armodafinil ball-and-stick xtal 2013.png
Names
Pronunciationar" moe daf' i nil[1]
Trade namesNuvigil, others
  • (–)-2-[(R)-(diphenylmethyl)sulfinyl]acetamide
Clinical data
Main usesNarcolepsy, obstructive sleep apnea, shift-work sleep disorder[1]
Side effectsHeadache, anxiety, nausea, decreased appetite, palpitations, disturbed sleep[1]
Dependence riskLow
Pregnancy
category
  • C
Routes of
use
Oral (tablets)
Typical dose150 to 250 mg OD[1]
External links
AHFS/Drugs.comMonograph
US NLMArmodafinil
MedlinePlusa602016
Legal
Legal status
Pharmacokinetics
MetabolismLiver, including CYP3A4 and other pathways
Elimination half-life12–15 hours
ExcretionUrine (as metabolites)
Chemical and physical data
FormulaC15H15NO2S
Molar mass273.35 g·mol−1
3D model (JSmol)
  • C1=CC=C(C=C1)C(C2=CC=CC=C2)[S@](=O)CC(=O)N
  • InChI=1S/C15H15NO2S/c16-14(17)11-19(18)15(12-7-3-1-4-8-12)13-9-5-2-6-10-13/h1-10,15H,11H2,(H2,16,17)/t19-/m1/s1 checkY
  • Key:YFGHCGITMMYXAQ-LJQANCHMSA-N checkY

Armodafinil, sold under the brand name Nuvigil among others, is a medication used for narcolepsy, obstructive sleep apnea, and shift-work sleep disorder.[1] It has also been studied for tiredness associated with chronic illness.[1] It is taken by mouth.[2] It may be used recreationally for its euphoria effects.[2]

Common side effects include headache, anxiety, nausea, decreased appetite, palpitations, and disturbed sleep.[1] Other side effects may include abuse, psychosis, suicide, and Stevens-Johnson syndrome.[1] Use in pregnancy may harm the baby.[3] It is the (R)-(−)-enantiomer of modafinil.[1]

It was approved for medical use in the United States in 2007.[4] It is available as a generic medication.[1] In the United States a month of 250 mg pills costs about 32 USD as of 2022.[5] In the United States it is a schedule IV controlled substance.[1]

Medical uses

Armodafinil is currently FDA-approved to treat excessive daytime sleepiness associated with obstructive sleep apnea, narcolepsy, and shift work disorder.[6] It is commonly used off-label to treat attention deficit hyperactivity disorder, chronic fatigue syndrome, and major depressive disorder, and has been repurposed as an adjunctive treatment for bipolar disorder.[7] It has been shown to improve vigilance in air traffic controllers,[8] however in the United States, sleep prevention medications such as flurazepam, modafinil, and armodafinil are not approved by the FAA for civilian controllers or pilots.

Bipolar disorder

Armodafinil, along with racemic modafinil, has been repurposed as an adjunctive treatment for acute depression in people with bipolar disorder.[7] Meta-analytic evidence showed that add-on modafinil and armodafinil were more effective than placebo on response to treatment, clinical remission, and reduction in depressive symptoms, with only minor side effects, but the effect sizes are small and the quality of evidence has to be considered low, limiting the clinical relevance of current evidence.[7]

Schizophrenia

In June 2010, it was revealed that a phase II study of armodafinil as an adjunctive therapy in adults with schizophrenia had failed to meet the primary endpoints, and the clinical program was subsequently terminated.[9] However, a study published later that year showed that schizophrenic patients treated with armodafinil showed fewer of the negative symptoms of schizophrenia.[10]

Jet lag

On March 30, 2010, the FDA declined to approve use to treat jet lag.[11][12]

Dosage

The usual dose in adults is 150 to 250 mg once daily.[1] For jet lag a lower dose of 50 to 150 mg is recommended.[1]

Side effects

The most commonly observed side effects were headache, xerostomia (dry mouth), nausea, dizziness, and insomnia.[7]

Possible side effects also include depression, anxiety, hallucinations, euphoria, extreme increase in activity and talking, anorexia, tremor, thirst, rash, suicidal thoughts, and aggression.

Symptoms of an overdose on armodafinil include trouble sleeping, restlessness, confusion, disorientation, feeling excited, mania, hallucinations, nausea, diarrhea, severely increased or decreased heart beat, chest pain, and increased blood pressure.[6][13][14]

Serious rashes can develop in rare cases, and require immediate medical attention due to the possibility of Steven's-Johnson Syndrome, or other hypersensitivities to armodafinil.[6]

Pharmacology

Pharmacodynamics

The mechanism of action of armodafinil is unknown. Armodafinil (R-(−)-modafinil) has pharmacological properties almost identical to those of modafinil (a mixture of R-(−)- and (S)-(+)-modafinil). The (R)- and (S)-enantiomers have similar pharmacological action in animals. Armodafinil has wake-promoting actions similar to sympathomimetic agents including amphetamine and methylphenidate, although its pharmacologic profile is not identical to that of the sympathomimetic amines. Armodafinil is an indirect dopamine receptor agonist; it binds in vitro to the dopamine transporter (DAT) and inhibits dopamine reuptake. For modafinil, this activity has been associated in vivo with increased extracellular dopamine levels. In genetically engineered mice lacking the dopamine transporter, modafinil lacked wake-promoting activity, suggesting that this activity was DAT-dependent. However, the wake-promoting effects of modafinil, unlike those of amphetamine, were not antagonized by the dopamine receptor antagonist haloperidol in rats. In addition, alpha-methyl-p-tyrosine, an inhibitor of dopamine synthesis, blocks the action of amphetamine but does not block locomotor activity induced by modafinil.

In addition to its wake-promoting effects and ability to increase locomotor activity in animals, according to Nuvigil prescribing information from manufacturer Cephalon, armodafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking, and feelings typical of other central nervous system (CNS) stimulants in humans.[6] Armodafinil, like racemic modafinil, may also possess reinforcing properties, as evidenced by its self-administration in monkeys previously trained to administer cocaine; armodafinil was also partially discriminated as stimulant-like. A Cephalon-founded study in which patients were administered modafinil, methylphenidate, and a placebo found that modafinil produces "psychoactive and euphoric effects and feelings consistent with [methylphenidate]."[6]

Pharmacokinetics

Armodafinil exhibits linear time-independent kinetics following single and multiple oral dose administration. Increase in systemic exposure is proportional over the dose range of 50–400 mg. No time-dependent change in kinetics was observed through 12 weeks of dosing. Apparent steady state for armodafinil was reached within 7 days of dosing. At steady state, the systemic exposure for armodafinil is 1.8 times the exposure observed after a single dose. The concentration-time profiles of the (R)-(−)-enantiomer following a single dose of 50 mg Nuvigil or 100 mg Provigil (modafinil being a 1:1 mixture of (R)-(−)- and (S)-(−)- enantiomers) are nearly superimposable. However, the Cmax of armodafinil at steady state was 37% higher following administration of 200 mg Nuvigil than the corresponding value of modafinil following administration of 200 mg Provigil due to the more rapid clearance of the (S)-(+)-enantiomer.

Absorption

Armodafinil is readily absorbed after oral administration. The absolute oral bioavailability was not determined due to the aqueous insolubility of armodafinil, which precluded intravenous administration. Peak plasma concentrations are attained at approximately 2 hours in the fasted state. Food effect on the overall bioavailability of armodafinil is considered minimal; however, time to reach peak concentration may be delayed 2–4 hours in the fed state. Since the delay in Tmax is also associated with elevated plasma concentration later in time, food can potentially affect the onset and time course of pharmacologic action of armodafinil.

Society and culture

Legal status

In Australia, and the United States, Armodafinil is considered to be a Schedule 4 prescription-only medicine or prescription animal remedy.[15] Schedule 4 is defined as "Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription."

Romania

As of 2021, new laws do not directly include Armodafinil as a doping agent, but they do include Modafinil, as Armodafinil is an enantiomer of Modafinil it will show up on lab tests, but it can be debated If it is or not the same substance.

New laws Archived 2021-09-15 at the Wayback Machine state that simple possession is not a criminal offence and is punished with a fine and confiscation. Importing into Romania and exporting from Romania of the substance, without a valid medical prescription, is a criminal offence and is punished with jail time between 2 to 7 years.

Brand names

Armodafinil is sold under a wide variety of brand names worldwide:

  • Acronite (by Consern Pharma): India
  • Armoda: ACI Pharmaceuticals (Symbiota), Bangladesh
  • Armod: India (by Emcure Pharmaceuticals Ltd)
  • Artvigil: India (by HAB Pharma)[16]
  • Neoresotyl: Chile, Colombia
  • Nuvigil: USA, Chile, Ukraine, Mexico[17]
  • R-Modawake: India
  • Waklert: India (by Sun Pharma)[18]
  • Modavital: El Salvador (Farmaceutica INHOSPI (by Laboratorios Marceli)
  • Nodement: Syrian Arab republic (by hama pharma)

References

  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 "Modafinil". LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases. 2012. Archived from the original on 12 February 2021. Retrieved 16 January 2022.
  2. 2.0 2.1 "Armodafinil Monograph for Professionals". Drugs.com. Archived from the original on 14 August 2021. Retrieved 16 January 2022.
  3. "Armodafinil (Nuvigil) Use During Pregnancy". Drugs.com. Archived from the original on 2021-02-05. Retrieved 2022-01-16.
  4. "DailyMed - ARMODAFINIL tablet". dailymed.nlm.nih.gov. Archived from the original on 16 January 2022. Retrieved 16 January 2022.
  5. "Armodafinil Prices, Coupons & Savings Tips - GoodRx". GoodRx. Archived from the original on 10 October 2020. Retrieved 16 January 2022.
  6. 6.0 6.1 6.2 6.3 6.4 "Archived copy" (PDF). Archived from the original (PDF) on 2018-01-07. Retrieved 2013-11-23.{{cite web}}: CS1 maint: archived copy as title (link)
  7. 7.0 7.1 7.2 7.3 Bartoli F, Cavaleri D, Bachi B, Moretti F, Riboldi I, Crocamo C, Carrà G (September 2021). "Repurposed drugs as adjunctive treatments for mania and bipolar depression: A meta-review and critical appraisal of meta-analyses of randomized placebo-controlled trials". Journal of Psychiatric Research. 143: 230–238. doi:10.1016/j.jpsychires.2021.09.018. PMID 34509090.
  8. Phillips, J. B.; Simmons, R. G.; Arnold, R. D. (2011). "A single dose of armodafinil significantly promotes vigilance 11 hours post-dose". Military Medicine. 176 (7): 833–839. doi:10.7205/milmed-d-10-00250. PMID 22128728.
  9. "Cephalon Provides Clinical Update on Phase II Study of NUVIGIL as an Adjunctive Therapy in Adults with Schizophrenia". Archived from the original on August 21, 2011. Retrieved August 21, 2011.
  10. Kane, J. M.; d'Souza, D. C.; Patkar, A. A.; Youakim, J. M.; Tiller, J. M.; Yang, R.; Keefe, R. S. E. (2010). "Armodafinil as Adjunctive Therapy in Adults with Cognitive Deficits Associated with Schizophrenia". The Journal of Clinical Psychiatry. 71 (11): 1475–1481. doi:10.4088/JCP.09m05950gry. PMID 20816042.
  11. Pollack, Andrew (January 6, 2010). "A Drug's Second Act: Battling Jet Lag". The New York Times. Archived from the original on January 28, 2010. Retrieved March 30, 2010.
  12. Pollack, Andrew (March 29, 2010). "Regulators Reject a Drug Maker's Plan to Use Its Alertness Pill to Overcome Jet Lag". The New York Times. Archived from the original on April 1, 2010. Retrieved March 30, 2010.
  13. "Nuvigil (Armodafinil): Side Effects, Interactions, Warning, Dosage & Uses". Archived from the original on 2017-05-04. Retrieved 2021-11-02.
  14. "Archived copy". Archived from the original on 2016-03-03. Retrieved 2014-10-14.{{cite web}}: CS1 maint: archived copy as title (link)
  15. Poisons Standard March 2018 https://www.legislation.gov.au/Details/F2018L00168 Archived 2020-08-07 at the Wayback Machine
  16. "Artvigil Review [2021 Guide] Uses, Side Effects, & Dosing". October 2021. Archived from the original on 2021-01-20. Retrieved 2021-11-02.
  17. Lundbeck Mexico, S.A. de C.V.
  18. "Waklert Review [2021 Guide] Uses, Side Effects, & Dosing". October 2021. Archived from the original on 2021-02-26. Retrieved 2021-11-02.

External links

Identifiers: