Armodafinil: Difference between revisions

{{Short description|Eugeroic medication}}

{{cs1 config|name-list-style=vanc}}

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 457152625

| IUPAC_name = (–)-2-[(''R'')-(diphenylmethyl)sulfinyl]acetamide

| image = Armodafinil structure.svg

| width = 200

| image2 = Armodafinil ball-and-stick xtal 2013.png

| width2 = 175

<!--Clinical data-->| tradename = Nuvigil, others

| Drugs.com = {{drugs.com|monograph|armodafinil}}

| MedlinePlus = a602016

| legal_US = Schedule IV

| legal_AU = S4

| legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new chemical entities in Australia, 2015 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/prescription-medicines-registration-new-chemical-entities-australia-2015 | access-date=10 April 2023}}</ref>

| legal_BR = B1

| legal_BR_comment = <ref>{{cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-03 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>

| legal_status =

| routes_of_administration = Oral ([[Tablet (pharmacy)|tablets]])

<!--Pharmacokinetic data-->| metabolism = [[Liver]], including [[CYP3A4]] and other pathways

| elimination_half-life = 15 hours

| excretion = Urine (as metabolites)

<!--Identifiers-->| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 112111-43-0

| ATC_prefix = N06

| ATC_suffix = BA13

| PubChem = 9690109

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 7962943

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = V63XWA605I

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 77590

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D03215

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 1201192

<!--Chemical data-->| C = 15

| H = 15

| N = 1

| O = 2

| S = 1

| smiles = C1=CC=C(C=C1)C(C2=CC=CC=C2)[S@](=O)CC(=O)N

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 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

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = YFGHCGITMMYXAQ-LJQANCHMSA-N

| dependency_liability = Low

'''Armodafinil''' (trade name '''Nuvigil''') is the [[enantiopure drug|enantiopure]] compound of the [[eugeroic]] [[modafinil]] (Provigil).<ref name="pmid9507929">{{cite journal | vauthors = Engber TM, Koury EJ, Dennis SA, Miller MS, Contreras PC, Bhat RV | title = Differential patterns of regional c-Fos induction in the rat brain by amphetamine and the novel wakefulness-promoting agent modafinil | journal = Neuroscience Letters | volume = 241 | issue = 2–3 | pages = 95–98 | date = January 1998 | pmid = 9507929 | doi = 10.1016/s0304-3940(97)00962-2 | s2cid = 24419972 }}</ref> It consists of only the (''R'')-(−)-[[enantiomer]] of the [[racemate|racemic]] [[modafinil]]. Armodafinil is produced by the [[pharmaceutical company]] [[Cephalon|Cephalon Inc.]]<ref name="Cephalon 2007">{{cite web |url=http://www.nuvigil.com/PDF/Full_Prescribing_Information.pdf |title=NUVIGIL (armodafinil) tablets, for oral use | work = Cephalon, Inc., Teva Pharmaceutical Industries Ltd. | publisher = U.S. Food and Drug Administration |access-date=2013-11-23 |archive-url=https://web.archive.org/web/20180107165205/http://www.nuvigil.com/PDF/Full_Prescribing_Information.pdf |archive-date=2018-01-07 |url-status=dead }}</ref> and was approved by the U.S. [[Food and Drug Administration]] (FDA) in June 2007.<ref name="titleCDER Drug and Biologic Approvals for Calendar Year 2007">{{cite web |url=http://corpina.org/wp-content/uploads/2014/01/Armodafinil_FDA_Approval-.pdf |title=CDER Drug and Biologic Approvals for Calendar Year 2007 |access-date=January 21, 2008 |archive-date=February 3, 2014 |archive-url=https://web.archive.org/web/20140203031823/http://corpina.org/wp-content/uploads/2014/01/Armodafinil_FDA_Approval-.pdf |url-status=dead }}</ref><ref name=ob>{{Citation |date=March 2012

|title=Search results from the "OB_Rx" table for query on "021875."

|work=[[Approved Drug Products with Therapeutic Equivalence Evaluations|Orange Book]] |publisher=U.S. [[Food and Drug Administration]]

|url=http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=021875&TABLE1=OB_Rx |access-date=April 30, 2012}}</ref> In 2016, the FDA granted [[Mylan]] rights for the first [[Generic drug|generic]] version of Cephalon's Nuvigil to be marketed in the U.S.<ref>{{cite web|url=http://newsroom.mylan.com/2016-06-01-Mylan-Launches-First-Generic-of-Nuvigil-Tablets|title=Mylan Launches First Generic of Nuvigil® Tablets|website=MediaRoom|access-date=February 9, 2017|archive-date=2017-02-11|archive-url=https://web.archive.org/web/20170211080455/http://newsroom.mylan.com/2016-06-01-Mylan-Launches-First-Generic-of-Nuvigil-Tablets|url-status=dead}}</ref>

Because armodafinil has a longer [[biological half life|half-life]] than [[modafinil]] does, it may be more effective at improving wakefulness in patients with [[excessive daytime sleepiness]].<ref>{{cite journal | vauthors = Darwish M, Kirby M, Hellriegel ET, Robertson P | title = Armodafinil and modafinil have substantially different pharmacokinetic profiles despite having the same terminal half-lives: analysis of data from three randomized, single-dose, pharmacokinetic studies | journal = Clinical Drug Investigation | volume = 29 | issue = 9 | pages = 613–623 | year = 2009 | pmid = 19663523 | doi = 10.2165/11315280-000000000-00000 | s2cid = 6607186 }}</ref>

==Uses==

Armodafinil is currently FDA-approved to treat [[excessive daytime sleepiness]] associated with [[obstructive sleep apnea]], [[narcolepsy]], and [[shift work sleep disorder|shift work disorder]].<ref name="Cephalon 2007"/> It is commonly used [[off-label use|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]].<ref name="repurposed2021">{{cite journal | vauthors = Bartoli F, Cavaleri D, Bachi B, Moretti F, Riboldi I, Crocamo C, Carrà G | title = 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 = Journal of Psychiatric Research | volume = 143 | pages = 230–238 | date = November 2021 | pmid = 34509090 | doi = 10.1016/j.jpsychires.2021.09.018 | s2cid = 237485915 }}</ref> It has been shown to improve vigilance in air traffic controllers,<ref name="Phillips 2011">{{cite journal | vauthors = Phillips JB, Simmons RG, Arnold RD | title = A single dose of armodafinil significantly promotes vigilance 11 hours post-dose | journal = Military Medicine | volume = 176 | issue = 7 | pages = 833–839 | date = July 2011 | pmid = 22128728 | doi = 10.7205/milmed-d-10-00250 | doi-access = free }}</ref> however in the United States, sleep prevention medications such as modafinil (Provigil) and armodafinil (Nuvigil) are not approved by the FAA for civilian controllers or pilots.<ref>{{cite web |date=2016-12-16 |title=Therapeutic Drug Guidelines for Air Traffic Control Specialists |url=https://www.aviationmedicine.com/wp-content/uploads/2018/08/Therapeutic-Drug-Guidelines-for-ATCS-FINAL-12-16-16-PDF-version.pdf |access-date=2022-05-31 |website=Aviation Medicine Advisory Service |quote=Stimulants, sometimes used for narcolepsy and attention deficit hyperactivity disorder, are not acceptable. Included are amphetamines (Adderall), pemoline (Cylert), methylphenidate (Ritalin), dextroamphetamine (Dexedrine), and modafinil (Provigil).}}</ref>

===Psychiatry===

====Bipolar disorder====

Armodafinil, along with racemic modafinil, has been repurposed as an adjunctive treatment for acute depression in people with [[bipolar disorder]].<ref name="repurposed2021"/> 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. However current dosage for bipolar disorder is 150&nbsp;mg once daily. Paradoxical tiredness and sleeping is observed in some cases.<ref name="repurposed2021"/>

====Schizophrenia====

{{See also|Modafinil#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.<ref name="titleCephalon Provides Clinical Update on Phase II Study of NUVIGIL as an Adjunctive Therapy in Adults with Schizophrenia, ">{{cite press release|url=http://www.prnewswire.com/news-releases/cephalon-provides-clinical-update-on-phase-ii-study-of-nuvigil-as-an-adjunctive-therapy-in-adults-with-schizophrenia-95449199.html|title=Cephalon Provides Clinical Update on Phase II Study of NUVIGIL as an Adjunctive Therapy in Adults with Schizophrenia|access-date=August 21, 2011}}</ref> However, a study published later that year showed that patients with schizophrenia treated with armodafinil showed fewer of the [[Schizophrenia#Negative symptoms|negative symptoms of schizophrenia]].<ref name="Kane 2010">{{cite journal | vauthors = Kane JM, D'Souza DC, Patkar AA, Youakim JM, Tiller JM, Yang R, Keefe RS | title = Armodafinil as adjunctive therapy in adults with cognitive deficits associated with schizophrenia: a 4-week, double-blind, placebo-controlled study | journal = The Journal of Clinical Psychiatry | volume = 71 | issue = 11 | pages = 1475–1481 | date = November 2010 | pmid = 20816042 | doi = 10.4088/JCP.09m05950gry }}</ref>

===Jet lag===

On March 30, 2010, the FDA declined to approve use of Nuvigil to treat [[jet lag]].<ref name="Consideration">{{cite news |url=https://www.nytimes.com/2010/01/07/business/07jetlag.html |title=A Drug's Second Act: Battling Jet Lag <!-- alt title: Fighting Jet Lag May Help Cephalon Extend Patent on Nuvigil --> | vauthors = Pollack A |date=January 6, 2010 |work=[[The New York Times]] |access-date=March 30, 2010}}</ref><ref name="Rejection">{{cite news |url=https://www.nytimes.com/2010/03/30/business/30drug.html |title=Regulators Reject a Drug Maker's Plan to Use Its Alertness Pill to Overcome Jet Lag <!-- alt title: F.D.A. Rejects Jet Lag Drug by Cephalon --> | vauthors = Pollack A |date=March 29, 2010 |work=[[The New York Times]] |access-date=March 30, 2010}}</ref>

===Abuse potential===

Armodafinil has a low abuse potential similar to [[modafinil]].

==Adverse effects==

In placebo-controlled studies, the most commonly observed side effects were [[headache]], [[xerostomia]] (dry mouth), [[nausea]], [[dizziness]], and [[insomnia]].<ref name="repurposed2021"/> 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.<ref name="Cephalon 2007"/><ref>{{cite web|url=http://www.rxlist.com/nuvigil-drug/side-effects-interactions.htm|title=Nuvigil (Armodafinil): Side Effects, Interactions, Warning, Dosage & Uses | work = RxList }}</ref><ref>{{cite web |url=http://armodexperiment.com/?s=dry+mouth |title = My Armodafinil Experiment |access-date=2014-10-14 |archive-url=https://web.archive.org/web/20160303235441/http://armodexperiment.com/?s=dry+mouth |archive-date=2016-03-03 |url-status=dead }}</ref> Serious rashes can develop in rare cases, and require immediate medical attention due to the possibility of [[Stevens–Johnson syndrome|Steven's-Johnson Syndrome]], or other [[Hypersensitivity|hypersensitivities]] to armodafinil.<ref name="Cephalon 2007" />

==Pharmacology==

[[File:Armodafinil 150mg.jpg|thumb|Armodafinil 150mg blister]]

===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.<ref>{{cite journal | vauthors = Qu WM, Huang ZL, Xu XH, Matsumoto N, Urade Y | title = Dopaminergic D1 and D2 receptors are essential for the arousal effect of modafinil | journal = The Journal of Neuroscience | volume = 28 | issue = 34 | pages = 8462–8469 | date = August 2008 | pmid = 18716204 | pmc = 6671058 | doi = 10.1523/JNEUROSCI.1819-08.2008 }}</ref> 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 [[Animal locomotion|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 [[euphoria|euphoric]] effects, alterations in mood, perception, thinking, and feelings typical of other [[central nervous system]] (CNS) [[stimulant]]s in humans.<ref name="Cephalon 2007"/> 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]."<ref name="Cephalon 2007"/>

===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&nbsp;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&nbsp;mg Nuvigil or 100&nbsp;mg Provigil (modafinil being a 1:1 mixture of (''R'')-(−)- and (''S'')-(−)- enantiomers) are nearly superimposable. However, the [[Cmax (pharmacology)|C_max]] of armodafinil at steady state was 37% higher following administration of 200&nbsp;mg Nuvigil than the corresponding value of modafinil following administration of 200&nbsp;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 [[Cmax (pharmacology)|T_max]] is also associated with elevated plasma concentration later in time, food can potentially affect the onset and time course of pharmacologic action of armodafinil.

==Legal status==

In Australia, and the United States, Armodafinil is considered to be a Schedule 4 prescription-only medicine or prescription animal remedy.<ref>{{cite web | title = Poisons Standard | date = March 2018 | url = https://www.legislation.gov.au/Details/F2018L00168 | work = Therapeutics Goods Administration, Department of Health | publisher = Australian Government }}</ref> 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 state that simple possession is not a criminal offence and is punished with a fine and confiscation.<ref>{{cite web | title = LAW no. 219 | language = Romanian | date = 26 July 2021 | work = Romanian Parliament | url = http://legislatie.just.ro/Public/DetaliiDocument/245003 }}</ref> 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 two and seven years.

==Marketing==

===Brand names===

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

{{cmn|colwidth=30em|

* '''Acronite''' (by Consern Pharma): India

* '''Armoda''': ACI Pharmaceuticals (Symbiota), Bangladesh

* '''Armod''': India (by Emcure Pharmaceuticals Ltd)

*'''Artvigil''': India (by HAB Pharma)<ref>{{cite web|url=https://modafinil.org/artvigil/|title = Artvigil Review &#91;2021 Guide&#93; Uses, Side Effects, & Dosing|date = October 2021 | work = modafinil.org }}</ref>

* '''Neoresotyl''': Chile, Colombia

* '''Nuvigil''': USA, Chile, Ukraine, Israel, Mexico,<ref>Lundbeck Mexico, S.A. de C.V.</ref> Australia

* '''R-Modawake''': India

* '''Waklert''': India (by [[Sun Pharmaceutical|Sun Pharma]])<ref>{{cite web|url=https://modafinil.org/waklert/|title=Waklert Review &#91;2021 Guide&#93; Uses, Side Effects, & Dosing|date=October 2021 | work = modafinil.org }}</ref>

* '''Modavital''': El Salvador (Farmaceutica INHOSPI (by Laboratorios Marceli)

* '''Nodement''': Syrian Arab republic (by hama pharma)

* '''Armowake''': Egypt (by EVA Pharma)

}}

== See also ==

{{cmn|colwidth=30em|

* [[Adrafinil]]

* [[CRL-40,940]]

* [[CRL-40,941]]

* [[Fluorenol]]

* [[Modafinil]]

* [[Esmodafinil]]

}}

== References ==

{{reflist}}

== External links ==

* [http://www.nuvigil.com/ Nuvigil (armodafinil) Tablets Official Site]

** [https://web.archive.org/web/20110519090541/http://nuvigil.com/media/Medication_Guide.pdf Medication Guide for Patients]

** [https://web.archive.org/web/20101219071137/http://nuvigil.com/media/Full_Prescribing_Information.pdf Full Prescribing Information]

{{Stimulants}}

{{Monoamine reuptake inhibitors}}

[[Category:Acetamides]]

[[Category:CYP3A4 inducers]]

[[Category:Dopamine reuptake inhibitors]]

[[Category:Drugs with unknown mechanisms of action]]

[[Category:Enantiopure drugs]]

[[Category:Stimulants]]

[[Category:Sulfoxides]]

[[Category:World Anti-Doping Agency prohibited substances]]