Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Reboxetine: Difference between pages

{{Short description|NRI antidepressant drug}}

| Watchedfields = changed

| verifiedrevid = 464380440

| IUPAC_name = ''rel''-(2''R'')-2-[(''R'')-(2-Ethoxyphenoxy)(phenyl)methyl]morpholine

| image = Reboxetine.svg

| width = 150px

| caption = (''R'',''R'')-(–)-reboxetine (top),<br />(''S'',''S'')-(+)-reboxetine (bottom)

| chirality = [[Racemic mixture|Racemate]]

| tradename = Edronax, others

| pregnancy_AU = B1

| legal_AU = S4

| legal_BR = C1

| 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=2023-08-16 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>

| legal_UK = POM

| legal_US = Not approved

| routes_of_administration = [[Oral administration|By mouth]] ([[tablet (pharmacy)|tablets]])

| bioavailability = ≥94%<ref name = TGA>{{cite web|title=PRODUCT INFORMATION EDRONAX® Reboxetine mesilate|work=TGA eBusiness Services|publisher=Pfizer Australia Pty Ltd|date=17 October 2012|access-date=10 November 2013|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-01174-3|format=PDF}}</ref><ref name = CNS1999/>

| protein_bound = 97–98%<ref name = TGA/><ref name = CNS1999/>

| metabolism = [[Liver]] ([[CYP3A4]]-mediated)<ref name = TGA/>

| elimination_half-life = 12–12.5 hours<ref name = TGA/><ref name = CNS1999>{{cite journal|title=Reboxetine|date=July 1999| vauthors = Holm KJ, Spencer CM |journal=CNS Drugs|volume=12|issue=1|pages=65–83|doi=10.2165/00023210-199912010-00006|s2cid=72813017 }}</ref>

| excretion = [[Urine]] (78%; 9–10% unchanged)<ref name = TGA/><ref name = CNS1999/>

| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 71620-89-8

| CAS_number2_Ref = {{cascite|changed|??}}

| CAS_number2 = 98769-84-7

| index2_label = Mesylate

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

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

| UNII2_Ref = {{fdacite|correct|FDA}}

| UNII2 = L94J81YNNY

| ChEMBL = 383921

<!--Chemical data-->

| C=19 | H=23 | N=1 | O=3

| SMILES = CCOC1=C(C=CC=C1)O[C@@H]([C@@H]2OCCNC2)C3=CC=CC=C3

'''Reboxetine''', sold under the brand name '''Edronax''' among others, is a drug of the [[norepinephrine reuptake inhibitor]] (NRI) class, marketed as an [[antidepressant]] by [[Pfizer]] for use in the treatment of [[major depressive disorder|major depression]], although it has also been used [[off-label]] for [[panic disorder]] and [[attention deficit hyperactivity disorder]] (ADHD).<ref name = MD>{{cite book|title=Reboxetine Mesilate|work=Martindale: The Complete Drug Reference|publisher=The Royal Pharmaceutical Society of Great Britain|date=8 November 2011|access-date=10 November 2013|url=http://www.medicinescomplete.com/mc/martindale/current/20430-f.htm}}</ref> It is approved for use in many countries worldwide, but has not been approved for use in the [[United States]]. Although its effectiveness as an antidepressant has been challenged in multiple published reports, its popularity has continued to increase.<ref name = BMJ>{{cite journal | vauthors = Eyding D, Lelgemann M, Grouven U, Härter M, Kromp M, Kaiser T, Kerekes MF, Gerken M, Wieseler B | title = Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials | journal = BMJ | volume = 341 | pages = c4737 | date = October 2010 | pmid = 20940209 | pmc = 2954275 | doi = 10.1136/bmj.c4737 }}</ref>

==Medical uses==

===Major depressive disorder===

There has been much debate as to whether reboxetine is more efficacious than placebo in the treatment of depression. According to a 2009 meta-analysis of 12 second-generation antidepressants, reboxetine was no more effective than placebo, and was "significantly less" effective and less acceptable than the other drugs in treating the acute-phase of adults with unipolar major depression.<ref name=Lancet2009>{{cite journal | vauthors = Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa A, Omori IM, McGuire H, Tansella M, Barbui C | title = Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis | journal = Lancet | volume = 373 | issue = 9665 | pages = 746–58 | date = February 2009 | pmid = 19185342 | doi = 10.1016/S0140-6736(09)60046-5 | s2cid = 35858125 | url = http://www.cipralex.co.il/sitecontent/ExternalFiles/213.pdf | archive-url = https://web.archive.org/web/20130929174834/http://www.cipralex.co.il/sitecontent/ExternalFiles/213.pdf | url-status = dead | archive-date = 2013-09-29 }}</ref>

The British [[Medicines and Healthcare products Regulatory Agency|MHRA]] said in September 2011 that the study had several limitations, and that "Overall the balance of benefits and risks for reboxetine remains positive in its authorised indication."<ref name = MHRA>{{cite web|title=Reboxetine: benefit-risk balance reviewed|date=September 2011|url=http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON128957|work=Drug Safety Update|publisher=Medicines and Healthcare products Regulatory Agency|access-date=10 November 2013}}</ref> A UK and Europe-wide review of available efficacy and safety data has confirmed that reboxetine has benefit over placebo in its authorised indication. Efficacy was clearly shown in patients with severe or very severe depression.<ref name = MHRA/>

According to a systematic review and meta-analysis by [[Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen|IQWiG]], including unpublished data, published data on reboxetine overestimated the benefit of reboxetine versus placebo by up to 115% and reboxetine versus SSRIs by up to 23%, and also underestimated harm, concluding that reboxetine was an ineffective and potentially harmful antidepressant. The study also showed that nearly three quarters of the data on patients who took part in trials of reboxetine had not been published by Pfizer.<ref name=BMJ/>

A 2018 systematic review and network meta-analysis comparing the efficacy and acceptability of 21 antidepressant drugs concluded that reboxetine was more effective than placebo but significantly less efficacious than other antidepressants tested.<ref name="Cipriani18">{{cite journal | vauthors = Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG, Turner EH, Higgins JP, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A, Ioannidis JP, Geddes JR | display-authors = 6 | title = Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis | journal = Lancet | volume = 391 | issue = 10128 | pages = 1357–1366 | date = April 2018 | pmid = 29477251 | pmc = 5889788 | doi = 10.1016/S0140-6736(17)32802-7 }}</ref>

===Panic disorder===

In a randomised double-blind placebo-controlled trial reboxetine significantly improved the symptoms of panic disorder.<ref>{{cite journal | vauthors = Versiani M, Cassano G, Perugi G, Benedetti A, Mastalli L, Nardi A, Savino M | title = Reboxetine, a selective norepinephrine reuptake inhibitor, is an effective and well-tolerated treatment for panic disorder | journal = The Journal of Clinical Psychiatry | volume = 63 | issue = 1 | pages = 31–7 | date = January 2002 | pmid = 11838623 | doi = 10.4088/JCP.v63n0107 }}</ref> Another randomised controlled trial that compared paroxetine to reboxetine found that paroxetine significantly outperformed reboxetine as a treatment for panic disorder.<ref>{{cite journal | vauthors = Bertani A, Perna G, Migliarese G, Di Pasquale D, Cucchi M, Caldirola D, Bellodi L | title = Comparison of the treatment with paroxetine and reboxetine in panic disorder: a randomized, single-blind study | journal = Pharmacopsychiatry | volume = 37 | issue = 5 | pages = 206–10 | date = September 2004 | pmid = 15359375 | doi = 10.1055/s-2004-832593 | s2cid = 12495057 }}</ref> Despite this discouraging finding an open-label trial examining the efficacy of reboxetine in SSRI-resistant panic disorder demonstrated significant benefit from reboxetine treatment.<ref>{{cite journal | vauthors = Dannon PN, Iancu I, Grunhaus L | title = The efficacy of reboxetine in the treatment-refractory patients with panic disorder: an open label study | journal = Human Psychopharmacology | volume = 17 | issue = 7 | pages = 329–33 | date = October 2002 | pmid = 12415550 | doi = 10.1002/hup.421 | s2cid = 19996027 }}</ref>

===Attention deficit hyperactivity disorder===

Numerous clinical trials have provided support for the efficacy of reboxetine in the treatment of attention deficit hyperactivity disorder (ADHD) in both the short<ref name = Daru2011>{{cite journal | vauthors = Hashemian F, Mohammadian S, Riahi F, Ghaeli P, Ghodsi D | title = A comparison of the effects of reboxetine and placebo on reaction time in adults with Attention Deficit-Hyperactivity Disorder (ADHD) | journal = Daru | volume = 19 | issue = 3 | pages = 231–5 | year = 2011 | pmid = 22615662 | pmc = 3232108 }}</ref><ref name = JCADP2008>{{cite journal | vauthors = Tehrani-Doost M, Moallemi S, Shahrivar Z | title = An open-label trial of reboxetine in children and adolescents with attention-deficit/hyperactivity disorder | journal = Journal of Child and Adolescent Psychopharmacology | volume = 18 | issue = 2 | pages = 179–84 | date = April 2008 | pmid = 18439114 | doi = 10.1089/cap.2006.0034 }}</ref><ref name = JAACADP2005>{{cite journal | vauthors = Ratner S, Laor N, Bronstein Y, Weizman A, Toren P | title = Six-week open-label reboxetine treatment in children and adolescents with attention-deficit/hyperactivity disorder | journal = Journal of the American Academy of Child and Adolescent Psychiatry | volume = 44 | issue = 5 | pages = 428–33 | date = May 2005 | pmid = 15843764 | doi = 10.1097/01.chi.0000155327.30017.8c }}</ref><ref name = HPH2010>{{cite journal | vauthors = Riahi F, Tehrani-Doost M, Shahrivar Z, Alaghband-Rad J | title = Efficacy of reboxetine in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled clinical trial | journal = Human Psychopharmacology | volume = 25 | issue = 7–8 | pages = 570–6 | date = November 2010 | pmid = 21312292 | doi = 10.1002/hup.1158 | s2cid = 8634761 }}</ref> and long-term<ref name = JCADP2010>{{cite journal | vauthors = Toren P, Ratner S, Weizman A, Lask M, Ben-Amitay G, Laor N | title = Reboxetine maintenance treatment in children with attention-deficit/hyperactivity disorder: a long-term follow-up study | journal = Journal of Child and Adolescent Psychopharmacology | volume = 17 | issue = 6 | pages = 803–12 | date = December 2007 | pmid = 18315452 | doi = 10.1089/cap.2006.0145 }}</ref><ref name = ADHD2010>{{cite journal | vauthors = Quintero J, López-Muñoz F, Alamo C, Loro M, García-Campos N | title = Reboxetine for ADHD in children non-responders or with poor tolerance to methylphenidate: a prospective long-term open-label study | journal = Attention Deficit and Hyperactivity Disorders | volume = 2 | issue = 3 | pages = 107–13 | date = November 2010 | pmid = 21432596 | doi = 10.1007/s12402-010-0027-x | s2cid = 41617072 }}</ref> and in both children/adolescents<ref name = JCADP2008/><ref name = JAACADP2005/><ref name = JCADP2010/><ref name = ADHD2010/> and adults.<ref name = Daru2011/><ref name = HPH2010/>

===Other uses===

A case series and open-label pilot study demonstrated the efficacy of reboxetine in treating [[bulimia nervosa]].<ref>{{cite journal | vauthors = El-Giamal N, de Zwaan M, Bailer U, Lennkh C, Schüssler P, Strnad A, Kasper S | title = Reboxetine in the treatment of bulimia nervosa: a report of seven cases | journal = International Clinical Psychopharmacology | volume = 15 | issue = 6 | pages = 351–6 | date = November 2000 | pmid = 11110011 | doi = 10.1097/00004850-200015060-00006 | s2cid = 21260625 }}</ref><ref>{{cite journal | vauthors = Fassino S, Daga GA, Boggio S, Garzaro L, Pierò A | title = Use of reboxetine in bulimia nervosa: a pilot study | journal = Journal of Psychopharmacology | volume = 18 | issue = 3 | pages = 423–8 | date = September 2004 | pmid = 15358988 | doi = 10.1177/026988110401800314 | s2cid = 24287884 }}</ref> Reboxetine may also have efficacy in treating therapy-resistant paediatric [[nocturnal enuresis]].<ref>{{cite journal | vauthors = Nevéus T | title = Reboxetine in therapy-resistant enuresis: results and pathogenetic implications | journal = Scandinavian Journal of Urology and Nephrology | volume = 40 | issue = 1 | pages = 31–4 | year = 2006 | pmid = 16452053 | doi = 10.1080/00365590500407803 | s2cid = 41990481 }}</ref> A pilot study demonstrated the efficacy of reboxetine in the treatment of [[narcolepsy]].<ref>{{cite journal | vauthors = Larrosa O, de la Llave Y, Bario S, Granizo JJ, Garcia-Borreguero D | title = Stimulant and anticataplectic effects of reboxetine in patients with narcolepsy: a pilot study | journal = Sleep | volume = 24 | issue = 3 | pages = 282–5 | date = May 2001 | pmid = 11322710 | url = http://www.journalsleep.org/ViewAbstract.aspx?pid=25527 | doi = 10.1093/sleep/24.3.282 | doi-access = free }}</ref> Individual trials and meta-analysis suggest that reboxetine can attenuate antipsychotic-induced weight gain<ref>{{cite journal | vauthors = Poyurovsky M, Isaacs I, Fuchs C, Schneidman M, Faragian S, Weizman R, Weizman A | title = Attenuation of olanzapine-induced weight gain with reboxetine in patients with schizophrenia: a double-blind, placebo-controlled study | journal = The American Journal of Psychiatry | volume = 160 | issue = 2 | pages = 297–302 | date = February 2003 | pmid = 12562576 | doi = 10.1176/appi.ajp.160.2.297 | url = http://ajp.psychiatryonline.org/data/Journals/AJP/3745/297.pdf }}</ref><ref name=":0">{{cite journal | vauthors = Matthews PR, Horder J, Pearce M | title = Selective noradrenaline reuptake inhibitors for schizophrenia | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD010219 | date = January 2018 | issue = 1 | pmid = 29368813 | pmc = 6491172 | doi = 10.1002/14651858.CD010219.pub2 }}</ref> and there is some evidence of a benefit on depressive, and possibly other symptoms of schizophrenia when added to antipsychotic treatment.<ref>{{cite journal | vauthors = Kishi T, Mukai T, Matsuda Y, Moriwaki M, Iwata N | title = Efficacy and safety of noradrenalin reuptake inhibitor augmentation therapy for schizophrenia: a meta-analysis of double-blind randomized placebo-controlled trials | journal = Journal of Psychiatric Research | volume = 47 | issue = 11 | pages = 1557–63 | date = November 2013 | pmid = 23899496 | doi = 10.1016/j.jpsychires.2013.07.003 }}</ref><ref name=":0" />

==Contraindications==

Reboxetine is contraindicated in narrow-angle [[glaucoma]], cardiovascular disease, [[epilepsy]], [[bipolar disorder]], [[urinary retention]], prostatic hypertrophy, those hypersensitive to reboxetine or any of its excipients.<ref name = TGA/><ref name="BNF">{{cite book | isbn = 978-0-85711-084-8 | title = British National Formulary (BNF) | last1 = Joint Formulary Committee | year = 2013 | publisher = Pharmaceutical Press | location = London, UK | edition = 65 | pages = [https://archive.org/details/bnf65britishnati0000unse/page/254 254–255] | url = https://archive.org/details/bnf65britishnati0000unse/page/254 }}</ref>

==Adverse effects==

Very common (>10% incidence) adverse effects include insomnia, dizziness, dry mouth, constipation, nausea, and excessive sweating.<ref name = EMC>{{cite web|title=Edronax 4mg Tablets|publisher=UK Electronic Medicines Compendium|date=October 2015|access-date=20 August 2017|url=http://www.medicines.org.uk/emc/medicine/8386/SPC/Edronax+4mg+Tablets/}}</ref>

Common (1–10%) adverse effects include loss of appetite, agitation, anxiety, headache, restlessness, tingling sensations, distorted sense of taste, difficulty with seeing near or far (problems with [[Accommodation (eye)|accommodation]]), fast heart beat, heart [[palpitations]], relaxing of blood vessels leading to low blood pressure, high blood pressure, vomiting, rash, sensation of incomplete bladder emptying, urinary tract infection, painful or difficult urination, [[urinary retention]], erectile dysfunction, ejaculatory pain or delay, and chills.<ref name = EMC/>

A 2009 meta-analysis found that reboxetine was significantly less well tolerated than the other 11 second-generation antidepressants compared in the analysis.<ref name = Lancet2009/>

==Overdose==

Reboxetine is considered a relatively low-risk antidepressant in [[overdose]].<ref name="Maudsley">{{cite book | isbn = 978-0-470-97948-8 | title = The Maudsley prescribing guidelines in psychiatry | vauthors = Taylor D, Paton C, Shitij K | year = 2012 | publisher = Wiley-Blackwell | location = West Sussex | page = 588 }}</ref> The symptoms are as follows:<ref name = Maudsley/>

* Sweating

* Tachycardia

* Changes in blood pressure

== Interactions ==

Because of its reliance on [[CYP3A4]], reboxetine ''O''-desethylation is markedly inhibited by [[papaverine]] and [[ketoconazole]].<!--

--><ref name="DMM1999-Wienkers"/> It weakly inhibits [[CYP2D6]] and [[CYP3A4]].<ref name = EMC/> Reboxetine is an intermediate-level inhibitor of [[P-glycoprotein]], which gives it the potential to interact with [[ciclosporin]], [[tacrolimus]], [[paroxetine]], [[sertraline]], [[quinidine]], [[fluoxetine]], [[fluvoxamine]].<!--

--><ref name="JPharmaExpTherap2003-Weiss">{{cite journal | vauthors = Weiss J, Dormann SM, Martin-Facklam M, Kerpen CJ, Ketabi-Kiyanvash N, Haefeli WE | title = Inhibition of P-glycoprotein by newer antidepressants | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 305 | issue = 1 | pages = 197–204 | date = April 2003 | pmid = 12649369 | doi = 10.1124/jpet.102.046532 | s2cid = 5897406 }}</ref>

==Pharmacology==

===Pharmacodynamics===

{| class="wikitable floatright"

|+ Reboxetine<ref name=PDSP>{{cite web | title = PDSD K_i Database | work = Psychoactive Drug Screening Program (PDSP)|author1-link=Bryan Roth | vauthors = Roth BL, Driscol J | url = http://pdsp.med.unc.edu/pdsp.php | publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | access-date = 2014-03-31 | url-status = dead | archive-url = https://web.archive.org/web/20131108013656/http://pdsp.med.unc.edu/pdsp.php | archive-date = 2013-11-08 }}</ref><ref name="GG">{{cite book | title = Goodman and Gilman's The Pharmacological Basis of Therapeutics | edition = 12th | vauthors = Brunton L, Chabner B, Knollman B | year = 2010 | publisher = McGraw-Hill Professional | location = New York | isbn = 978-0-07-162442-8 }}</ref>

|-

! Site !! K_i (nM)

|-

| '''{{abbrlink|SERT|Serotonin transporter}}''' || '''273.5'''

|-

| '''{{abbrlink|NET|Norepinephrine transporter}}''' || '''13.4'''

|-

| {{abbrlink|DAT|Dopamine transporter}} || >10,000

|-

| [[5-HT1A receptor|5-HT_1A]] || >10,000

|-

| [[5-HT1B receptor|5-HT_1B]] || >10,000

|-

| [[5-HT1D receptor|5-HT_1D]] || >10,000

|-

| [[5-HT2A receptor|5-HT_2A]] || >10,000

|-

| '''[[5-HT2C receptor|5-HT_2C]]''' || '''457'''

|-

| [[Alpha-1A adrenergic receptor|α_1A]] || 11,900

|-

| [[Alpha-2A adrenergic receptor|α_2A]] || >10,000

|-

| [[Dopamine D2 receptor|D₂]] || >10,000

|-

| [[Dopamine D3 receptor|D₃]] || >10,000

|-

| '''[[Histamine H1 receptor|H₁]]''' || '''312'''

|-

| {{abbrlink|mACh|Muscarinic acetylcholine receptor}} || 6,700

|-

| {{abbrlink|nACh|Nicotinic acetylcholine receptor}} || {{abbr|ND|No data}}

|-

| {{abbrlink|GIRK|G protein-coupled inwardly-rectifying potassium channel}} || {{abbr|ND|No data}}

|}

Reboxetine is a fairly selective [[norepinephrine reuptake inhibitor]] (NRI), with approximately 20-fold [[binding selectivity|selectivity]] for the [[norepinephrine transporter]] (NET) over the [[serotonin transporter]] (SERT).<ref name=PDSP /> Despite this selectivity, reboxetine does slightly inhibit the reuptake of serotonin at therapeutic doses.<ref name="AMH">{{cite book | editor = Rossi, S | isbn = 978-0-9805790-9-3 | title = Australian Medicines Handbook | place = Adelaide | publisher = The Australian Medicines Handbook Unit Trust | year = 2013 | edition = 2013 }}</ref> It does not interact with or inhibit the [[dopamine transporter]] (DAT).<ref name = PDSP /><ref name="GG" />

Reboxetine has been found to inhibit both brain and cardiac [[G protein-coupled inwardly-rectifying potassium channel|GIRKs]], a characteristic it shares with the NRI [[atomoxetine]].<ref>{{cite journal | vauthors = Kobayashi T, Washiyama K, Ikeda K | title = Inhibition of G-protein-activated inwardly rectifying K+ channels by the selective norepinephrine reuptake inhibitors atomoxetine and reboxetine | journal = Neuropsychopharmacology | volume = 35 | issue = 7 | pages = 1560–9 | date = June 2010 | pmid = 20393461 | pmc = 3055469 | doi = 10.1038/npp.2010.27 }}</ref>

===Pharmacokinetics===

Both the (''R'',''R'')-(–) and (''S'',''S'')-(+)-enantiomers of reboxetine are predominantly metabolized by the [[CYP3A4]] [[isoenzyme]].<ref name="DMM1999-Wienkers">{{cite journal | vauthors = Wienkers LC, Allievi C, Hauer MJ, Wynalda MA | title = Cytochrome P-450-mediated metabolism of the individual enantiomers of the antidepressant agent reboxetine in human liver microsomes | journal = Drug Metabolism and Disposition | volume = 27 | issue = 11 | pages = 1334–40 | date = November 1999 | pmid = 10534319 }}</ref>

The primary metabolite of reboxetine is ''O''-desethylreboxetine, and there are also three minor metabolites&mdash;Phenol A, Phenol B, and UK1, Phenol B being the most minor.<ref name="DMM1999-Wienkers"/>

==Chemistry==

Reboxetine has two [[chirality (chemistry)|chiral centers]]. Thus, four stereoisomers may exist, the (''R'',''R'')-, (''S'',''S'')-, (''R'',''S'')-, and (''S'',''R'')-isomers. The active ingredient of reboxetine is a racemic mixture of two [[enantiomer]]s, the (''R'',''R'')-(–)- and (''S'',''S'')-(+)-isomer.<ref name="Tetrahedron1985-Melloni">{{cite journal |vauthors=Melloni P, Della Torre A, Lazzari E, Mazzini G, Meroni M | title=Configuration studies on 2-[alpha -(2-ethoxyphenoxy)benzyl]-morpholine FCE 20124|journal=Tetrahedron | volume=41 | issue=1 | year=1985 | pages=1393–1399 | doi=10.1016/S0040-4020(01)96541-X}}</ref>

==History==

Reboxetine was discovered at [[Farmitalia-Carlo Erba]] and was first published in 1984; Farmitalia did the first clinical studies.<ref>{{cite journal | vauthors = Cocchiara G, Battaglia R, Pevarello P, Strolin Benedetti M | title = Comparison of the disposition and of the metabolic pattern of Reboxetine, a new antidepressant, in the rat, dog, monkey and man | journal = European Journal of Drug Metabolism and Pharmacokinetics | volume = 16 | issue = 3 | pages = 231–9 | year = 1991 | pmid = 1814741 | doi = 10.1007/bf03189965 | s2cid = 874781 }}</ref><ref>First publication per prior citation: {{cite journal |author= Melloni M |year=1984 |title= Potential antidepressant agents. α-aryloxy-benzyl derivatives of ethanolamine and morpholine |journal= Eur J Med Chem |volume=3 |pages= 235–242 |display-authors=etal}}</ref> Farmitalia was acquired by [[Pharmacia]] in 1993,<ref>{{cite journal |title=Farmitalia bought by Kabi Pharmacia |journal=Annals of Oncology |date=May 1993 |volume=4 |issue=5 |pages=345 |doi=10.1093/oxfordjournals.annonc.a058508|doi-access=free }}</ref> and Pharmacia in turn was acquired by [[Pfizer]] in 2003.<ref>{{cite news |work=CNN/Money | date = 16 April 2003 | url = https://money.cnn.com/2003/04/16/news/companies/pfizer_pharma/ | title = It's official: Pfizer buys Pharmacia }}</ref>

It was first approved in Europe in 1997 and was provisionally approved by the FDA in 1999.<ref name=Lowe2011>{{cite web | first = Derek | last = Lowe | name-list-style = vanc | work = In the pipeline | date = 17 January 2011 | url = https://www.science.org/content/blog-post/reboxetine-doesn-t-work-s-not-real-problem | title = Reboxetine Doesn't Work. But That's Not the Real Problem }}</ref> In 2001 the FDA issued Pfizer a "not approvable" letter based on clinical trials the FDA had required when it issued the preliminary approval letter.<ref>{{cite web | work = Adis Insight | url = http://adisinsight.springer.com/drugs/800000662 | title = Reboxetine | access-date = 17 April 2016 }}</ref><ref>{{cite journal | vauthors = Page ME | title = The promises and pitfalls of reboxetine | journal = CNS Drug Reviews | volume = 9 | issue = 4 | pages = 327–42 | year = 2003 | pmid = 14647527 | doi = 10.1111/j.1527-3458.2003.tb00258.x | pmc = 6741698 }}</ref>

In 2010, the German [[Institute for Quality and Efficiency in Health Care]] (IQEHC) published results of a meta-analysis of clinical trial data for reboxetine in acute depression, which included data on about 3,000 subjects that Pfizer had never published but had mentioned; IQEHC had combed through Pfizer's publications and reboxetine approvals and had determined this data was missing from the publication record. The analysis of the complete data set yielded a result that reboxetine was not more effective than placebo but had more side effects than placebo and more than [[fluoxetine]]; the paper led to widespread and sharp criticism of Pfizer, and stronger calls for publication of all clinical trial data.<ref name = BMJ/><ref name=Lowe2011/><ref>{{cite web | author = Staff | work = Genetic Engineering News | date = 14 October 2010 | url = http://www.genengnews.com/gen-news-highlights/did-sneaky-publication-tactics-help-pfizer-s-reboxetine-slip-through-to-market/81244066/ | title = Did Sneaky Publication Tactics Help Pfizer's Reboxetine Slip Through to Market? }}</ref>

==Society and culture==

===Brand names===

Edronax is the brand name of reboxetine in every English-speaking country that has approved it for clinical use. Brand names include (where † denotes a product that is no longer marketed):<ref name = MD/>

* '''Davedax''' <small>([[Italy|IT]])</small>

* '''Edronax''' <small>([[Australia|AU]], [[Austria|AT]], [[Belgium|BE]], [[Czech Republic|CZ]], [[Denmark|DK]], [[Finland|FI]], [[Germany|DE]], [[Ireland|IE]], [[Israel|IL]], [[Italy|IT]], [[Mexico|MX]], [[New Zealand|NZ]], [[Norway|NO]], [[Philippines|PH]], [[Poland|PL]], [[Portugal|PT]], [[South Africa|ZA]], [[Sweden|SE]], [[Switzerland|CH]], [[Thailand|TH]], [[Turkey|TR]], [[United Kingdom|UK]])</small>

* '''Irenor''' <small>([[Spain|ES]])</small>

* '''Norebox''' <small>([[Spain|ES]])</small>

* '''Prolift''' <small>([[Argentina|AR]],^† [[Brazil|BR]], [[Chile|CL]], [[Venezuela|VE]]^†)</small>

* '''Solvex''' <small>([[Germany|DE]])</small>

* '''Yeluoshu''' <small>([[China|CN]])</small>

* '''Zuolexin''' <small>([[China|CN]])</small>

== References ==

https://www.cambridge.org/core/journals/cns-spectrums/article/prescribers-guide-to-classic-mao-inhibitors-phenelzine-tranylcypromine-isocarboxazid-for-treatmentresistant-depression/29C70FD3DA65E23A024D5E05C4369983

{{Reflist|2}}

== External links ==

* [http://www.jpgmonline.com/article.asp?issn=0022-3859;year=2003;volume=49;issue=4;spage=373;epage=375;aulast=Kadhe Reboxetine: A Novel Antidepressant]

{{Stimulants}}

{{Antidepressants}}

{{ADHD pharmacotherapies}}

{{Nicotinic acetylcholine receptor modulators}}

{{Monoamine reuptake inhibitors}}

[[Category:Antidepressants]]

[[Category:Morpholines]]

[[Category:Nicotinic antagonists]]

[[Category:Drugs developed by Pfizer]]

[[Category:Norepinephrine reuptake inhibitors]]

[[Category:Phenol ethers]]

[[Category:Potassium channel blockers]]

[[Category:Italian inventions]]