Reboxetine

Overview

Reboxetine, sold under the brand name Edronax among others, is a selective norepinephrine reuptake inhibitor (sNRI) medication marketed as an antidepressant by Pfizer for use in the treatment of major depressive disorder, although it has also been used off-label for panic disorder and attention deficit hyperactivity disorder (ADHD). It is approved for use in many countries worldwide, but is not approved for use in the United States.[1][2] WP

Drug class

Norepinephrine reuptake inhibitor WP

From the Wikipedia article's infobox.

Uses, dosage and effects

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.[3] WP

The British 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." 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.[4] WP

According to a systematic review and meta-analysis by IQWiG, including unpublished data, published data on reboxetine overestimated the benefit of reboxetine versus placebo by up to 115% and reboxetine versus SSRIs by up to 23%, and also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.[2] WP

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.[5] WP

Panic disorder

In a randomised double-blind placebo-controlled trial reboxetine significantly improved the symptoms of panic disorder. Another randomised controlled trial that compared paroxetine to reboxetine found that paroxetine significantly outperformed reboxetine as a treatment for panic disorder. Despite this discouraging finding an open-label trial examining the efficacy of reboxetine in SSRI-resistant panic disorder demonstrated significant benefit from reboxetine treatment.[6][7][8] WP

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 and long-term and in both children/adolescents and adults.[9–14] WP

Other uses

A case series and open-label pilot study demonstrated the efficacy of reboxetine in treating bulimia nervosa. Reboxetine may also have efficacy in treating therapy-resistant paediatric nocturnal enuresis. A pilot study demonstrated the efficacy of reboxetine in the treatment of narcolepsy. Individual trials and meta-analysis suggest that reboxetine can attenuate antipsychotic-induced weight gain and there is some evidence of a benefit on depressive, and possibly other symptoms of schizophrenia when added to antipsychotic treatment.[15–21] WP

Risks and side effects

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.[22][23] WP

There is conflicting information regarding use with MAOIs: one says the combination is possible with monitoring of side effects but the product informations indicate them as contraindicated.[22][24] WP

Adverse effects

Very common (>10% incidence) adverse effects include insomnia, dizziness, dry mouth, constipation, nausea, and excessive sweating.[25] WP

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), 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.[25] WP

A 2009 meta-analysis found that reboxetine was significantly less well tolerated than the other 11 second-generation antidepressants compared in the analysis.[3] WP

Overdose

Reboxetine is considered a relatively low-risk antidepressant in overdose. The symptoms are as follows:[26] WP

• Sweating[26] WP
• Tachycardia[26] WP
• Changes in blood pressure[26] WP

Interactions

Interactions

Because of its reliance on CYP3A4, reboxetine O-desethylation is markedly inhibited by papaverine and ketoconazole. It weakly inhibits CYP2D6 and CYP3A4. Reboxetine is an intermediate-level inhibitor of P-glycoprotein, which gives it the potential to interact with ciclosporin, tacrolimus, paroxetine, sertraline, quinidine, fluoxetine, and fluvoxamine.[25][27][28] WP

Pharmacology

Pharmacodynamics

Reboxetine is a fairly selective norepinephrine reuptake inhibitor (NRI), with approximately 20-fold selectivity for the norepinephrine transporter (NET) over the serotonin transporter (SERT). Despite this selectivity, reboxetine does slightly inhibit the reuptake of serotonin at therapeutic doses. It does not interact with or inhibit the dopamine transporter (DAT).[29][30][31] WP

Reboxetine has been found to inhibit both brain and cardiac GIRKs, a characteristic it shares with the NRI atomoxetine.[32] WP

Pharmacokinetics

Both the (R,R)-(–) and (S,S)-(+)-enantiomers of reboxetine are predominantly metabolized by the CYP3A4 isoenzyme. The primary metabolite of reboxetine is O-desethylreboxetine, and there are also three minor metabolites—Phenol A, Phenol B, and UK1, Phenol B being the most minor.[27] WP

History

History

Reboxetine was discovered at Farmitalia-Carlo Erba and was first published in 1984; Farmitalia did the first clinical studies. Farmitalia was acquired by Pharmacia in 1993, and Pharmacia in turn was acquired by Pfizer in 2003.[33–36] WP

It was first approved in Europe in 1997 and was provisionally approved by the FDA in 1999. 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.[37][38][39] WP

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.[2][37][40] WP

Legal status

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):[1] WP

• Davedax (IT)[1] WP
• Edronax (AU, AT, BE, CZ, DK, FI, DE, IE, IL, IT, MX, NZ, NO, PH, PL, PT, RU†, ZA, SE, CH, TH, TR, UK)[1] WP
• Irenor (ES)[1] WP
• Norebox (ES)[1] WP
• Prolift (AR†, BR, CL, VE†)[1] WP
• Solvex (DE)[1] WP
• Yeluoshu (CN)[1] WP
• Zuolexin (CN)[1] WP

Chemistry

Formula

C19H23NO3 PC

Molar mass (g/mol)

313.4 PC

IUPAC name (computed by PubChem)

(2R)-2-[(R)-(2-ethoxyphenoxy)-phenylmethyl]morpholine PC

SMILES

CCOC1=CC=CC=C1O[C@@H]([C@H]2CNCCO2)C3=CC=CC=C3 PC

InChIKey

CBQGYUDMJHNJBX-RTBURBONSA-N PC

PubChem CID

127151

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

1. Other Reboxetine Mesilate. 8 November 2011
2. Journal / agency Eyding D, Lelgemann M, Grouven U, Härter M, Kromp M, Kaiser T, Kerekes MF, Gerken M, Wieseler B. Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials. BMJ. October 2010. doi:10.1136/bmj.c4737 · PMID 20940209 · PMC2954275
3. Journal / agency Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa A, Omori IM, McGuire H, Tansella M, Barbui C. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. February 2009. doi:10.1016/S0140-6736(09)60046-5 · PMID 19185342
4. Other Reboxetine: benefit-risk balance reviewed. September 2011
5. Journal / agency 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. 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. Lancet. April 2018. doi:10.1016/S0140-6736(17)32802-7 · PMID 29477251 · PMC5889788
6. Journal / agency Versiani M, Cassano G, Perugi G, Benedetti A, Mastalli L, Nardi A, Savino M. Reboxetine, a selective norepinephrine reuptake inhibitor, is an effective and well-tolerated treatment for panic disorder. The Journal of Clinical Psychiatry. January 2002. doi:10.4088/JCP.v63n0107 · PMID 11838623
7. Journal / agency Bertani A, Perna G, Migliarese G, Di Pasquale D, Cucchi M, Caldirola D, Bellodi L. Comparison of the treatment with paroxetine and reboxetine in panic disorder: a randomized, single-blind study. Pharmacopsychiatry. September 2004. doi:10.1055/s-2004-832593 · PMID 15359375
8. Journal / agency Dannon PN, Iancu I, Grunhaus L. The efficacy of reboxetine in the treatment-refractory patients with panic disorder: an open label study. Human Psychopharmacology. October 2002. doi:10.1002/hup.421 · PMID 12415550
9. Journal / agency Hashemian F, Mohammadian S, Riahi F, Ghaeli P, Ghodsi D. A comparison of the effects of reboxetine and placebo on reaction time in adults with Attention Deficit-Hyperactivity Disorder (ADHD). Daru. 2011. PMID 22615662 · PMC3232108
10. Journal / agency Tehrani-Doost M, Moallemi S, Shahrivar Z. An open-label trial of reboxetine in children and adolescents with attention-deficit/hyperactivity disorder. Journal of Child and Adolescent Psychopharmacology. April 2008. doi:10.1089/cap.2006.0034 · PMID 18439114
11. Journal / agency Ratner S, Laor N, Bronstein Y, Weizman A, Toren P. Six-week open-label reboxetine treatment in children and adolescents with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry. May 2005. doi:10.1097/01.chi.0000155327.30017.8c · PMID 15843764
12. Journal / agency Riahi F, Tehrani-Doost M, Shahrivar Z, Alaghband-Rad J. Efficacy of reboxetine in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled clinical trial. Human Psychopharmacology. November 2010. doi:10.1002/hup.1158 · PMID 21312292
13. Journal / agency Toren P, Ratner S, Weizman A, Lask M, Ben-Amitay G, Laor N. Reboxetine maintenance treatment in children with attention-deficit/hyperactivity disorder: a long-term follow-up study. Journal of Child and Adolescent Psychopharmacology. December 2007. doi:10.1089/cap.2006.0145 · PMID 18315452
14. Journal / agency Quintero J, López-Muñoz F, Alamo C, Loro M, García-Campos N. Reboxetine for ADHD in children non-responders or with poor tolerance to methylphenidate: a prospective long-term open-label study. Attention Deficit and Hyperactivity Disorders. November 2010. doi:10.1007/s12402-010-0027-x · PMID 21432596
15. Journal / agency El-Giamal N, de Zwaan M, Bailer U, Lennkh C, Schüssler P, Strnad A, Kasper S. Reboxetine in the treatment of bulimia nervosa: a report of seven cases. International Clinical Psychopharmacology. November 2000. doi:10.1097/00004850-200015060-00006 · PMID 11110011
16. Journal / agency Fassino S, Daga GA, Boggio S, Garzaro L, Pierò A. Use of reboxetine in bulimia nervosa: a pilot study. Journal of Psychopharmacology. September 2004. doi:10.1177/026988110401800314 · PMID 15358988
17. Journal / agency Nevéus T. Reboxetine in therapy-resistant enuresis: results and pathogenetic implications. Scandinavian Journal of Urology and Nephrology. 2006. doi:10.1080/00365590500407803 · PMID 16452053
18. Journal / agency Larrosa O, de la Llave Y, Bario S, Granizo JJ, Garcia-Borreguero D. Stimulant and anticataplectic effects of reboxetine in patients with narcolepsy: a pilot study. Sleep. May 2001. doi:10.1093/sleep/24.3.282 · PMID 11322710
19. Journal / agency Poyurovsky M, Isaacs I, Fuchs C, Schneidman M, Faragian S, Weizman R, Weizman A. Attenuation of olanzapine-induced weight gain with reboxetine in patients with schizophrenia: a double-blind, placebo-controlled study. The American Journal of Psychiatry. February 2003. doi:10.1176/appi.ajp.160.2.297 · PMID 12562576
20. Journal / agency Matthews PR, Horder J, Pearce M. Selective noradrenaline reuptake inhibitors for schizophrenia. The Cochrane Database of Systematic Reviews. January 2018. doi:10.1002/14651858.CD010219.pub2 · PMID 29368813 · PMC6491172
21. Journal / agency Kishi T, Mukai T, Matsuda Y, Moriwaki M, Iwata N. Efficacy and safety of noradrenalin reuptake inhibitor augmentation therapy for schizophrenia: a meta-analysis of double-blind randomized placebo-controlled trials. Journal of Psychiatric Research. November 2013. doi:10.1016/j.jpsychires.2013.07.003 · PMID 23899496
22. Other PRODUCT INFORMATION EDRONAX® Reboxetine mesilate. 17 October 2012
23. Other Joint Formulary Committee. British National Formulary (BNF). 2013
24. Journal / agency Van den Eynde V, Abdelmoemin WR, Abraham MM, Amsterdam JD, Anderson IM, Andrade C, et al. The Prescriber's Guide to Classic MAO Inhibitors (Phenelzine, Tranylcypromine, Isocarboxazid) for Treatment-Resistant Depression. CNS Spectrums. 2023. doi:10.1017/S1092852922000906 · PMID 35837681
25. Other Edronax 4mg Tablets. October 2015
26. Other Taylor D, Paton C, Shitij K. The Maudsley prescribing guidelines in psychiatry. 2012
27. Journal / agency Wienkers LC, Allievi C, Hauer MJ, Wynalda MA. Cytochrome P-450-mediated metabolism of the individual enantiomers of the antidepressant agent reboxetine in human liver microsomes. Drug Metabolism and Disposition. November 1999. doi:10.1016/S0090-9556(24)14936-7 · PMID 10534319
28. Journal / agency Weiss J, Dormann SM, Martin-Facklam M, Kerpen CJ, Ketabi-Kiyanvash N, Haefeli WE. Inhibition of P-glycoprotein by newer antidepressants. The Journal of Pharmacology and Experimental Therapeutics. April 2003. doi:10.1124/jpet.102.046532 · PMID 12649369
29. Other Roth BL, Driscol J. PDSD Kᵢ Database
30. Other Australian Medicines Handbook. 2013
31. Other Brunton L, Chabner B, Knollman B. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 2010
32. Journal / agency Kobayashi T, Washiyama K, Ikeda K. Inhibition of G-protein-activated inwardly rectifying K+ channels by the selective norepinephrine reuptake inhibitors atomoxetine and reboxetine. Neuropsychopharmacology. June 2010. doi:10.1038/npp.2010.27 · PMID 20393461 · PMC3055469
33. Journal / agency Cocchiara G, Battaglia R, Pevarello P, Strolin Benedetti M. Comparison of the disposition and of the metabolic pattern of Reboxetine, a new antidepressant, in the rat, dog, monkey and man. European Journal of Drug Metabolism and Pharmacokinetics. 1991. doi:10.1007/bf03189965 · PMID 1814741
34. Journal / agency Melloni M. Potential antidepressant agents. α-aryloxy-benzyl derivatives of ethanolamine and morpholine. Eur J Med Chem. 1984
35. Journal / agency Farmitalia bought by Kabi Pharmacia. Annals of Oncology. May 1993. doi:10.1093/oxfordjournals.annonc.a058508
36. Other It's official: Pfizer buys Pharmacia. 16 April 2003
37. Other Lowe, Derek. Reboxetine Doesn't Work. But That's Not the Real Problem. 17 January 2011
38. Journal / agency Reboxetine
39. Journal / agency Page ME. The promises and pitfalls of reboxetine. CNS Drug Reviews. 2003. doi:10.1111/j.1527-3458.2003.tb00258.x · PMID 14647527 · PMC6741698
40. Other Staff. Did Sneaky Publication Tactics Help Pfizer's Reboxetine Slip Through to Market?. 14 October 2010

Text and values on this page are quoted from Wikipedia (CC BY-SA 4.0), PubChem (public domain). Each value links to the exact revision it came from.