Chemistry:Reboxetine

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Short description: NRI antidepressant drug
Reboxetine
Reboxetine.svg
(R,R)-(–)-reboxetine (top),
(S,S)-(+)-reboxetine (bottom)
Clinical data
Trade namesEdronax, others
Pregnancy
category
  • AU: B1
Routes of
administration		By mouth (tablets)
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • BR: Class C1 (Other controlled substances)
  • UK: POM (Prescription only)
  • US: Not approved
Pharmacokinetic data
Bioavailability≥94%[1][2]
Protein binding97–98%[1][2]
MetabolismLiver (CYP3A4-mediated)[1]
Elimination half-life12–12.5 hours[1][2]
ExcretionUrine (78%; 9–10% unchanged)[1][2]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC19H23NO3
Molar mass313.397 g·mol−1
3D model (JSmol)
ChiralityRacemate
 ☒N☑Y (what is this?)  (verify)

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 depression, although it has also been used off-label for panic disorder and attention deficit hyperactivity disorder (ADHD).[3] 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.[4]

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.[5]

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."[6] 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.[6]

According to a systematic review and meta-analysis by IQWiG, including unpublished data, published data on reboxetine overestimated the benefit of reboxetine versus placebo by up to 115% and reboxetine versus SSRIs by up to 23%, and also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.[4]

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.[7]

Panic disorder

In a randomised double-blind placebo-controlled trial reboxetine significantly improved the symptoms of panic disorder.[8] Another randomised controlled trial that compared paroxetine to reboxetine found that paroxetine significantly outperformed reboxetine as a treatment for panic disorder.[9] Despite this discouraging finding an open-label trial examining the efficacy of reboxetine in SSRI-resistant panic disorder demonstrated significant benefit from reboxetine treatment.[10]

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[11][12][13][14] and long-term[15][16] and in both children/adolescents[12][13][15][16] and adults.[11][14]

Other uses

A case series and open-label pilot study demonstrated the efficacy of reboxetine in treating bulimia nervosa.[17][18] Reboxetine may also have efficacy in treating therapy-resistant paediatric nocturnal enuresis.[19] A pilot study demonstrated the efficacy of reboxetine in the treatment of narcolepsy.[20] Individual trials and meta-analysis suggest that reboxetine can attenuate antipsychotic-induced weight gain[21][22] and there is some evidence of a benefit on depressive, and possibly other symptoms of schizophrenia when added to antipsychotic treatment.[23][22]

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.[1][24]

Adverse effects

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

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]

A 2009 meta-analysis found that reboxetine was significantly less well tolerated than the other 11 second-generation antidepressants compared in the analysis.[5]

Overdose

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

  • Sweating
  • Tachycardia
  • Changes in blood pressure

Interactions

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

Pharmacology

Pharmacodynamics

Site Ki (nM)
SERT 273.5
NET 13.4
DAT >10,000
5-HT1A >10,000
5-HT1B >10,000
5-HT1D >10,000
5-HT2A >10,000
5-HT2C 457
α1A 11,900
α2A >10,000
D2 >10,000
D3 >10,000
H1 312
mACh 6,700
nACh ND
GIRK ND

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

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

Pharmacokinetics

Both the (R,R)-(–) and (S,S)-(+)-enantiomers of reboxetine are predominantly metabolized by the CYP3A4 isoenzyme.[27] 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]

Chemistry

Reboxetine has two 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 enantiomers, the (R,R)-(–)- and (S,S)-(+)-isomer.[33]

History

Reboxetine was discovered at Farmitalia-Carlo Erba and was first published in 1984; Farmitalia did the first clinical studies.[34][35] Farmitalia was acquired by Pharmacia in 1993,[36] and Pharmacia in turn was acquired by Pfizer in 2003.[37]

It was first approved in Europe in 1997 and was provisionally approved by the FDA in 1999.[38] 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.[39][40]

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.[4][38][41]

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):[3]

References

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

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "PRODUCT INFORMATION EDRONAX® Reboxetine mesilate" (PDF). TGA eBusiness Services. Pfizer Australia Pty Ltd. 17 October 2012. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-01174-3. 
  2. ↑ 2.0 2.1 2.2 2.3 "Reboxetine". CNS Drugs 12 (1): 65–83. July 1999. doi:10.2165/00023210-199912010-00006. 
  3. ↑ 3.0 3.1 Reboxetine Mesilate. The Royal Pharmaceutical Society of Great Britain. 8 November 2011. http://www.medicinescomplete.com/mc/martindale/current/20430-f.htm. Retrieved 10 November 2013. 
  4. ↑ 4.0 4.1 4.2 "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 341: c4737. October 2010. doi:10.1136/bmj.c4737. PMID 20940209. 
  5. ↑ 5.0 5.1 "Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis". Lancet 373 (9665): 746–58. February 2009. doi:10.1016/S0140-6736(09)60046-5. PMID 19185342. http://www.cipralex.co.il/sitecontent/ExternalFiles/213.pdf. 
  6. ↑ 6.0 6.1 "Reboxetine: benefit-risk balance reviewed". Drug Safety Update. Medicines and Healthcare products Regulatory Agency. September 2011. http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON128957. 
  7. ↑ "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 391 (10128): 1357–1366. April 2018. doi:10.1016/S0140-6736(17)32802-7. PMID 29477251. 
  8. ↑ "Reboxetine, a selective norepinephrine reuptake inhibitor, is an effective and well-tolerated treatment for panic disorder". The Journal of Clinical Psychiatry 63 (1): 31–7. January 2002. doi:10.4088/JCP.v63n0107. PMID 11838623. 
  9. ↑ "Comparison of the treatment with paroxetine and reboxetine in panic disorder: a randomized, single-blind study". Pharmacopsychiatry 37 (5): 206–10. September 2004. doi:10.1055/s-2004-832593. PMID 15359375. 
  10. ↑ "The efficacy of reboxetine in the treatment-refractory patients with panic disorder: an open label study". Human Psychopharmacology 17 (7): 329–33. October 2002. doi:10.1002/hup.421. PMID 12415550. 
  11. ↑ 11.0 11.1 "A comparison of the effects of reboxetine and placebo on reaction time in adults with Attention Deficit-Hyperactivity Disorder (ADHD)". Daru 19 (3): 231–5. 2011. PMID 22615662. 
  12. ↑ 12.0 12.1 "An open-label trial of reboxetine in children and adolescents with attention-deficit/hyperactivity disorder". Journal of Child and Adolescent Psychopharmacology 18 (2): 179–84. April 2008. doi:10.1089/cap.2006.0034. PMID 18439114. 
  13. ↑ 13.0 13.1 "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 44 (5): 428–33. May 2005. doi:10.1097/01.chi.0000155327.30017.8c. PMID 15843764. 
  14. ↑ 14.0 14.1 "Efficacy of reboxetine in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled clinical trial". Human Psychopharmacology 25 (7–8): 570–6. November 2010. doi:10.1002/hup.1158. PMID 21312292. 
  15. ↑ 15.0 15.1 "Reboxetine maintenance treatment in children with attention-deficit/hyperactivity disorder: a long-term follow-up study". Journal of Child and Adolescent Psychopharmacology 17 (6): 803–12. December 2007. doi:10.1089/cap.2006.0145. PMID 18315452. 
  16. ↑ 16.0 16.1 "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 2 (3): 107–13. November 2010. doi:10.1007/s12402-010-0027-x. PMID 21432596. 
  17. ↑ "Reboxetine in the treatment of bulimia nervosa: a report of seven cases". International Clinical Psychopharmacology 15 (6): 351–6. November 2000. doi:10.1097/00004850-200015060-00006. PMID 11110011. 
  18. ↑ "Use of reboxetine in bulimia nervosa: a pilot study". Journal of Psychopharmacology 18 (3): 423–8. September 2004. doi:10.1177/026988110401800314. PMID 15358988. 
  19. ↑ "Reboxetine in therapy-resistant enuresis: results and pathogenetic implications". Scandinavian Journal of Urology and Nephrology 40 (1): 31–4. 2006. doi:10.1080/00365590500407803. PMID 16452053. 
  20. ↑ "Stimulant and anticataplectic effects of reboxetine in patients with narcolepsy: a pilot study". Sleep 24 (3): 282–5. May 2001. doi:10.1093/sleep/24.3.282. PMID 11322710. http://www.journalsleep.org/ViewAbstract.aspx?pid=25527. 
  21. ↑ "Attenuation of olanzapine-induced weight gain with reboxetine in patients with schizophrenia: a double-blind, placebo-controlled study". The American Journal of Psychiatry 160 (2): 297–302. February 2003. doi:10.1176/appi.ajp.160.2.297. PMID 12562576. http://ajp.psychiatryonline.org/data/Journals/AJP/3745/297.pdf. 
  22. ↑ 22.0 22.1 "Selective noradrenaline reuptake inhibitors for schizophrenia". The Cochrane Database of Systematic Reviews 1 (1): CD010219. January 2018. doi:10.1002/14651858.CD010219.pub2. PMID 29368813. 
  23. ↑ "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 47 (11): 1557–63. November 2013. doi:10.1016/j.jpsychires.2013.07.003. PMID 23899496. 
  24. ↑ Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. pp. 254–255. ISBN 978-0-85711-084-8. https://archive.org/details/bnf65britishnati0000unse/page/254. 
  25. ↑ 25.0 25.1 25.2 "Edronax 4mg Tablets". UK Electronic Medicines Compendium. October 2015. http://www.medicines.org.uk/emc/medicine/8386/SPC/Edronax+4mg+Tablets/. 
  26. ↑ 26.0 26.1 The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. 2012. p. 588. ISBN 978-0-470-97948-8. 
  27. ↑ 27.0 27.1 27.2 "Cytochrome P-450-mediated metabolism of the individual enantiomers of the antidepressant agent reboxetine in human liver microsomes". Drug Metabolism and Disposition 27 (11): 1334–40. November 1999. PMID 10534319. 
  28. ↑ "Inhibition of P-glycoprotein by newer antidepressants". The Journal of Pharmacology and Experimental Therapeutics 305 (1): 197–204. April 2003. doi:10.1124/jpet.102.046532. PMID 12649369. 
  29. ↑ 29.0 29.1 Cite error: Invalid <ref> tag; no text was provided for refs named PDSP
  30. ↑ Rossi, S, ed (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3. 
  31. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named GG
  32. ↑ "Inhibition of G-protein-activated inwardly rectifying K+ channels by the selective norepinephrine reuptake inhibitors atomoxetine and reboxetine". Neuropsychopharmacology 35 (7): 1560–9. June 2010. doi:10.1038/npp.2010.27. PMID 20393461. 
  33. ↑ "Configuration studies on 2-[alpha -(2-ethoxyphenoxy)benzyl]-morpholine FCE 20124". Tetrahedron 41 (1): 1393–1399. 1985. doi:10.1016/S0040-4020(01)96541-X. 
  34. ↑ "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 16 (3): 231–9. 1991. doi:10.1007/bf03189965. PMID 1814741. 
  35. ↑ First publication per prior citation: Melloni M (1984). "Potential antidepressant agents. α-aryloxy-benzyl derivatives of ethanolamine and morpholine". Eur J Med Chem 3: 235–242. 
  36. ↑ "Farmitalia bought by Kabi Pharmacia". Annals of Oncology 4 (5): 345. May 1993. doi:10.1093/oxfordjournals.annonc.a058508. 
  37. ↑ "It's official: Pfizer buys Pharmacia". CNN/Money. 16 April 2003. https://money.cnn.com/2003/04/16/news/companies/pfizer_pharma/. 
  38. ↑ 38.0 38.1 Lowe, Derek (17 January 2011). "Reboxetine Doesn't Work. But That's Not the Real Problem". In the pipeline. https://www.science.org/content/blog-post/reboxetine-doesn-t-work-s-not-real-problem. 
  39. ↑ "Reboxetine". Adis Insight. http://adisinsight.springer.com/drugs/800000662. 
  40. ↑ "The promises and pitfalls of reboxetine". CNS Drug Reviews 9 (4): 327–42. 2003. doi:10.1111/j.1527-3458.2003.tb00258.x. PMID 14647527. 
  41. ↑ Staff (14 October 2010). "Did Sneaky Publication Tactics Help Pfizer's Reboxetine Slip Through to Market?". Genetic Engineering News. http://www.genengnews.com/gen-news-highlights/did-sneaky-publication-tactics-help-pfizer-s-reboxetine-slip-through-to-market/81244066/. 

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