Reboxetine

Reboxetine
(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)
  • 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
IUPAC name
  • rel-(2R)-2-[(R)-(2-Ethoxyphenoxy)(phenyl)methyl]morpholine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC19H23NO3
Molar mass313.397 g·mol−1
3D model (JSmol)
ChiralityRacemate
SMILES
  • CCOC1=C(C=CC=C1)O[C@@H]([C@@H]2OCCNC2)C3=CC=CC=C3
InChI
  • InChI=1S/C19H23NO3/c1-2-21-16-10-6-7-11-17(16)23-19(15-8-4-3-5-9-15)18-14-20-12-13-22-18/h3-11,18-20H,2,12-14H2,1H3/t18-,19-/m1/s1 checkY
  • Key:CBQGYUDMJHNJBX-RTBURBONSA-N checkY
 ☒NcheckY (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 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, patients concomitantly on MAOIs and 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

Reboxetine[29][30]
SiteKi (nM)
SERT273.5
NET13.4
DAT>10,000
5-HT1A>10,000
5-HT1B>10,000
5-HT1D>10,000
5-HT2A>10,000
5-HT2C457
α1A11,900
α2A>10,000
D2>10,000
D3>10,000
H1312
mACh6,700
nAChND
GIRKND

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.[31] It does not interact with or inhibit the dopamine transporter (DAT).[29][30]

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]

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

References

  1. 1 2 3 4 5 6 "PRODUCT INFORMATION EDRONAX® Reboxetine mesilate" (PDF). TGA eBusiness Services. Pfizer Australia Pty Ltd. 17 October 2012. Retrieved 10 November 2013.
  2. 1 2 3 4 Holm KJ, Spencer CM (July 1999). "Reboxetine". CNS Drugs. 12 (1): 65–83. doi:10.2165/00023210-199912010-00006.
  3. 1 2 Reboxetine Mesilate. Martindale: The Complete Drug Reference. The Royal Pharmaceutical Society of Great Britain. 8 November 2011. Retrieved 10 November 2013.
  4. 1 2 3 Eyding D, Lelgemann M, Grouven U, Härter M, Kromp M, Kaiser T, Kerekes MF, Gerken M, Wieseler B (October 2010). "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. doi:10.1136/bmj.c4737. PMC 2954275. PMID 20940209.
  5. 1 2 Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa A, Omori IM, McGuire H, Tansella M, Barbui C (February 2009). "Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis" (PDF). Lancet. 373 (9665): 746–58. doi:10.1016/S0140-6736(09)60046-5. PMID 19185342. S2CID 35858125. Archived from the original (PDF) on 2013-09-29.
  6. 1 2 "Reboxetine: benefit-risk balance reviewed". Drug Safety Update. Medicines and Healthcare products Regulatory Agency. September 2011. Retrieved 10 November 2013.
  7. ↑ Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, et al. (April 2018). "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. doi:10.1016/S0140-6736(17)32802-7. PMC 5889788. PMID 29477251.
  8. ↑ Versiani M, Cassano G, Perugi G, Benedetti A, Mastalli L, Nardi A, Savino M (January 2002). "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. doi:10.4088/JCP.v63n0107. PMID 11838623.
  9. ↑ Bertani A, Perna G, Migliarese G, Di Pasquale D, Cucchi M, Caldirola D, Bellodi L (September 2004). "Comparison of the treatment with paroxetine and reboxetine in panic disorder: a randomized, single-blind study". Pharmacopsychiatry. 37 (5): 206–10. doi:10.1055/s-2004-832593. PMID 15359375.
  10. ↑ Dannon PN, Iancu I, Grunhaus L (October 2002). "The efficacy of reboxetine in the treatment-refractory patients with panic disorder: an open label study". Human Psychopharmacology. 17 (7): 329–33. doi:10.1002/hup.421. PMID 12415550. S2CID 19996027.
  11. 1 2 Hashemian F, Mohammadian S, Riahi F, Ghaeli P, Ghodsi D (2011). "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. PMC 3232108. PMID 22615662.
  12. 1 2 Tehrani-Doost M, Moallemi S, Shahrivar Z (April 2008). "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. doi:10.1089/cap.2006.0034. PMID 18439114.
  13. 1 2 Ratner S, Laor N, Bronstein Y, Weizman A, Toren P (May 2005). "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. doi:10.1097/01.chi.0000155327.30017.8c. PMID 15843764.
  14. 1 2 Riahi F, Tehrani-Doost M, Shahrivar Z, Alaghband-Rad J (November 2010). "Efficacy of reboxetine in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled clinical trial". Human Psychopharmacology. 25 (7–8): 570–6. doi:10.1002/hup.1158. PMID 21312292. S2CID 8634761.
  15. 1 2 Toren P, Ratner S, Weizman A, Lask M, Ben-Amitay G, Laor N (December 2007). "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. doi:10.1089/cap.2006.0145. PMID 18315452.
  16. 1 2 Quintero J, López-Muñoz F, Alamo C, Loro M, García-Campos N (November 2010). "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. doi:10.1007/s12402-010-0027-x. PMID 21432596. S2CID 41617072.
  17. ↑ El-Giamal N, de Zwaan M, Bailer U, Lennkh C, Schüssler P, Strnad A, Kasper S (November 2000). "Reboxetine in the treatment of bulimia nervosa: a report of seven cases". International Clinical Psychopharmacology. 15 (6): 351–6. doi:10.1097/00004850-200015060-00006. PMID 11110011. S2CID 21260625.
  18. ↑ Fassino S, Daga GA, Boggio S, Garzaro L, Pierò A (September 2004). "Use of reboxetine in bulimia nervosa: a pilot study". Journal of Psychopharmacology. 18 (3): 423–8. doi:10.1177/026988110401800314. PMID 15358988. S2CID 24287884.
  19. ↑ Nevéus T (2006). "Reboxetine in therapy-resistant enuresis: results and pathogenetic implications". Scandinavian Journal of Urology and Nephrology. 40 (1): 31–4. doi:10.1080/00365590500407803. PMID 16452053. S2CID 41990481.
  20. ↑ Larrosa O, de la Llave Y, Bario S, Granizo JJ, Garcia-Borreguero D (May 2001). "Stimulant and anticataplectic effects of reboxetine in patients with narcolepsy: a pilot study". Sleep. 24 (3): 282–5. doi:10.1093/sleep/24.3.282. PMID 11322710.
  21. ↑ Poyurovsky M, Isaacs I, Fuchs C, Schneidman M, Faragian S, Weizman R, Weizman A (February 2003). "Attenuation of olanzapine-induced weight gain with reboxetine in patients with schizophrenia: a double-blind, placebo-controlled study" (PDF). The American Journal of Psychiatry. 160 (2): 297–302. doi:10.1176/appi.ajp.160.2.297. PMID 12562576.
  22. 1 2 Matthews PR, Horder J, Pearce M (January 2018). "Selective noradrenaline reuptake inhibitors for schizophrenia". The Cochrane Database of Systematic Reviews. 1: CD010219. doi:10.1002/14651858.CD010219.pub2. PMC 6491172. PMID 29368813.
  23. ↑ Kishi T, Mukai T, Matsuda Y, Moriwaki M, Iwata N (November 2013). "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. 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.
  25. 1 2 3 "Edronax 4mg Tablets". UK Electronic Medicines Compendium. October 2015. Retrieved 20 August 2017.
  26. 1 2 Taylor D, Paton C, Shitij K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. p. 588. ISBN 978-0-470-97948-8.
  27. 1 2 3 Wienkers LC, Allievi C, Hauer MJ, Wynalda MA (November 1999). "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. PMID 10534319.
  28. ↑ Weiss J, Dormann SM, Martin-Facklam M, Kerpen CJ, Ketabi-Kiyanvash N, Haefeli WE (April 2003). "Inhibition of P-glycoprotein by newer antidepressants". The Journal of Pharmacology and Experimental Therapeutics. 305 (1): 197–204. doi:10.1124/jpet.102.046532. PMID 12649369. S2CID 5897406.
  29. 1 2 3 Roth BL, Driscol J. "PDSD Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Archived from the original on 2013-11-08. Retrieved 2014-03-31.
  30. 1 2 Brunton L, Chabner B, Knollman B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.
  31. ↑ Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  32. ↑ Kobayashi T, Washiyama K, Ikeda K (June 2010). "Inhibition of G-protein-activated inwardly rectifying K+ channels by the selective norepinephrine reuptake inhibitors atomoxetine and reboxetine". Neuropsychopharmacology. 35 (7): 1560–9. doi:10.1038/npp.2010.27. PMC 3055469. PMID 20393461.
  33. ↑ Melloni P, Della Torre A, Lazzari E, Mazzini G, Meroni M (1985). "Configuration studies on 2-[alpha -(2-ethoxyphenoxy)benzyl]-morpholine FCE 20124". Tetrahedron. 41 (1): 1393–1399. doi:10.1016/S0040-4020(01)96541-X.{{cite journal}}: CS1 maint: uses authors parameter (link)
  34. ↑ Cocchiara G, Battaglia R, Pevarello P, Strolin Benedetti M (1991). "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. doi:10.1007/bf03189965. PMID 1814741. S2CID 874781.
  35. ↑ First publication per prior citation: Melloni M; et al. (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. ↑ Staff (16 April 2003). "It's official: Pfizer buys Pharmacia". CNN/Money.{{cite web}}: CS1 maint: uses authors parameter (link)
  38. 1 2 Lowe D (17 January 2011). "Reboxetine Doesn't Work. But That's Not the Real Problem". In the pipeline.
  39. ↑ "Reboxetine". Adis Insight. Retrieved 17 April 2016.
  40. ↑ Page ME (2003). "The promises and pitfalls of reboxetine". CNS Drug Reviews. 9 (4): 327–42. doi:10.1111/j.1527-3458.2003.tb00258.x. PMC 6741698. PMID 14647527.
  41. ↑ Staff (14 October 2010). "Did Sneaky Publication Tactics Help Pfizer's Reboxetine Slip Through to Market?". Genetic Engineering News.
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