Reboxetine

Reboxetine

(R,R)-(–)-reboxetine (top),
(S,S)-(+)-reboxetine (bottom)
Clinical data
Trade names Edronax, others
Pregnancy
category
Routes of
administration		 Oral (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 binding 97–98%[1][2]
Metabolism Liver (CYP3A4-mediated)[1]
Biological half-life 12–12.5 hours[1][2]
Excretion Urine (78%; 9–10% unchanged)[1][2]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C19H23NO3
Molar mass 313.391 g/mol
3D model (JSmol)
Chirality Racemate
 NYesY (what is this?)  (verify)

Reboxetine (brand names: Edronax (AU, IE, IL, NZ, ZA, UK), Prolift (AR,† BR, CL, VE†))[3] is a drug of the norepinephrine reuptake inhibitor class, marketed as an antidepressant by Pfizer for use in the treatment of unipolar depression, although it has also been used off-label for panic disorder and ADHD. It is approved for use in many countries worldwide, but has not been approved for use in the United States. Although its efficacy 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 into 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According to a systematic review and meta-analysis by IQWiG, including unpublished data, published data on reboxetine overestimated the benefit of reboxetine versus placebo by up to 115% and reboxetine versus SSRIs by up to 23%, and also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 were not published by Pfizer until now.[4]

Panic disorder

In a randomised double-blind placebo-controlled trial reboxetine significantly improved the symptoms of panic disorder.[7] Another randomised controlled trial that compared paroxetine to reboxetine found that paroxetine significantly outperformed reboxetine as a treatment for panic disorder.[8] Despite this discouraging finding an open-label trial examining the efficacy of reboxetine in SSRI-resistant panic disorder demonstrated significant benefit from reboxetine treatment.[9]

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[10][11][12][13] and long-term[14][15] and in both children/adolescents[11][12][14][15] and adults.[10][13]

Other uses

A case series and open-label pilot study have demonstrated the efficacy of reboxetine in treating bulimia nervosa.[16][17] Reboxetine's efficacy in treating therapy-resistant paediatric nocturnal enuresis.[18] A pilot study demonstrated the efficacy of reboxetine in the treatment of narcolepsy.[19] Reboxetine may also attenuate olanzapine-induced weight gain.[20]

Adverse effects

Very common (>10% incidence) adverse effects include:[21][22]

Common (1–10%) adverse effects include:[21][22]

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

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][23]

Interactions

Because of its reliance on CYP3A4, reboxetine O-desethylation is markedly inhibited by papaverine and ketoconazole.[24] It weakly inhibits CYP2D6 and CYP3A4.[21] Reboxetine is an intermediate-level inhibitor of P-glycoprotein, which gives it the potential to interact with ciclosporin, tacrolimus, paroxetine, sertraline, quinidine, fluoxetine, fluvoxamine.[25]

Overdose

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

Pharmacology

Pharmacodynamics

Reboxetine is a fairly selective norepinephrine reuptake inhibitor (NRI) with approximately 20.4x selectivity for the norepinephrine transporter over the serotonin transporter.[27] Despite this selectivity reboxetine does slightly inhibit the reuptake of serotonin at therapeutic doses.[22]

Reboxetine has been found to inhibit both brain and cardiac GIRKs, a characteristic it shares with the norepinephrine reuptake inhibitor atomoxetine.[28]

Binding profile[29][30]

Protein Ki (nM)
SERT 273.5
NET 13.4
DAT >10000
5-HT1A >10000
5-HT1B >10000
5-HT1D >10000
5-HT2A >10000
5-HT2C 457
α1A 11900
α2A >10000
D2 >10000
D3 >10000
mAChRs 6700
H1 312

Pharmacokinetics

Both the (R,R)-(–) and (S,S)-(+)-enantiomers of reboxetine are predominantly metabolized by the CYP3A4 isoenzyme.[24] 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.[24]

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.[31]

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]

History

Reboxetine was discovered at Farmitalia-Carlo Erba and was first published in 1984; Farmitalia did the first clinical studies.[32][33] Farmitalia was acquired by Pharmacia in 1993,[34] and Pharmacia in turn acquired by Pfizer in 2003.[35]

It was first approved in Europe in 1997 and was provisionally approved by the FDA in 1999.[36] 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]

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 3000 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][36][39]

See also

Notes and 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. PMC 2954275 Freely accessible. PMID 20940209. doi:10.1136/bmj.c4737.
  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): 746–758. PMID 19185342. doi:10.1016/S0140-6736(09)60046-5.
  6. 1 2 "Reboxetine: benefit-risk balance reviewed". Drug Safety Update. Medicines and Healthcare products Regulatory Agency. September 2011. Retrieved 10 November 2013.
  7. ↑ 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): 31–37. PMID 11838623. doi:10.4088/JCP.v63n0107.
  8. ↑ 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): 206–210. doi:10.1055/s-2004-832593.
  9. ↑ 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): 329–333. PMID 12415550. doi:10.1002/hup.421.
  10. 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): 231–235. PMC 3232108 Freely accessible. PMID 22615662.
  11. 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): 179–184. PMID 18439114. doi:10.1089/cap.2006.0034.
  12. 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): 428–433. PMID 15843764. doi:10.1097/01.chi.0000155327.30017.8c.
  13. 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): 570–576. PMID 21312292. doi:10.1002/hup.1158.
  14. 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): 803–812. PMID 18315452. doi:10.1089/cap.2006.0145.
  15. 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): 107–113. PMID 21432596. doi:10.1007/s12402-010-0027-x.
  16. ↑ 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. PMID 11110011. doi:10.1097/00004850-200015060-00006.
  17. ↑ 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): 423–428. PMID 15358988. doi:10.1177/026988110401800314.
  18. ↑ Nevéus, T (2006). "Reboxetine in therapy-resistant enuresis: results and pathogenetic implications". Scandinavian Journal of Urology and Nephrology. 40 (1): 31–34. PMID 16452053. doi:10.1080/00365590500407803.
  19. ↑ 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): 282–285. PMID 11322710.
  20. ↑ 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. PMID 12562576. doi:10.1176/appi.ajp.160.2.297.
  21. 1 2 3 "Edronax 4mg Tablets". electronic Medicines Compendium. Pfitzer Limited. 12 July 2013. Retrieved 10 November 2013.
  22. 1 2 3 Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  23. ↑ Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. pp. 254–255. ISBN 978-0-85711-084-8.
  24. 1 2 3 Wienkers LC, Allievi C, Hauer MJ, Wynalda MA (1999). "Cytochrome P-450-Mediated Metabolism of the Individual Enantiomers of the Antidepressant Agent Reboxetine in Human Liver Microsomes". Drug Metabolism & Disposition. 27 (11): 1334–1340. PMID 10534319.
  25. ↑ Weiss, J; Dormann, SM; Martin-Facklam, M; Kerpen, CJ; Ketabi-Kiyanvash, N; Haefeli, WE (2003). "Inhibition of P-glycoprotein by newer antidepressants". Journal of Pharmacology & Experimental Therapeutics. 305 (1): 197–204. PMID 12649369. doi:10.1124/jpet.102.046532.
  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. ↑ Roth, BL; Driscol, J (12 January 2011). "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 10 November 2013.
  28. ↑ Kobayashi, T; Washiyama, K; Ikeda, K (Jun 2010). "Inhibition of G-protein-activated inwardly rectifying K+ channels by the selective norepinephrine reuptake inhibitors atomoxetine and reboxetine.". Neuropsychopharmacology. 35 (7): 1560–9. PMC 3055469 Freely accessible. PMID 20393461. doi:10.1038/npp.2010.27.
  29. ↑ 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.
  30. ↑ 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. Retrieved 2014-03-31.
  31. ↑ 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.
  32. ↑ Cocchiara G; et al. (1991). "Comparison of the disposition and of the metabolic pattern of Reboxetine, a new antidepressant, in the rat, dog, monkey and man". Eur J Drug Metab Pharmacokinet. 16 (3): 231–9. PMID 1814741. doi:10.1007/bf03189965.
  33. ↑ 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.
  34. ↑ Staff (1993). "News: Farmitalia bought by Kabi Pharmacia". Ann Oncol. 4 (5): 345.
  35. ↑ Staff, CNN/Money. April 16, 2003 It's official: Pfizer buys Pharmacia
  36. 1 2 Derek Lowe for In the pipeline. January 17, 2011 Reboxetine Doesn’t Work. But That’s Not the Real Problem
  37. ↑ Adis Insight. Reboxetine Page accessed April 17, 2016
  38. ↑ Page, M. E. (2003). "The promises and pitfalls of reboxetine". CNS Drug Rev. 9 (4): 327–42. PMID 14647527. doi:10.1111/j.1527-3458.2003.tb00258.x.
  39. ↑ Staff, Genetic Engineering News. Oct 14, 2010 Did Sneaky Publication Tactics Help Pfizer’s Reboxetine Slip Through to Market?

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