Reboxetine
Clinical data | |
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Trade names | Edronax, others |
Pregnancy category |
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Routes of administration | By mouth (tablets) |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | ≥94%[2][3] |
Protein binding | 97–98%[2][3] |
Metabolism | Liver (CYP3A4-mediated)[2] |
Elimination half-life | 12–12.5 hours[2][3] |
Excretion | Urine (78%; 9–10% unchanged)[2][3] |
Identifiers | |
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JSmol) | |
Chirality | Racemate |
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Reboxetine, sold under the brand name Edronax among others, is a drug of the
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.[6]
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."[7] 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.[7]
According to a systematic review and meta-analysis by
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.[8]
Panic disorder
In a randomised double-blind placebo-controlled trial reboxetine significantly improved the symptoms of panic disorder.[9] Another randomised controlled trial that compared paroxetine to reboxetine found that paroxetine significantly outperformed reboxetine as a treatment for panic disorder.[10] Despite this discouraging finding an open-label trial examining the efficacy of reboxetine in SSRI-resistant panic disorder demonstrated significant benefit from reboxetine treatment.[11]
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[12][13][14][15] and long-term[16][17] and in both children/adolescents[13][14][16][17] and adults.[12][15]
Other uses
A case series and open-label pilot study demonstrated the efficacy of reboxetine in treating bulimia nervosa.[18][19] Reboxetine may also have efficacy in treating therapy-resistant paediatric nocturnal enuresis.[20] A pilot study demonstrated the efficacy of reboxetine in the treatment of narcolepsy.[21] Individual trials and meta-analysis suggest that reboxetine can attenuate antipsychotic-induced weight gain[22][23] and there is some evidence of a benefit on depressive, and possibly other symptoms of schizophrenia when added to antipsychotic treatment.[24][23]
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.[2][25]
Adverse effects
Very common (>10% incidence) adverse effects include insomnia, dizziness, dry mouth, constipation, nausea, and excessive sweating.[26]
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
A 2009 meta-analysis found that reboxetine was significantly less well tolerated than the other 11 second-generation antidepressants compared in the analysis.[6]
Overdose
Reboxetine is considered a relatively low-risk antidepressant in
- Sweating
- Tachycardia
- Changes in blood pressure
Interactions
Because of its reliance on CYP3A4, reboxetine O-desethylation is markedly inhibited by papaverine and ketoconazole.[28] It weakly inhibits CYP2D6 and CYP3A4.[26] Reboxetine is an intermediate-level inhibitor of P-glycoprotein, which gives it the potential to interact with ciclosporin, tacrolimus, paroxetine, sertraline, quinidine, fluoxetine, fluvoxamine.[29]
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).[30] Despite this selectivity, reboxetine does slightly inhibit the reuptake of serotonin at therapeutic doses.[32] It does not interact with or inhibit the dopamine transporter (DAT).[30][31]
Reboxetine has been found to inhibit both brain and cardiac
Pharmacokinetics
Both the (R,R)-(–) and (S,S)-(+)-enantiomers of reboxetine are predominantly metabolized by the
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.[34]
History
Reboxetine was discovered at
It was first approved in Europe in 1997 and was provisionally approved by the FDA in 1999.[39] 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.[40][41]
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.[5][39][42]
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):[4]
- 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
- ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
- ^ a b c d e f "PRODUCT INFORMATION EDRONAX® Reboxetine mesilate" (PDF). TGA eBusiness Services. Pfizer Australia Pty Ltd. 17 October 2012. Retrieved 10 November 2013.
- ^ S2CID 72813017.
- ^ a b Reboxetine Mesilate. The Royal Pharmaceutical Society of Great Britain. 8 November 2011. Retrieved 10 November 2013.
{{cite book}}
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ignored (help) - ^ PMID 20940209.
- ^ S2CID 35858125. Archived from the original(PDF) on 2013-09-29.
- ^ a b "Reboxetine: benefit-risk balance reviewed". Drug Safety Update. Medicines and Healthcare products Regulatory Agency. September 2011. Retrieved 10 November 2013.
- PMID 29477251.
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- ^ PMID 29368813.
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- ISBN 978-0-85711-084-8.
- ^ a b c "Edronax 4mg Tablets". UK Electronic Medicines Compendium. October 2015. Retrieved 20 August 2017.
- ^ ISBN 978-0-470-97948-8.
- ^ PMID 10534319.
- S2CID 5897406.
- ^ a b c 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.
- ^ ISBN 978-0-07-162442-8.
- ISBN 978-0-9805790-9-3.
- PMID 20393461.
- .
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- ^ 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.
- .
- ^ "It's official: Pfizer buys Pharmacia". CNN/Money. 16 April 2003.
- ^ a b Lowe D (17 January 2011). "Reboxetine Doesn't Work. But That's Not the Real Problem". In the pipeline.
- ^ "Reboxetine". Adis Insight. Retrieved 17 April 2016.
- PMID 14647527.
- ^ Staff (14 October 2010). "Did Sneaky Publication Tactics Help Pfizer's Reboxetine Slip Through to Market?". Genetic Engineering News.