Reboxetine

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Reboxetine
350px
Reboxetine3Dan2.gif
Systematic (IUPAC) name
(R*,R*)-2-[(2-ethoxyphenoxy)-phenyl-methyl]morpholine
Clinical data
Trade names Davedax, Edronax, Narebox, Prolift, Solvex, Yeluoshu, Zuolexin
Pregnancy
category
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
Routes of
administration		 Oral
Pharmacokinetic data
Bioavailability ≥94%[1][2]
Protein binding 97-98%[1][2]
Metabolism Hepatic, CYP3A4-mediated[1]
Biological half-life 12-12.5 hours[1][2]
Excretion Renal (78%; 9-10% unchanged)[1][2]
Identifiers
CAS Number 98769-81-4 YesY
ATC code N06AX18 (WHO)
PubChem CID: 127151
DrugBank DB00234 YesY
ChemSpider 112870 YesY
UNII 947S0YZ36I YesY
KEGG D08472 YesY
ChEMBL CHEMBL14370 N
Chemical data
Formula C19H23NO3
Molecular mass 313.391 g/mol
  • CCOC1=C(C=CC=C1)O[C@@H]([C@@H]2OCCNC2)C3=CC=CC=C3
  • 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 YesY
  • Key:CBQGYUDMJHNJBX-RTBURBONSA-N YesY
 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

In his book Bad Pharma, Ben Goldacre exposed the dishonesty around the medical trialling of Reboxetine, revealing that for every medical trial favourable to the drug, there were seven that showed poor results of efficacy. However, trials that produced poor results for the drug were withheld from the public and regulators.[21]

Incidence of adverse effects[22][23]

Very common (>10% incidence) adverse effects include:

  • Insomnia
  • Nausea
  • Excessive sweating
  • Dry mouth
  • Constipation

Common (1-10%) adverse effects include:

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Uncommon (0.1-1%) adverse effects include:

Rare (<0.1%) adverse effects include:

Unknown frequency adverse effects include:

  • Hyponatraemia (low blood sodium)
  • Aggressive behaviour
  • Hallucination
  • Suicidal Ideation/behaviour
  • Increased intraocular pressure
  • Peripheral coldness
  • Raynaud`s phenomenon
  • Allergic dermatitis
  • Testicular pain
  • Irritability

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][24]

Interactions

Because of its reliance on CYP3A4, reboxetine O-desethylation is markedly inhibited by papaverine and ketoconazole.[25] It weakly inhibits CYP2D6 and CYP3A4.[22] Reboxetine is an intermediate-level inhibitor of P-glycoprotein, which gives it the potential to interact with ciclosporin, tacrolimus, paroxetine, sertraline, quinidine, fluoxetine, fluvoxamine.[26]

Overdose

Reboxetine is considered a relatively low-risk antidepressant in overdose.[27] The symptoms are as follows:[27]

  • Sweating
  • Tachycardia
  • Changes in blood pressure

Pharmacology

Pharmacodynamics

Reboxetine is a fairly selective norepinephrine reuptake inhibitor (NRI) with approximately 20.4x selectivity for the norepinephrine transporter over the serotonin transporter.[28] Despite this selectivity reboxetine does slightly inhibit the reuptake of serotonin at therapeutic doses.[23]

Reboxetine has been found to inhibit both brain and cardiac GIRKs, a characteristic it shares with the norepinephrine reuptake inhibitor atomoxetine.[29]

Binding profile[30][31]

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.[25] 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.[25]

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.[32]

[33]

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]

  • Norebox (ES)
  • Solvex (DE)
  • Yeluoshu (CN)
  • Zuolexin (CN)

See also

Notes and references

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ 2.0 2.1 2.2 2.3 Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ 3.0 3.1 Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ 4.0 4.1 Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ 5.0 5.1 Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ 6.0 6.1 Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ 10.0 10.1 Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ 11.0 11.1 Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ 12.0 12.1 Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ 13.0 13.1 Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ 14.0 14.1 Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ 15.0 15.1 Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  18. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  19. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  20. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  21. ↑ Bad Pharma: How drug companies mislead doctors and harm patients, Fourth Estate, 2012 (UK). ISBN 978-0-00-735074-2
  22. ↑ 22.0 22.1 Lua error in package.lua at line 80: module 'strict' not found.
  23. ↑ 23.0 23.1 Lua error in package.lua at line 80: module 'strict' not found.
  24. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  25. ↑ 25.0 25.1 25.2 Lua error in package.lua at line 80: module 'strict' not found.
  26. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  27. ↑ 27.0 27.1 Lua error in package.lua at line 80: module 'strict' not found.
  28. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  29. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  30. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  31. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  32. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  33. ↑ Lua error in package.lua at line 80: module 'strict' not found.

External links

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