Reboxetine

Last updated
Reboxetine
Reboxetine.svg
(R,R)-(–)-reboxetine (top),
(S,S)-(+)-reboxetine (bottom)
Clinical data
Trade names Edronax, 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) [1]
  • UK: POM (Prescription only)
  • US:Not approved
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
  • rel-(2R)-2-[(R)-(2-Ethoxyphenoxy)(phenyl)methyl]morpholine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C19H23NO3
Molar mass 313.397 g·mol−1
3D model (JSmol)
Chirality Racemate
  • 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 Yes check.svgY
  • Key:CBQGYUDMJHNJBX-RTBURBONSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (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). [4] 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. [5]

Contents

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 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. [5]

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 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. [26]

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 overdose. [27] The symptoms are as follows: [27]

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

Reboxetine [30] [31]
SiteKi (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 GIRKs, a characteristic it shares with the NRI atomoxetine. [33]

Pharmacokinetics

Both the (R,R)-(–) and (S,S)-(+)-enantiomers of reboxetine are predominantly metabolized by the CYP3A4 isoenzyme. [28] 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. [28]

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 Farmitalia-Carlo Erba and was first published in 1984; Farmitalia did the first clinical studies. [35] [36] Farmitalia was acquired by Pharmacia in 1993, [37] and Pharmacia in turn was acquired by Pfizer in 2003. [38]

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]

Related Research Articles

<span class="mw-page-title-main">Antidepressant</span> Class of medication used to treat depression and other conditions

Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction.

<span class="mw-page-title-main">Tricyclic antidepressant</span> Class of medications

Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains three rings of atoms. Tetracyclic antidepressants (TeCAs), which contain four rings of atoms, are a closely related group of antidepressant compounds.

<span class="mw-page-title-main">Sertraline</span> Antidepressant (SSRI class) medication

Sertraline, sold under the brand name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. The efficacy of sertraline for depression is similar to that of other antidepressants, and the differences are mostly confined to side effects. Sertraline is better tolerated than the older tricyclic antidepressants. Sertraline is effective for panic disorder, social anxiety disorder, generalized anxiety disorder (GAD), and obsessive–compulsive disorder (OCD). However, for OCD, cognitive behavioral therapy, particularly in combination with sertraline, is a better treatment. Although approved for post-traumatic stress disorder (PTSD), sertraline leads to only modest improvement in this condition. Sertraline also alleviates the symptoms of premenstrual dysphoric disorder (PMDD) and can be used in sub-therapeutic doses or intermittently for its treatment.

<span class="mw-page-title-main">Bupropion</span> Substituted cathinone medication mainly used for depression and smoking cessation

Bupropion, sold under the brand name Wellbutrin among others, is an atypical antidepressant primarily used to treat major depressive disorder and to support smoking cessation. It is also popular as an add-on medication in the cases of "incomplete response" to the first-line selective serotonin reuptake inhibitor (SSRI) antidepressant. Bupropion has several features that distinguish it from other antidepressants: it does not usually cause sexual dysfunction, it is not associated with weight gain and sleepiness, and it is more effective than SSRIs at improving symptoms of hypersomnia and fatigue. Bupropion, particularly the immediate release formulation, carries a higher risk of seizure than many other antidepressants, hence caution is recommended in patients with a history of seizure disorder.

<span class="mw-page-title-main">Venlafaxine</span> Antidepressant medication

Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin-norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, panic disorder, and social anxiety disorder. Studies have shown that Venlafaxine improves quality of life. It may also be used for chronic pain. It is taken by mouth. It is also available as the salt venlafaxine besylate in an extended-release formulation.

<span class="mw-page-title-main">Serotonin–norepinephrine reuptake inhibitor</span> Class of antidepressant medication

Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant medications used to treat major depressive disorder (MDD), anxiety disorders, obsessive–compulsive disorder (OCD), social phobia, attention-deficit hyperactivity disorder (ADHD), chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopausal symptoms. SNRIs are monoamine reuptake inhibitors; specifically, they inhibit the reuptake of serotonin and norepinephrine. These neurotransmitters are thought to play an important role in mood regulation. SNRIs can be contrasted with the selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (NRIs), which act upon single neurotransmitters.

<span class="mw-page-title-main">Atomoxetine</span> Medication used to treat ADHD

Atomoxetine, sold under the brand name Strattera, is a medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, cognitive disengagement syndrome. It may be used alone or along with psychostimulants. It is also used as a cognitive and executive functioning enhancer to improve self-motivation, persistence, attention, inhibition, and working memory. Use of atomoxetine is only recommended for those who are at least six years old. It is taken orally. Atomoxetine is a selective norepinephrine reuptake inhibitor and is believed to work by increasing norepinephrine and dopamine levels in the brain. The effectiveness of atomoxetine is comparable to the commonly prescribed stimulant medication methylphenidate.

<span class="mw-page-title-main">Norepinephrine reuptake inhibitor</span> Class of drug

A norepinephrine reuptake inhibitor or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline) by blocking the action of the norepinephrine transporter (NET). This in turn leads to increased extracellular concentrations of norepinephrine and epinephrine and therefore can increase adrenergic neurotransmission.

<span class="mw-page-title-main">Viloxazine</span> Medication used to treat ADHD

Viloxazine, sold under the brand name Qelbree and formerly as Vivalan among others, is a selective norepinephrine reuptake inhibitor medication which is used in the treatment of attention deficit hyperactivity disorder (ADHD) in children and adults. It was marketed for almost 30 years as an antidepressant for the treatment of depression before being discontinued and subsequently repurposed as a treatment for ADHD. Viloxazine is taken orally. It was used as an antidepressant in an immediate-release form and is used in ADHD in an extended-release form.

<span class="mw-page-title-main">Milnacipran</span> Antidepressant

Milnacipran is a serotonin–norepinephrine reuptake inhibitor (SNRI) used in the clinical treatment of fibromyalgia. It is not approved for the clinical treatment of major depressive disorder in the US, but it is in other countries.

<span class="mw-page-title-main">NS-2359</span> Chemical compound

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<span class="mw-page-title-main">Dasotraline</span> Chemical compound

Dasotraline is a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI) that was under development by Sunovion for the treatment of attention-deficit hyperactivity disorder (ADHD) and binge eating disorder (BED). Structurally, dasotraline is a stereoisomer of desmethylsertraline (DMS), which is an active metabolite of the marketed selective serotonin reuptake inhibitor (SSRI) antidepressant sertraline (Zoloft).

<span class="mw-page-title-main">Vortioxetine</span> Serotonin modulator antidepressant

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<span class="mw-page-title-main">Levomilnacipran</span> SNRI antidepressant drug

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<span class="mw-page-title-main">Selective serotonin reuptake inhibitor</span> Class of antidepressant medication

Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions.

<span class="mw-page-title-main">Esreboxetine</span> Chemical compound

Esreboxetine (developmental code names AXS-14, PNU-165442G) is a selective norepinephrine reuptake inhibitor which was under development by Pfizer for the treatment of neuropathic pain and fibromyalgia but failed to show significant benefit over currently available medications and was discontinued. It is the (S,S)-(+)-enantiomer of reboxetine and is even more selective as a norepinephrine reuptake inhibitor in comparison.

<span class="mw-page-title-main">Amitifadine</span> Chemical compound

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<span class="mw-page-title-main">Dextromethorphan/bupropion</span> Combination medication

Dextromethorphan/bupropion (DXM/BUP), sold under the brand name Auvelity, is a combination medication for the treatment of major depressive disorder (MDD). Its active components are dextromethorphan (DXM) and bupropion. Patients who stayed on the medication had an average of 11% greater reduction in depressive symptoms than placebo in an FDA approval trial. It is taken as a tablet by mouth.

<span class="mw-page-title-main">Solriamfetol</span> Medication used for the treatment of excessive sleepiness

Solriamfetol, sold under the brand name Sunosi, is a wakefulness-promoting medication used in the treatment of excessive sleepiness related to narcolepsy and sleep apnea. It is taken by mouth.

Selective norepinephrine reuptake inhibitors (sNRIs) are a class of drugs that have been marketed as antidepressants and are used for various mental disorders, mainly depression and attention-deficit hyperactivity disorder (ADHD). The norepinephrine transporter (NET) serves as the fundamental mechanism for the inactivation of noradrenergic signaling because of the NET termination in the reuptake of norepinephrine (NE). The selectivity and mechanism of action for the NRI drugs remain mostly unresolved and, to date, only a limited number of NRI-selective inhibitors are available. The first commercially available selective NRI was the drug reboxetine (Edronax), developed as a first-line therapy for major depressive disorder. Atomoxetine (Strattera) is another potent and selective NRI which is also effective and well tolerated for the treatment of ADHD in adults; it may also be a new treatment option for adults with ADHD, particularly for those patients at risk of substance abuse.

References

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

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