Absorption, Distribution and Excretion
Reboxetine is rapidly and extensively absorbed following oral administration.
Multiple samples of blood and milk were obtained over a dose interval at steady-state from four women who were taking reboxetine for postnatal depression. Drug concentrations in plasma and milk were measured by high performance liquid chromatography and milk/plasma ratio (M/P), absolute infant dose and relative infant dose were estimated by standard methods. Their four, breastfed, infants were also examined clinically, and a blood sample was taken for drug analysis. The median (range) dose taken by the women was 6 (4-10) mg/day. There was no significant difference in reboxetine concentration between paired fore-and hind-milk samples. The mean (95% CI) M/P was 0.06 (0.03, 0.09). Absolute infant dose was 1.7 (0.7, 2.4) ug/kg/day for reboxetine while the relative infant dose was 2.0% (1.3, 2.7%). ... The concentrations of reboxetine in plasma from the four infants were <4 ug/L, 2.6 ug/L, 2.3 ug/L and 5 ug/L, respectively.
Reboxetine is known to be excreted in breast milk.
The drug appears to be distributed into total body water. Reboxetine is 97% bound to human plasma proteins in young and 92% in elderly (with affinity markedly higher for alpha1 acid glycoprotein than albumin), with no significant dependence of the concentration of drug.
After oral administration of a single 4 mg reboxetine dose to healthy volunteers, peak levels of about 130 ng/mL are achieved within 2 hr post-dosing. Data indicate that absolute bioavailability is at least 60%. Reboxetine plasma levels decreased monoexponentially with a half-life of about 13 hr. Steady-state conditions are observed within 5 days. Linearity of the pharmacokinetics was shown in the range of single oral doses in the clinically recommended dose-ranges.
For more Absorption, Distribution and Excretion (Complete) data for REBOXETINE (6 total), please visit the HSDB record page.

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Metabolism / Metabolites
Reboxetine is metabolized by dealkylation, hydroxylation and oxidation followed by glucuronide or sulphate conjugation. It is metabolized by the cytochrome P450 CYP isoenzyme 3A4.
The purpose of this study was to compare the disposition and the metabolic pattern of Reboxetine in several species, including man. (14)C-Reboxetine was given orally to the rat, the dog, the monkey (5 mg/kg) and man (2 and 4 mg/kg). Radioactivity was eliminated both by the renal and faecal route in the rat and the dog, mainly in urine in the monkey and man. Reboxetine was extensively metabolized. A number of urinary metabolites were quantified by radio-HPLC and tentatively identified by comparison with the retention times of reference compounds. Suggested routes of metabolic transformation are: 2-O-dealkylation; hydroxylation of the ethoxyphenoxy ring; oxidation of the morpholine ring; morpholine ring-opening; and combinations of these. Metabolites were partially or completely conjugated with glucuronic acid and/or sulphuric acid.
Reboxetine is predominantly metabolized in vitro via cytochrome P4503A (CYP3A4). In vitro studies have shown that reboxetine does not inhibit the activity of the following isozymes of cytochrome P450: CYP1A2, CYP2C9, CYP2C19, and CYP2E1. Reboxetine inhibits both CYP2D6 and CYP3A4 with low binding affinities, but has shown no effect on the in vivo clearance of drugs metabolized by these enzymes. Reboxetine should be co-prescribed with caution with potent inhibitors of CYP3A4.

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Biological Half-Life
12.5 hours
After oral administration of a single 4 mg reboxetine dose to healthy volunteers ... reboxetine plasma levels decreased monoexponentially with a half-life of about 13 hr.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Reboxetine is not approved for marketing in the United States by the U.S. Food and Drug Administration, but is available in other countries. Limited information indicates that maternal doses of up to 10 mg daily produce low levels in milk and appear to not result in any adverse effects in breastfed infants. Until more data are available, reboxetine should be used with careful monitoring during breastfeeding.
◉ Effects in Breastfed Infants
Four infants whose mothers had postpartum depression had been breastfed (extent not stated) for 1.3 to 2.1 months during maternal reboxetine therapy at an average dose of 6.5 mg (79 mcg/kg) daily. One of the mothers was also taking escitalopram 20 mg daily and another was taking sertraline 300 mg daily. None of the infants exhibited any adverse reactions. Three of the infants had normal Denver developmental scores; the fourth whose mother was taking reboxetine had a developmental age of only 71% of normal, but the problem predated maternal reboxetine therapy.
Five women used reboxetine during pregnancy and lactation (extent not stated) in unspecified doses. No adverse effects were noted in their infants and normal developmental milestones were reported.
◉ Effects on Lactation and Breastmilk
Reboxetine increased serum prolactin in male subjects. The relevance of this finding to nursing mothers is not clear. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.
An observational study looked at outcomes of 2859 women who took an antidepressant during the 2 years prior to pregnancy. Compared to women who did not take an antidepressant during pregnancy, mothers who took an antidepressant during all 3 trimesters of pregnancy were 37% less likely to be breastfeeding upon hospital discharge. Mothers who took an antidepressant only during the third trimester were 75% less likely to be breastfeeding at discharge. Those who took an antidepressant only during the first and second trimesters did not have a reduced likelihood of breastfeeding at discharge. The antidepressants used by the mothers were not specified.
A retrospective cohort study of hospital electronic medical records from 2001 to 2008 compared women who had been dispensed an antidepressant during late gestation (n = 575) to those who had a psychiatric illness but did not receive an antidepressant (n = 1552) and mothers who did not have a psychiatric diagnosis (n = 30,535). Women who received an antidepressant were 37% less likely to be breastfeeding at discharge than women without a psychiatric diagnosis, but no less likely to be breastfeeding than untreated mothers with a psychiatric diagnosis. None of the mothers were taking reboxetine.
In a study of 80,882 Norwegian mother-infant pairs from 1999 to 2008, new postpartum antidepressant use was reported by 392 women and 201 reported that they continued antidepressants from pregnancy. Compared with the unexposed comparison group, late pregnancy antidepressant use was associated with a 7% reduced likelihood of breastfeeding initiation, but with no effect on breastfeeding duration or exclusivity. Compared with the unexposed comparison group, new or restarted antidepressant use was associated with a 63% reduced likelihood of predominant, and a 51% reduced likelihood of any breastfeeding at 6 months, as well as a 2.6-fold increased risk of abrupt breastfeeding discontinuation. Specific antidepressants were not mentioned.

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Protein Binding
98%

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Interactions
In vitro metabolism studies indicate that reboxetine is primarily metabolised by the CYP3A4 isozyme of cytochrome P450; reboxetine is not metabolized by CYP2D6. Therefore potent inhibitors of CYP3A4 (ketoconazole, nefazodone, erythromycin and fluvoxamine), would be expected to increase plasma concentrations of reboxetine. In a study in healthy volunteers, ketoconazole, a potent inhibitor of CYP3A4, was found to increase plasma concentrations of the reboxetine enantiomers by approximately 50%. Because of reboxetine's narrow therapeutic margin, inhibition of elimination is a major concern. Reboxetine, therefore should not be given together with drugs known to inhibit CYP3A4 such as azole antifungal agents, macrolide antibiotics such as erythromycin, or fluvoxamine.
Concomitant use of MAO-inhibitors and reboxetine should be avoided in view of the potential risk (tyramine-like effect) based on their mechanisms of action.
Although data are not available from clinical studies, the possibility of hypokalaemia with concomitant use of potassium losing diuretics should be considered.
Concomitant use of ergot derivatives and reboxetine might result in increased blood pressure.
The interaction between ketoconazole and reboxetine enantiomers was studied in 11 healthy volunteers (age range, 18-47 yr) who received 4 mg of oral reboxetine on the second day of a 5-day regimen of 200 mg/day of ketoconazole or 4 mg of reboxetine alone in a crossover design. Results showed that ketoconazole increased R,R-(-)-reboxetine and S,S-(+)-reboxetine mean area under the plasma concentration-time curves (AUC) by 58 and 43%, respectively. Oral clearance of both enantiomers was subsequently decreased 34 and 24%, respectively. Ketoconazole did not significantly affect maximal plasma concentrations. Mean terminal half-life after administration of ketoconazole was significantly longer than after reboxetine alone. The AUC ratio for R,R-(-)-reboxetine to S,S-(+)-reboxetine was reduced by ketoconazole administration.

[1]. Reboxetine prevents the tranylcypromine-induced increase in tyramine levels in rat heart. J Neural Transm Suppl. 1994;41:149-53.

Reboxetine is an aromatic ether.
Reboxetine is an antidepressant drug used in the treatment of clinical depression, panic disorder and ADD/ADHD. Its mesylate (i.e. methanesulfonate) salt is sold under tradenames including Edronax, Norebox, Prolift, Solvex, Davedax or Vestra. Reboxetine has two chiral centers, but it only exists as two enantiomers, (R,R)-(-)- and (S,S)-(+)-reboxetine.
A morpholine derivative that is a selective and potent noradrenaline reuptake inhibitor; it is used in the treatment of DEPRESSIVE DISORDER.

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Drug Indication
For the treatment of clinical depression.

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Mechanism of Action
Reboxetine is a selective inhibitor of noradrenaline reuptake. It inhibits noradrenaline reuptake in vitro to a similar extent to the tricyclic antidepressant desmethylimipramine. Reboxetine does not affect dopamine or serotonin reuptake and it has low in vivo and in vitro affinity for adrenergic, cholinergic, histaminergic, dopaminergic and serotonergic receptors.
Reboxetine is a highly selective and potent inhibitor of noradrenaline reuptake. It has only a weak effect on the 5-HT reuptake and does not affect the uptake of dopamine. Noradrenaline reuptake inhibition and the consequent increase of noradrenaline availability in the synaptic cleft and modification of noradrenergic transmission, reportedly is among the most relevant mechanisms of action of known antidepressant drugs.

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Therapeutic Uses
This open-label study assessed the effectiveness of reboxetine, a selective norepinephrine reuptake inhibitor, in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) resistant to a previous methylphenidate trial. Thirty-one child and adolescent outpatients, aged 8 to 18 (mean age, 11.7; SD = 2.87) years, diagnosed with ADHD were enrolled in a 6-week open-label study. Assessments included rater-administered scales (DSM-IV ADHD Scale; Clinical Global Impressions Scale), parent-administered scales (the Abbreviated Conners Rating Scale), and self-administered-scales for the evaluation of depressive (Children's Depression Inventory) and anxiety (the Revised Children's Manifest Anxiety Scale) symptoms. Reboxetine was initiated and maintained at a dose of 4 mg/day. RESULTS: A significant decrease in ADHD symptoms, on all scales measured, was noted. Adverse effects were relatively mild and transient. The most common adverse effects were drowsiness/sedation and gastrointestinal complaints. CONCLUSIONS: The results of the current open-label study suggest the effectiveness of reboxetine in the treatment of ADHD in methylphenidate-resistant children and adolescents. Double-blind, placebo-, and active comparator-controlled studies are indicated to rigorously test the efficacy of reboxetine in ADHD. /Not approved for use in the US/
Reboxetine, a potent and selective noradrenaline reuptake inhibitor, has been approved for treatment of major depression. The aim of this study was to investigate the efficacy and tolerability of reboxetine in depressive outpatients undergoing treatment in routine clinical practice. STUDY DESIGN AND METHODS: This post-marketing surveillance study was conducted to evaluate the therapeutic efficacy and tolerability of standard therapeutic doses of reboxetine in patients with depressive symptoms, particularly when administered in routine clinical practice. The 1835 patients (mean 54 years of age) evaluated showed demographic characteristics representative of the general depressive population. The majority of patients received the recommended dose of reboxetine 8 mg/day. Measures of efficacy showed improvement in depressive symptoms with reboxetine therapy over the mean observational period of 9.6 weeks. Response to therapy, defined as Hamilton depression scale 21-item version score reduction of greater or equal to 50%, was reported in 83% of patients. The effects of reboxetine were rated by physicians as 'good' or 'very good' in 86% of patients at the last visit. The tolerability of reboxetine was rated by physicians as 'good' or 'very good' in 92% of patients at all evaluations. No adverse events that were possibly related to reboxetine therapy occurred in greater than 1% of patients. The results of this study suggest that reboxetine is safe and well tolerated and may improve symptoms in depressive patients treated in routine clinical practice. /Not approved for use in the US/
/EXPL/ Although several approaches have been attempted for cocaine dependence, the pharmacological treatment of this serious disorder remains unclear. To date, desipramine, a tricyclic antidepressant of great noradrenergic activity, has shown the best results. Reboxetine, a selective noradrenaline reuptake inhibitor, might be an effective therapeutic option for this severe drug addiction. The aim was preliminarily to assess reboxetine in a group of cocaine-dependent patients ... Twenty six patients with a diagnosis of cocaine dependence disorder (DSM-IV 304.20) were selected to receive open treatment with reboxetine, 8 mg/day, for 12 weeks. Follow up assessments comprised cocaine consumption, treatment retention rate and change in standard structured psychometric instrument scores: cocaine selective severity assessment, Hamilton anxiety scale, Hamilton depression scale and clinical global impression, throughout the treatment period. Data were obtained from 20 patients; 10 of them remained abstinent, whereas the other 10 consumed cocaine at some time during the study. The treatment retention rate at week 12 was 61.5%. The psychometric instrument mean scores showed marked decreases throughout the treatment period. Reboxetine might be an effective and safe therapeutic option for cocaine dependence disorder. The aversive effects, as well as the high blockage reported by some patients consuming cocaine during the trial, might be related to treatment.
Reboxetine is indicated for the acute treatment of depressive illness/major depression and for maintaining the clinical improvement in patients initially responding to treatment. /Not approved for use in the US/

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Drug Warnings
Reboxetine should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviors (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behavior and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioral development are lacking.
Elderly patients have been studied in clinical trials at doses of 2 mg twice a day. However, safety and efficacy have not been evaluated in placebo-controlled conditions. Therefore, as for other antidepressants that have not been studied in placebo-controlled conditions, reboxetine cannot be recommended.
As reboxetine has not been tested in patients with convulsive disorders in clinical studies and since rare cases of seizures have been reported in clinical studies, it should be given under close supervision to subjects with a history of convulsive disorders and it must be discontinued if the patient develops seizures.
As with all antidepressants, switches to mania/hypomania have occurred during the clinical studies. Close supervision of bipolar patients is, therefore, recommended.
For more Drug Warnings (Complete) data for REBOXETINE (13 total), please visit the HSDB record page.

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Pharmacodynamics
Reboxetine is a selective noradrenaline reuptake inhibitor (NaRI), the first drug of new antidepressant class. Reboxetine is an a-ariloxybenzyl derivative of morpholine. Reboxetine is primarily used to treat depression but has also been found useful in the treatment of narcolepsy and panic disorders.

C19H24NO3+

314.39876

313.167

71620-89-8

Reboxetine mesylate;98769-84-7;Reboxetine-d5 mesylate;1285918-53-7

127151

Typically exists as solid at room temperature

1.1±0.1 g/cm3

443.7±30.0 °C at 760 mmHg

141-143ºC

188.2±14.0 °C

0.0±1.1 mmHg at 25°C

1.553

2.82

1

4

6

23

333

2

O([C@@H]([C@H]1CNCCO1)c1ccccc1)c1c(OCC)cccc1

CBQGYUDMJHNJBX-RTBURBONSA-N

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

(2R)-2-[(R)-(2-ethoxyphenoxy)-phenylmethyl]morpholine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)