Absorption, Distribution and Excretion
Following oral administration, reboxetine is rapidly and extensively absorbed. Multiple blood and breast milk samples were collected from four women taking reboxetine for postpartum depression over steady-state dosing intervals. Plasma and breast milk concentrations were determined using high-performance liquid chromatography (HPLC), and the milk/plasma ratio (M/P), infant absolute dose, and relative dose were estimated using standard methods. Simultaneously, four breastfed infants underwent clinical examinations, and blood samples were collected for drug analysis. The median dose (range) administered to these women was 6 (4–10) mg/day. There were no significant differences in reboxetine concentrations between paired foremilk and hindmilk samples. The mean (95% CI) M/P was 0.06 (0.03, 0.09). The infant absolute dose of reboxetine was 1.7 (0.7, 2.4) μg/kg/day, and the relative dose was 2.0% (1.3, 2.7%). …The plasma concentrations of reboxetine in four infants were <4 μg/L, 2.6 μg/L, 2.3 μg/L, and 5 μg/L, respectively. Reboxetine is known to be excreted into breast milk. The drug appears to be distributed throughout the body's water system. The plasma protein binding rates of reboxetine in young and elderly individuals were 97% and 92%, respectively (with a significantly higher affinity for α1 acid glycoprotein than albumin), and these rates were not significantly correlated with drug concentration. In healthy volunteers, after a single oral dose of 4 mg reboxetine, the peak plasma concentration was approximately 130 ng/mL within 2 hours. Data showed an absolute bioavailability of at least 60%. Reboxetine plasma concentrations exhibit a single exponential decline, with a half-life of approximately 13 hours. Steady-state is reached within 5 days. Within the clinically recommended dose range, the pharmacokinetics are linear within the single oral dose range.
For more complete data on absorption, distribution, and excretion of reboxetine (6 items), please visit the HSDB record page.

---

Metabolism/Metabolites
Reboxetine is metabolized via dealkylation, hydroxylation, and oxidation, followed by binding to glucuronic acid or sulfate. It is metabolized by cytochrome P450 CYP isoenzyme 3A4.
This study aimed to compare the distribution and metabolic patterns of reboxetine in several species, including humans. (14)C-Reboxetine was administered orally to rats, dogs, monkeys (5 mg/kg), and humans (2 and 4 mg/kg). The radioactive material was excreted primarily via the kidneys and feces in rats and dogs, and primarily via urine in monkeys and humans. Reboxetine is extensively metabolized. A variety of urinary metabolites were quantitatively analyzed using radio-HPLC and preliminarily identified by comparison of retention times with reference compounds. The hypothesized metabolic pathways include: 2-O-dealkylation; hydroxylation of the ethoxyphenoxy ring; oxidation of the morpholine ring; ring-opening of the morpholine ring; and combinations of these pathways. The metabolite is partially or completely bound to glucuronic acid and/or sulfate. Reboxetine is primarily metabolized in vitro via cytochrome P450 3A (CYP3A4). In vitro studies have shown that reboxetine does not inhibit the activity of the following cytochrome P450 isoenzymes: CYP1A2, CYP2C9, CYP2C19, and CYP2E1. Reboxetine has weak inhibitory activity against CYP2D6 and CYP3A4, but has no effect on the in vivo clearance of drugs metabolized by these enzymes. Reboxetine should be used with caution in combination with potent CYP3A4 inhibitors.

---

Biological half-life
12.5 hours
In healthy volunteers, after a single oral dose of 4 mg reboxetine, plasma reboxetine concentrations showed a single exponential decrease, with a half-life of approximately 13 hours.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Reboxetine has not been approved for marketing by the U.S. Food and Drug Administration (FDA), but it is available in other countries. Limited information suggests that even with daily doses up to 10 mg, low concentrations of the drug in breast milk do not appear to have any adverse effects on breastfed infants. Breastfeeding women should be closely monitored for reboxetine use until more data become available.
◉ Effects on Breastfed Infants
Four infants whose mothers had postpartum depression were breastfed for 1.3 to 2.1 months (feeding duration not specified) while their mothers were receiving reboxetine treatment (mean daily dose of 6.5 mg (79 mcg/kg)). One mother was also taking 20 mg of escitalopram daily, and another was taking 300 mg of sertraline daily. No adverse reactions were observed in any of the infants. Three of the infants had normal Denver developmental scores; the fourth infant, whose mother was taking reboxetine, had a developmental age of only 71% of normal, but this problem existed before the mother started taking reboxetine. Five women took reboxetine during pregnancy and lactation (time of use not specified), at unknown dosages. Their infants experienced no adverse reactions and all developmental milestones were normal. ◉ Effects on Lactation and Breast Milk Reboxetine increases serum prolactin levels in male subjects. The significance of this finding for lactating mothers is unclear. For mothers who have established lactation, prolactin levels may not affect their ability to breastfeed. An observational study investigated the outcomes of 2,859 women who took antidepressants for two years prior to pregnancy. Compared to women who did not take antidepressants during pregnancy, mothers who took antidepressants during all three stages of pregnancy were 37% less likely to breastfeed at discharge. Mothers who took antidepressants only in the third trimester were 75% less likely to breastfeed at discharge. Mothers who took antidepressants only in the first and second trimesters were not less likely to breastfeed at discharge. The study did not specify the type of antidepressant used by the mothers. A retrospective cohort study analyzed hospital electronic medical records from 2001 to 2008, comparing women who took antidepressants in late pregnancy (n = 575), women with mental illness but not taking antidepressants (n = 1552), and mothers not diagnosed with mental illness (n = 30,535). Women treated with antidepressants were 37% less likely to breastfeed at discharge than women not diagnosed with mental illness, but there was no difference in the likelihood of breastfeeding compared to untreated mothers diagnosed with mental illness. None of the mothers were taking reboxetine. A study of 80,882 Norwegian mother-infant pairs between 1999 and 2008 showed that 392 women reported starting antidepressants postpartum, and 201 women reported starting antidepressants during pregnancy. Compared to the control group unexposed to antidepressants, use of antidepressants in late pregnancy was associated with a 7% lower likelihood of initiating breastfeeding, but had no effect on the duration of breastfeeding or the rate of exclusive breastfeeding. Compared to the control group unexposed to antidepressants, new use or restart of antidepressants was associated with a 63% lower likelihood of primary breastfeeding at 6 months, a 51% lower likelihood of any breastfeeding, and a 2.6-fold increased risk of abrupt cessation of breastfeeding. No specific antidepressant was mentioned.

---

Protein binding rate
98%Drug interactions
In vitro metabolism studies have shown that reboxetine is primarily metabolized by the CYP3A4 isoenzyme of cytochrome P450; reboxetine is not metabolized by CYP2D6. Therefore, potent CYP3A4 inhibitors (ketoconazole, nefazodone, erythromycin, and fluvoxamine) are expected to increase plasma concentrations of reboxetine. A study in healthy volunteers found that the potent CYP3A4 inhibitor ketoconazole increased the plasma concentration of reboxetine enantiomers by approximately 50%. Due to the narrow therapeutic window of reboxetine, inhibiting its elimination is a major concern. Therefore, reboxetine should not be used concomitantly with drugs known to inhibit CYP3A4, such as azole antifungals, macrolide antibiotics like erythromycin, or fluvoxamine. Given the mechanisms of action of monoamine oxidase inhibitors and reboxetine, there may be a potential risk (tyramine-like effect), therefore concomitant use should be avoided. Although there are currently no clinical data, concomitant use with potassium-depleting diuretics should be considered as a potential cause of hypokalemia. Concomitant use with ergot derivatives may lead to increased blood pressure. One study investigated the interaction between ketoconazole and reboxetine enantiomers in 11 healthy volunteers (aged 18–47 years). Subjects received 4 mg of reboxetine orally on the second day of a 5-day ketoconazole 200 mg/day regimen, or 4 mg of reboxetine alone. A crossover design was used. Results showed that ketoconazole increased the mean plasma concentration-time area under the curve (AUC) of R,R-(-)-reboxetine and S,S-(+)-reboxetine by 58% and 43%, respectively. Subsequently, the oral clearance of the two enantiomers decreased by 34% and 24%, respectively. Ketoconazole had no significant effect on maximum plasma concentrations. Compared with reboxetine alone, ketoconazole administration significantly prolonged the mean terminal half-life of the drug. Ketoconazole administration reduced the AUC ratio of R,R-(-)-reboxetine to S,S-(+)-reboxetine.

[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 used to treat clinical depression, panic disorder, and attention deficit hyperactivity disorder (ADHD). Its mesylate (i.e., methylsulfonate) is marketed under several brand names, including Edronax, Norebox, Prolift, Solvex, Davedax, and Vestra. Reboxetine has two chiral centers but exists only in two enantiomers: (R,R)-(-)- and (S,S)-(+)-reboxetine. It is a morpholine derivative and a selective and potent norepinephrine reuptake inhibitor; used to treat depression. Drug Indications For the treatment of clinical depression. Mechanism of Action Reboxetine is a selective norepinephrine reuptake inhibitor. Reboxetine inhibits norepinephrine reuptake to a similar degree in vitro as the tricyclic antidepressant desipramine. Reboxetine does not affect the reuptake of dopamine or serotonin and has low affinity for adrenergic, cholinergic, histamine, dopaminergic, and serotonergic receptors both in vivo and in vitro. Reboxetine is a highly selective and potent norepinephrine reuptake inhibitor. It has a weak effect on serotonin reuptake and does not affect dopamine uptake. Norepinephrine reuptake inhibition and the resulting increase in synaptic cleft norepinephrine availability and alterations in norepinephrine transmission have been reported as one of the most relevant mechanisms of action of known antidepressants.
Therapeutic Use
This open-label study evaluated the efficacy of the selective norepinephrine reuptake inhibitor reboxetine in children and adolescents with attention deficit hyperactivity disorder (ADHD) who were unresponsive to prior methylphenidate therapy. Thirty-one outpatients with ADHD aged 8 to 18 years (mean age 11.7 years; standard deviation = 2.87 years) participated in a 6-week open-label study. Assessment methods included: rating scales administered by raters (DSM-IV ADHD scale; Clinical Global Impression Scale), scales administered by parents (Short Connors Rating Scale), and patient-reported scales for assessing depressive symptoms (Childhood Depression Scale) and anxiety symptoms (Revised Childhood Overt Anxiety Scale). The starting and maintenance dose of reboxetine was 4 mg/day. Results: All assessment scales showed significant reduction in ADHD symptoms. Adverse reactions were relatively mild and transient. The most common adverse reactions were somnolence/sedation and gastrointestinal discomfort. Conclusion: The results of this open-label study indicate that reboxetine is effective in treating ADHD in children and adolescents resistant to methylphenidate. Double-blind, placebo-controlled, and active-controlled studies are needed to rigorously examine the efficacy of reboxetine in treating attention deficit hyperactivity disorder (ADHD). /Not approved in the US/
Reboxetine is a potent and selective norepinephrine reuptake inhibitor approved for the treatment of major depressive disorder. This study aims to investigate the efficacy and tolerability of reboxetine in outpatients with depression in routine clinical practice. Study Design and Methods: This postmarketing surveillance study aimed to evaluate the efficacy and tolerability of standard-dose reboxetine in patients with depressive symptoms, particularly in routine clinical practice. The demographic characteristics of the 1835 patients evaluated (mean age 54 years) were representative of the depressive population. Most patients received the recommended dose of reboxetine, 8 mg daily. Efficacy endpoints showed that reboxetine treatment improved depressive symptoms over a mean observation period of 9.6 weeks. Treatment response was defined as a ≥50% reduction in the Hamilton Depression Rating Scale 21-item score, and 83% of patients reported a response. At the last visit, 86% of patients were rated as having “good” or “very good” efficacy with reboxetine by their physicians. In all assessments, 92% of patients were rated as having “good” or “very good” tolerability with reboxetine by their physicians. No adverse events possibly related to reboxetine treatment occurred in more than 1% of cases. These results suggest that reboxetine is safe and well-tolerated and may improve symptoms in patients with depression in routine clinical practice. /Not approved for use in the US/
/EXPL/ Although various approaches have been explored to treat cocaine dependence, the pharmacological treatment for this serious condition remains unclear. To date, desipramine (a tricyclic antidepressant with strong norepinephrine activity) has shown the best efficacy. Reboxetine, a selective norepinephrine reuptake inhibitor, may be an effective option for treating severe drug addiction. This study aimed to preliminarily evaluate the efficacy of reboxetin in patients with cocaine dependence… 26 patients diagnosed with cocaine dependence (DSM-IV 304.20) received 12 weeks of open-label treatment with reboxetin (8 mg/day). Follow-up assessments included cocaine consumption, treatment maintenance rate, and changes in scores on standard structured psychometric tools, including the Cocaine Selective Severity Assessment, Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, and Clinical Global Impression. Data were collected from 20 patients; 10 remained abstinent, while the other 10 used cocaine during the study period. The treatment maintenance rate at week 12 was 61.5%. Mean scores on psychometric tools decreased significantly throughout the treatment period. Reboxetin may be an effective and safe option for treating cocaine dependence. Adverse events and the high rate of block reported by some patients after cocaine use during the trial may be related to treatment.
Reboxetine is indicated for the treatment of acute depression/major depressive disorder and for maintaining clinical improvement in patients who have responded to initial treatment. /Not approved for use in the United States/

---

Drug Warnings
Reboxetine should not be used to treat children and adolescents under the age of 18. In clinical trials, children and adolescents receiving antidepressants were more likely to experience suicide-related behaviors (suicide attempts and suicidal ideation) and hostility (primarily manifested as aggression, confrontational behavior, and anger) compared to the placebo group. If treatment is still decided based on clinical need, patients should be closely monitored for suicidal symptoms. Furthermore, data on the safety of long-term use of reboxetine in children and adolescents regarding growth, maturation, and cognitive and behavioral development are lacking.
Dose studies of 2 mg twice daily in elderly patients have been conducted in clinical trials. However, its safety and efficacy have not been evaluated in a placebo-controlled setting. Therefore, as with other antidepressants not studied in a placebo-controlled setting, reboxetine is not recommended.
Because reboxetine has not been clinically studied in patients with seizure disorders, and rare cases of seizures have been reported in clinical studies, reboxetine should be used under close monitoring in subjects with a history of seizure disorders, and the drug must be discontinued if a seizure occurs.
As with all antidepressants, manic/hypomanic transitions have occurred during clinical studies. Therefore, close monitoring is recommended for patients with bipolar disorder.
For more complete data on drug warnings for reboxetine (13 in total), please visit the HSDB record page.

---

Pharmacodynamics
Reboxetine is a selective norepinephrine reuptake inhibitor (NaRI) and is the first novel antidepressant. Reboxetine is an α-aryloxybenzyl derivative of morpholine. Reboxetine is primarily used to treat depression, but has also been found to be effective in treating narcolepsy and panic disorder.

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.

---

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).

View More

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)

---

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).

View More

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

---

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.

---

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