Reboxetine

313.39

313.39

39.72000

3.52260

170-171°

8 mg/mL (Mesylate salt)

Do not store above 25 °C.

1.23X10-7 mm Hg at 25 °C (est)

Henry's Law constant = 4.2X10-12 atm-cu m/mol at 25 °C (est)

pKa = 7.1 (amine) (est)

Hydroxyl radical reaction rate constant = 1.73X10-10 cu-cm/molecule-sec at 25 °C (est)

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

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.

Elderly might be particularly vulnerable to overdose.

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.

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/

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.

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.

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.

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.

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.

In case of overdose, monitoring of cardiac function and vital signs is recommended. General symptomatic supportive ... might be required.|/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/SIGNS AND SYMPTOMS/ In a few cases doses higher than those recommended were administered to patients (12 mg to 20 mg/day) for a period ranging from a few days to some weeks during clinical studies: newly reported complaints include postural hypotension, anxiety and hypertension. Elderly might be particularly vulnerable to overdose.|/CASE REPORTS/ A case of significant weight loss experienced by a 44-year-old Caucasian woman treated with reboxetine /was reported/. She was treated with this drug at 12 mg daily for a total duration of 11 months. During the corresponding period her body mass index (BMI) decreased from a baseline of 21.4 kg m(-2) to a low of 16.8 kg m(-2). Withdrawal of the drug led to a full recovery of her BMI. The strongest evidence linking reboxetine to this woman's weight loss laid in the fact that the re-introduction of the drug subsequently caused a similar negative impact in her BMI.|/CASE REPORTS/ A 44 year old male who had been suffering from depression without any sexual dysfunction was put on venlafaxine XR treatment. Due to delayed ejaculation and occasional episodes of absence of ejaculation he was switched to reboxetine. At the second week of treatment he reported erectile dysfunction and premature ejaculation, and seminal emission and ejaculation during defecation and micturition occurred later at 8th week of treatment. After he was switched to sertraline 50 mg/day, his erectile dysfunction, premature and spontaneous ejaculation symptoms subsided in 2 weeks. Although reboxetine is reported to be free of sexual side effects, individual vulnerabilities to such unwanted effects should be considered, and sexual dysfunction should be assessed thoroughly during the treatment.|/CASE REPORTS/ Hyponatremia is a well-known side effect of antidepressant treatment with serotonin reuptake inhibitors (SSRI) or combined serotonin and noradrenaline reuptake inhibitors (SNRI), and is linked to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in most cases. In contrast, only very few data are available on hyponatremia following treatment with selective noradrenalin reuptake inhibitors (NaRI). ... The case of a patient who developed severe hyponatremia after treatment with reboxetine /is reported/. However, extensive laboratory testing did not reveal inappropriate secretion of ADH, suggesting that SIADH did not account for hyponatremia in this case.

Oral: 4 mg tablets Edronax (Pharmacia Limited, United Kingdom)

Analyte: reboxetine; matrix: blood (plasma); procedure: reversed-phase high-performance liquid chromatography with fluorescence detection at 260 nm (excitation) and 315 nm (emission) and comparison to standards; limit of quantitation: 1 ng/mL|Analyte: reboxetine; matrix: blood (plasma); procedure: high-performance liquid chromatography with ultraviolet detection at 210 nm; limit of quantitation: 10 ng/mL