(R,R)-レボキセチン

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.

Reboxetine is a selective inhibitor of noradrenaline reuptake. It inhibits noradrenaline reuptake <i>in vitro</i> to a similar extent to the tricyclic antidepressant desmethylimipramine. Reboxetine does not affect dopamine or serotonin reuptake and it has low <i>in vivo</i> and <i>in vitro</i> affinity for adrenergic, cholinergic, histaminergic, dopaminergic and serotonergic receptors.

/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.

/LABORATORY ANIMALS: Acute Exposure/ The acute toxicity studies carried out in animals indicate a very low toxicity, with a wide safety margin with respect to the pharmacologically active doses. Clinical signs and cause of death were related to CNS stimulation (mainly convulsive symptoms).

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Studies in animals have not demonstrated any teratogenic effect or any effect of the compound on global reproductive performance. Dosages that produced plasma concentrations within the therapeutic range for humans induced an impairment of growth and development and long term behavioural changes in offspring of rats.

/GENOTOXICITY/ Reboxetine did not induce gene mutations in bacterial or mammalian cells in vitro but induced chromosomal aberrations in human lymphocytes in vitro. Reboxetine did not cause DNA damage in yeast cells or rat hepatocytes in vitro. Reboxetine did not cause chromosomal damage in an in vivo mouse micronucleus test, and did not increase tumor incidence in carcinogenecity studies in mice and rats.

/OTHER TOXICITY INFORMATION/ In vitro, studies have shown that reboxetine has no significant affinity for adrenergic (alpha1, alpha2, beta) and muscarinic receptors; antagonism of such receptors has been described to be associated with cardiovascular, anticholinergic and sedative side effects of other antidepressant drugs. Reboxetine is devoid of in vitro binding affinity for either a1 or a2 adrenoceptors, however, a functional interference with a-adrenoceptors at high doses in vivo cannot be excluded.

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/

Mood-stimulating drugs used primarily in the treatment of affective disorders and related conditions. Several MONOAMINE OXIDASE INHIBITORS are useful as antidepressants apparently as a long-term consequence of their modulation of catecholamine levels. The tricyclic compounds useful as antidepressive agents (ANTIDEPRESSIVE AGENTS, TRICYCLIC) also appear to act through brain catecholamine systems. A third group (ANTIDEPRESSIVE AGENTS, SECOND-GENERATION) is a diverse group of drugs including some that act specifically on serotonergic systems.

Drugs that block the transport of adrenergic transmitters into axon terminals or into storage vesicles within terminals. The tricyclic antidepressants (ANTIDEPRESSIVE AGENTS, TRICYCLIC) and amphetamines are among the therapeutically important drugs that may act via inhibition of adrenergic transport. Many of these drugs also block transport of serotonin.

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.