Xanor/Xanor XR Mechanism of Action

Pharmacologic Category: Anxiolytic.
Pharmacology: Pharmacodynamics: CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereo specific receptors at several sites within the central nervous system. Their exact mechanism of action is unknown. Clinically all benzodiazepines cause a dose-related central nervous system depressant activity varying from mild impairment of task performance to hypnosis.
Clinical Studies: Alprazolam (Xanor) tablets were compared to placebo in double blind clinical trials in patients with a diagnosis of anxiety or anxiety with associated depressive symptomatology. Alprazolam (Xanor) was significantly better than placebo at each of the evaluation periods of these four week studies as judged by the following psychometric instruments: Physician's Global Impressions, Hamilton Anxiety Rating Scale, Target Symptoms, Patient's Global Impressions and Self-Rating Symptom Scale.
Pharmacokinetics: Following oral administration, alprazolam is readily absorbed. Peak concentrations in the plasma occur in one to two hours following administration. Plasma levels are proportions to the dose given over the dose range of 0.5 to 3.0 mg. Peak levels of 8.0 to 37 mg/mL were observed. The mean elimination half-life of alprazolam is 12-15 hours. The predominant metabolites are α-hydroxy-alprazolam and a benzophenone derived from alprazolam. The biological activity of α-hydroxy-alprazolam is approximately one-half that of alprazolam. The benzophenone metabolites is essentially inactive. Plasma levels of these metabolites are extremely low, thus, precluding precise pharmacokinetic description. However, their half-lives appear to be of the same order of magnitude as alprazolam. Alprazolam and its metabolites are excreted primarily in the urine.
The ability of alprazolam to induce human hepatic enzyme systems has not yet been determined. However, this is not a property of benzodiazepines in general. Further, alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally.
In vitro, alprazolam is bound (80 percent) to human serum protein.
Changes in the absorption, distribution, metabolism and excretion of benzodiazepines have been reported in a variety of disease states including alcoholism, impaired hepatic function and impaired renal function changes have also been demonstrated in geriatric patients. It has not yet been determined if similar changes occur in the pharmacokinetics of alprazolam.
Because of its similarity to other benzodiazepines, it is assumed that alprazolam undergoes transplacental passage and is excreted in human milk.
Toxicology: Preclinical Safety Data: Mutagenesis: Alprazolam was not mutagenic in the in vitro Ames test. Alprazolam did not produce chromosomal aberrations in the in vivo micronucleus assay in rats up to the highest dose tested of 100 mg/kg, which is 500 times greater than the maximum recommended daily human dose of 10 mg/day.
Carcinogenesis: No evidence of carcinogenic potential was observed during 2-year bioassay studies of alprazolam in rats at doses up to 30 mg/kg/day (150 times the maximum recommended daily human dose of 10 mg/day) and in mice at doses up to 10 mg/kg/day (50 times the maximum recommended daily human dose of 10 mg/day).
Fertility: Alprazolam did not impair fertility in rats up to the highest dose tested of 5 mg/kg/day, which is 25 times the maximum recommended daily human dose of 10 mg/day.
Ocular Effects: When rats were treated orally with alprazolam at 3, 10, and 30 mg/kg/day (15 to 150 times the maximum recommended daily human dose of 10 mg/day) for 2 years, a tendency for a dose related increase in the number of cataracts (females) and corneal vascularization (males) was observed. These lesions did not appear until after 11 months of treatment.
Effect of anesthetic and sedative drugs: Nonclinical research has shown that administration of anesthetic and sedation drugs that block N-methyl-D-aspartate (NMDA) receptors and/or potentiate gamma-aminobutyric acid (GABA) activity can increase neuronal cell death in the brain and result in long term deficits in cognition and behavior of juvenile animals when administered during the period of peak brain development. Based on comparisons across nonclinical species, the window of vulnerability of the brain to these effects is believed to correlate with human exposures in the third trimester of pregnancy through the first year of life, but may extend to approximately 3 years of age. While there is limited information of this effect with alprazolam, since the mechanism of action includes potentiation of GABA activity, a similar effect may occur. The relevance of these nonclinical findings to human use is unknown.