Xanax

XANAX® 

alprazolam tablets, USP

DESCRIPTION

Alprazolam is in XANAX Tablets. It is a triazolo analog of the 1,4 benzodiazepine class of compounds that affect the central nervous system. 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-] [1,4] benzodiazepine is the chemical name for alprazolam. Alprazolam is a white, crystalline powder that  dissolves in methanol or ethanol but not in water at a pH close to that of the body. Each XANAX Tablet, which is taken by mouth, has 0.25, 0.5, 1, or 2 mg of alprazolam in it.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Agents of the class 1,4 benzodiazepines that act on the central nervous system are thought to do their jobs by binding to stereo-specific receptors in different parts of the CNS. Their exact way of working is not known. In the clinic, all benzodiazepines cause a central nervous system depressant effect that depends on the dose and ranges from mild problems with doing tasks to hypnosis.

Pharmacokinetics

When alprazolam is taken by mouth, it is quickly absorbed into the body. Peak concentrations in the plasma happen between 1 and 2 hours after the drug is given. Plasma levels are related to the dose given; between 0.5 mg and 3 mg, peak levels ranged from 8 to 37 ng/mL. Using a specific assay method, the average half-life of alprazolam in the blood of healthy adults has been found to be 11.2 hours (range: 6.3–26.9 hours).

Distribution

In a lab, 80% of the alprazolam is bound to human serum protein. Most of the binding is done by albumin in the blood.

Metabolism/Elimination

Alprazolam is broken down in the body a lot, mostly by an enzyme called cytochrome P450 3A4 (CYP3A4). The main metabolites of alprazolam in the blood are 4-hydroxyalprazolam and -hydroxyalprazolam. People also have a benzophenone that comes from alprazolam.

Their half-lives look like they are the same as alprazolam's. The amount of 4­hydroxyalprazolam and -hydroxyalprazolam in the plasma compared to the amount of unchanged alprazolam was always less than 4%. In experiments where benzodiazepine receptors were bound and in animal models of induced seizure inhibition, the relative potencies of 4-hydroxyalprazolam and -hydroxyalprazolam were found to be 0.20 and 0.66, respectively. Because 4-hydroxyalprazolam and -hydroxyalprazolam are found in such low amounts and don't work as well as alprazolam, it's unlikely that they add much to its pharmacological effects. The metabolite of benzophenone doesn't do much. Alprazolam and its by products are mostly passed out of the body in the urine.

Special Populations

Changes in how benzodiazepines are absorbed, distributed, broken down, and passed out of the body have been linked to a number of diseases, such as alcoholism, liver disease, and kidney disease. Changes have also been seen in patients who are older. Alprazolam has a mean half-life of 16.3 hours in healthy elderly people (range: 9.0-26.9 hours, n=16), but only 11.0 hours in healthy adults (range: 6.3-15.8 hours, n=16). Alprazolam's half-life was between 5.8 and 65.3 hours (mean: 19.7 hours, n=17) in people with alcoholic liver disease. In healthy people, it was between 6.3 and 26.9 hours (mean: 11.4 hours, n=17). Alprazolam's half-life ranged from 9.9 to 40.4 hours (mean = 21.8 hours, n=12) in a group of obese people, but it ranged from 6.3 to 15.8 hours (mean = 10.6 hours, n=12) in a group of healthy people.

Alprazolam is thought to pass through the placenta and out of the body in human milk because it is similar to other benzodiazepines.

• Race: The maximum concentration of alprazolam and its half-life are about 15% and 25% higher in Asians than in Caucasians.
• Pediatrics: No research has been done on the pharmacokinetics of alprazolam in children.
• Gender: The way alprazolam works is the same for both men and women.
• Cigarette smoking: Compared to people who don't smoke, smokers may have up to 50% less alprazolam in their bodies than people who don't smoke.

Interactions Between Drugs

• Alprazolam is mostly broken down by the enzyme cytochrome P450 3A. (CYP3A). Most of the known interactions between alprazolam and other drugs are with those that stop or speed up CYP3A4.
• Compounds that strongly stop CYP3A from working should raise the amount of alprazolam in the blood. In vivo studies have shown that ketoconazole increases alprazolam AUC by 3.98 times, itraconazole by 2.70 times, nefazodone by 1.98 times, fluvoxamine by 1.96 times, and erythromycin by 1.61 times.
• Alprazolam levels should go down when CYP3A inducers are present, and this is what has been seen in real life. After 10 days of taking 300 mg/day of carbamazepine, the oral clearance of alprazolam (given as a single dose of 0.8 mg) went from 0.900.21 mL/min/kg to 2.130.54 mL/min/kg, and the elimination half-life went from 17.14.9 h to 7.71.7 h.. But the dose of carbamazepine used in this study was pretty low compared to the recommended doses (1000–1200 mg/day). It is not known what the effect is at the usual doses of carbamazepine.
• We don't yet know if alprazolam can trigger enzyme systems in the liver of humans. But this is not something that all benzodiazepines do. Also, giving sodium warfarin by mouth to male volunteers did not change the levels of prothrombin or plasma warfarin.

STUDIES IN CLINICS

In double-blind clinical studies (doses up to 4 mg/day), people with anxiety or anxiety with depressive symptoms were given either XANAX Tablets or a sugar pill (placebo). At each point of evaluation in these 4-week studies, XANAX was much better than placebo. 

Three short-term, placebo-controlled studies (up to 10 weeks) with people whose diagnoses were close to those in the DSM-III-R for panic disorder showed that XANAX is effective for treating panic disorder. In two of the studies, the average dose of XANAX was 5–6 mg/day, and in the third, the doses were fixed at 2–6 mg/day. In all three studies, XANAX was better than the placebo on a measure called "the number of patients with no panic attacks" (37–83%) and on a measure of overall improvement. In two of the three studies, XANAX was better than a placebo for a variable called "change from baseline on the number of panic attacks per week" (range: 3.3–5.2) and for a phobia rating scale. In one of these trials, XANAX was given to a small group of people who got better after short-term treatment, and they kept getting it for up to 8 months without losing any apparent benefit.

HOW AND WHEN TO USE

XANAX Tablets (alprazolam) are used to treat anxiety disorder (which is most similar to the diagnosis of generalized anxiety disorder in the APA Diagnostic and Statistical Manual [DSMIII-R]) or to relieve anxiety symptoms for a short time. Most of the time, you don't need an anxiolytic to treat anxiety or tension caused by the stress of everyday life. Generalized anxiety disorder is when a person has unrealistic or too much worry (apprehensive expectation) about two or more things in their life for at least 6 months, and these worries bother them more days than not. At least 6 of the 18 symptoms below are common in these people: Motor tension (shaking, trembling, or a shaky feeling; muscle tension, aches, or soreness; restlessness; getting tired easily); Autonomic Hyperactivity (shortness of breath or a feeling of suffocation; palpitations or a fast heart rate; sweating or cold, clammy hands; dry mouth; dizziness or lightheadedness; nausea, diarrhea, or other abdominal pain; flushes or chills; frequent urination; trouble swallowing or a "lump in the throat"); Vigilance and scanning (feeling tense or on edge; exaggerated startle response; trouble concentrating or "mind going blank" because of anxiety; trouble falling asleep or staying asleep; irritability). These symptoms can't be a result of another mental disorder or be caused by something in the body.

XANAX is also used to treat panic disorder, whether or not the person has agoraphobia.

Patients whose diagnoses were close to the DSM-III-R/IV criteria for panic disorder were used in studies that back up this claim (see CLINICAL STUDIES).

Panic disorder, as defined by the DSM-IV, is marked by unexpected panic attacks that happen over and over again. A panic attack is a short period of intense fear or discomfort in which four (or more) of the following symptoms appear suddenly and reach their peak within 10 minutes: (1) palpitations, pounding heart, or fast heart rate; (2) sweating; (3) trembling or shaking; (4) feelings of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of not being in the real world) or depersonalization (feeling disconnected from oneself); (10) fear of  losingSystematic clinical studies of XANAX's effectiveness have only been done for 4 months for anxiety disorders and 4 to 10 weeks for panic disorders. However, people with panic disorders have been treated for up to 8 months without seeming to lose any benefit. The doctor should look at how useful the drug is for each patient on a regular basis.