Product Description
Alprazolam (Aloram 2mg) /ælˈpræzəlæm/ (trade name Xanax, available among other generic names) is a short-acting anxiolytic of the benzodiazepine class of psychoactive drugs. Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA gamma-amino-butyric acid receptor. Alprazolam is commonly used and FDA approved for the medical treatment of panic disorder, and anxiety disorders, such as generalized anxiety disorder (GAD) or social anxiety disorder (SAD). Alprazolam is available for oral administration in compressed tablet (CT) and extended-release capsule (XR) formulations. Alprazolam possesses anxiolytic, sedative, hypnotic, skeletal muscle relaxant, anticonvulsant, and amnestic properties.
Alprazolam has a fast onset of action and symptomatic relief. Ninety percent of peak benefits are achieved within the first hour (although onset may begin at 8-25 minutes of ingestion) of using either preparation for panic disorder, and full peak benefits are achieved in 1.5 and 1.6 hours respectively. Peak benefits achieved for generalized anxiety disorder (GAD) may take up to a week.Tolerance to the anxiolytic/antipanic effects is controversial with some authoritative sources reporting the development of tolerance and others reporting no development of tolerance tolerance will however, develop to the sedative effects within a couple of days. Withdrawal symptoms or rebound symptoms may occur after ceasing treatment abruptly following a few weeks or longer of steady dosing, and may necessitate a gradual dose reduction.
Alprazolam is the most prescribed and the most misused benzodiazepine on the U.S. retail market. The potential for abuse among those taking it for medical reasons is controversial with some expert reviews stating that the risk is low and similar to that of other benzodiazepine drugs and others stating that there is a substantial risk of abuse and dependence in both patients and non-medical users of alprazolam and that the pharmacological properties of alprazolam, high affinity binding, high potency, having a short elimination half-life as well as a rapid onset of action increase the abuse potential of alprazolam. Compared to the large number of prescriptions, relatively few individuals increase their dose on their own initiative or engage in drug-seeking behavior.Alprazolam is classified as a schedule IV controlled substance by the U.S. Drug Enforcement Administration (DEA).
Medical uses:
Alprazolam is mostly used to treat anxiety disorders, panic disorders, and nausea due to chemotherapy. The FDA label advises that the physician should periodically reassess the usefulness of the drug.
Panic disorder:
Alprazolam is effective in the relief of moderate to severe anxiety and panic attacks.It however is not a first line treatment, since the development of selective serotonin reuptake inhibitors, and alprazolam is no longer recommended for the treatment of panic disorder (in Australia) due to concerns regarding tolerance, dependence and abuse.Evidence supporting the effectiveness of alprazolam in treating panic disorder has been limited to 4 to 10 weeks. However, people with panic disorder have been treated on an open basis for up to 8 months without apparent loss of benefit.
In the US alprazolam is FDA-approved for the treatment of panic disorder with or without agoraphobia.[4] Alprazolam is recommended by the World Federation of Societies of Biological Psychiatry (WFSBP) for treatment-resistant cases of panic disorder where there is no history of tolerance or dependence, as of 2002.
Anxiety disorders:
In the US alprazolam is FDA-approved for the management of anxiety disorders (a condition corresponding most closely to the APA Diagnostic and Statistical Manual DSM-III-R diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. Anxiety associated with depression is responsive to alprazolam. Demonstrations of the effectiveness by systematic clinical study are limited to 4 months duration for anxiety disorder.[4] However, the research into antidepressant properties of alprazolam is of poor quality and only assessed the short-term effects of alprazolam against depression.[19] In one study, some long term, high-dosage users of alprazolam developed reversible depression.[20] In the UK, alprazolam is recommended for the short-term treatment (2–4 weeks) of severe acute anxiety.
Nausea due to chemotherapy:
Alprazolam may be used in combination with other medications for chemotherapy-induced nausea and vomiting.
Pregnancy and lactation:
Benzodiazepines cross the placenta, enter into the fetus and are also excreted with breast milk. The use of benzodiazepines during pregnancy or lactation has potential risks. The use of alprazolam in pregnancy is believed to be associated with congenital abnormalities. Diazepam and chlordiazepoxide have a better safety profile in pregnancy than alprazolam.
Women who are pregnant or are planning on becoming pregnant should avoid starting alprazolam. Use in the last trimester may cause fetal drug dependence and withdrawal symptoms in the post-natal period as well as neonatal flaccidity and respiratory problems. However, in long-term users of benzodiazepines abrupt discontinuation due to concerns of teratogenesis has a high risk of causing extreme withdrawal symptoms and a severe rebound effect of the underlying mental health disorder. Spontaneous abortions may also result from abrupt withdrawal of psychotropic medications including benzodiazepines.
Benzodiazepines, including alprazolam, are known to be excreted in human milk. Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight.
Contraindications:
Benzodiazepines require special precaution if used in children and in alcohol- or drug-dependent individuals. Particular care should be taken in pregnant or elderly patients, patients with substance abuse history, particularly alcohol dependence and patients with comorbid psychiatric disorders. Use of alprazolam should be avoided or carefully monitored by medical professionals in individuals with the following conditions: myasthenia gravis, acute narrow-angle glaucoma, severe liver deficiencies (e.g., cirrhosis), severe sleep apnea, pre-existing respiratory depression, marked neuromuscular respiratory weakness including unstable myasthenia gravis, acute pulmonary insufficiency, chronic psychosis, hypersensitivity or allergy to alprazolam or other drugs in the benzodiazepine class, borderline personality disorder (may induce suicidality and dyscontrol).
Like all central nervous system depressants, including alcohol, alprazolam in larger-than-normal doses can cause significant deterioration in alertness, combined with increased feelings of drowsiness, especially in those unaccustomed to the drug's effects. People driving or conducting activities that require vigilance should exercise caution in using alprazolam or any other depressant.
Elderly individuals should be cautious in the use of alprazolam due to the possibility of increased susceptibility to side-effects, especially loss of coordination and drowsiness.
Adverse effects:
Xanax (alprazolam) 2 mg tri-score tablets
Allergic reactions are unlikely to occur. The only common side effect is sleepiness when treatment is initiated.
Possible side effects include:
Disinhibition
Change in libido
Jaundice (very rare)
Hallucinations (rare)
Dry mouth (infrequent)
Ataxia, slurred speech
Suicidal ideation (rare)
Urinary retention (infrequent)
Skin rash, respiratory depression, constipation
Anterograde amnesia and concentration problems
Drowsiness, dizziness, lightheadedness, fatigue, unsteadiness and impaired coordination, vertigo
Paradoxical reactions
Although unusual, the following paradoxical reactions have been shown to occur:
Aggression
Rage, hostility
Twitches and tremor
Mania, agitation, hyperactivity and restlessness
Food and drug interactions
Alprazolam is primarily metabolised via CYP3A4. Combining CYP3A4 inhibitors such as cimetidine, erythromycin, fluoxetine, fluvoxamine, itraconazole, ketoconazole, nefazodone, propoxyphene, and ritonavir delay the hepatic clearance of alprazolam, which may result in excessive accumulation of alprazolam. This may result in exacerbation of its adverse effect profile.
Imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of alprazolam tablets in doses up to 4 mg/day. Combined oral contraceptive pills reduce the clearance of alprazolam, which may lead to increased plasma levels of alprazolam and accumulation.
Alcohol is one of the most important and common interactions. Alcohol and benzodiazepines such as alprazolam taken in combination have a synergistic effect on one another, which can cause severe sedation, behavioral changes, and intoxication. The more alcohol and alprazolam taken the worse the interaction.Combination of alprazolam with the herb kava can result in the development of a semi-comatose state.[58] Hypericum conversely can lower the plasma levels of alprazolam and reduce its therapeutic effect
Overdose:
Xanax 0.25, 0.5 and 1 mg scored tablets
Main article:
Benzodiazepine overdose
Overdoses of alprazolam can be mild to severe depending on how much of the drug is taken and any other drugs that have been taken.
Alprazolam overdoses cause excess central nervous system (CNS) depression and may include one or more of the following symptoms
Somnolence (sleepy state)Hypotension (low blood pressure)Hypoventilation (shallow breathing)Impaired motor functions DizzinessImpaired balanceMuscle weaknessImpaired or absent reflexes
FaintingComaDeath (very rare):
In a study of deaths in Palm Beach County where the drug alprazolam was detected, approx. 50% of cases were attributed to poly-drug use (the combined toxicity of two or more drugs). The majority of these cases included either cocaine or methadone. Alprazolam alone caused only 1% of the deaths. These results indicate alprazolam has a very low incidence of causing death when taken alone.[63]
Dependence and withdrawal:
Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA gamma-amino-butyric acid receptor. When bound to these sites, which are referred to as benzodiazepine receptors, it modulates the effect of GABA A receptors and, thus, GABAergic neurons. Long-term use causes adaptive changes in the benzodiazepine receptors, making them less sensitive to stimulation and less powerful in their effects.
Withdrawal and rebound symptoms occur commonly and necessitate a gradual reduction in dosage to minimize withdrawal effects when discontinuing.
Not all withdrawal effects are evidence of true dependence or withdrawal. Recurrence of symptoms such as anxiety may simply indicate that the drug was having its expected anti-anxiety effect and that, in the absence of the drug, the symptom has returned to pretreatment levels. If the symptoms are more severe or frequent, the patient may be experiencing a rebound effect due to the removal of the drug. Either of these can occur without the patient's actually being drug-dependent.
Alprazolam and other benzodiazepines may also cause the development of physical dependence, tolerance, and benzodiazepine withdrawal symptoms during rapid dose reduction or cessation of therapy after long-term treatment. There is a higher chance of withdrawal reactions if the drug is administered in a higher dosage than recommended, or if a patient stops taking the medication altogether without slowly allowing the body to adjust to a lower-dosage regimen.
Some common symptoms of alprazolam discontinuation include malaise, weakness, insomnia, tachycardia, lightheadedness, and dizziness.
Patients taking a dosing regimen larger than 4 mg per day have an increased potential for dependence. This medication may cause withdrawal symptoms upon abrupt withdrawal or rapid tapering, which in some cases have been known to cause seizures. The discontinuation of this medication may also cause a reaction called rebound anxiety.
Delirium and seizures have been anecdotally reported in the medical literature from abrupt alprazolam discontinuation.
The benzodiazepines diazepam (Valium) and oxazepam (Serepax) have been found to produce fewer withdrawal reactions than alprazolam (Xanax), temazepam (Restoril/Normison), or lorazepam (Temesta/Ativan). Factors that determine the risk of psychological dependence or physical dependence and the severity of the benzodiazepine withdrawal symptoms experienced during dose reduction of alprazolam include: dosage used, length of use, frequency of dosing, personality characteristics of the individual, previous use of cross-dependent/cross-tolerant drugs (alcohol or other sedative-hypnotic drugs), current use of cross-dependent/-tolerant drugs, use of other short-acting, high-potency benzodiazepines, and method of discontinuation.
Pharmacology:
Alprazolam is classed as a high-potency benzodiazepine and is a triazolobenzodiazepine, namely a benzodiazepine with a triazole ring attached to its structure. Benzodiazepines produce a variety of therapeutic and adverse effects by binding to the benzodiazepine receptor site on the GABAA receptor and modulating the function of the GABA receptor, the most prolific inhibitory receptor within the brain. The GABA chemical and receptor system mediates inhibitory or calming effects of alprazolam on the nervous system. The GABAA receptor is made up of 5 subunits out of a possible 19, and GABAA receptors made up of different combinations of subunits have different properties, different locations within the brain, and, importantly, different activities with regard to benzodiazepines. Benzodiazepines and in particular alprazolam causes a marked suppression of the hypothalamicpituitary-adrenal axis. The therapeutic properties of alprazolam are similar to other benzodiazepines and include anxiolytic, anticonvulsant, muscle relaxant, hypnotic and amnesic.
Pharmacokinetics:
Absorption:
Following oral administration, alprazolam is readily absorbed. Peak concentrations in the plasma occur in one to two hours following administration. Plasma levels are proportionate to the dose given; over the dose range of 0.5 to 3.0 mg, peak levels of 8.0 to 37 ng/mL were observed. Using a specific assay methodology, the mean plasma elimination half-life of alprazolam has been found to be about 11.2 hours (range: 6.3 to 26.9 hours) in healthy adults.
Metabolism/Elimination:
Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (Cyp3A4), to two major metabolites in plasma: 4-hydroxyalprazolam and α- hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans. Theirs half-lives appear to be similar to that of alprazolam. The plasma concentrations of 4-hydroxyalprazolam and α-hydroxyalprazolam relative to unchanged alprazolam coincentration were always less than 4%. The reported relative potencies in benzodiazepines receptor binding experiments and in animals models of induced seizure inhibition are 0.2 and 0.66, respectively, for 4-hydroxyalprazolam and α-hydroxyalprazolam. Such low concentrations and lesser potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam suggest that they are unlikely to contribute much to the pharmacological effects of alprazolam. The benzophenone metabolite is essentially inactive.
Alprazolam and its metabolites are excreted primarily in the urine.
