Alprazolam (Page 5 of 7)

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Alprazolam is a Schedule IV controlled substance.

9.3 Dependence

Withdrawal symptoms similar in character to those noted with sedative/hypnotics and alcohol have occurred following discontinuance of benzodiazepines, including alprazolam. The symptoms can range from mild dysphoria and insomnia to a major syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors and convulsions. Distinguishing between withdrawal emergent signs and symptoms and the recurrence of illness is often difficult in patients undergoing dose reduction. The long term strategy for treatment of these phenomena will vary with their cause and the therapeutic goal. When necessary, immediate management of withdrawal symptoms requires re-institution of treatment at doses of alprazolam sufficient to suppress symptoms. There have been reports of failure of other benzodiazepines to fully suppress these withdrawal symptoms. These failures have been attributed to incomplete cross-tolerance but may also reflect the use of an inadequate dosing regimen of the substituted benzodiazepine or the effects of concomitant medications.

While it is difficult to distinguish withdrawal from recurrence of anxiety symptoms, the time course and the nature of the symptoms may be helpful. A withdrawal syndrome typically includes the occurrence of new symptoms, tends to appear toward the end of taper or shortly after discontinuation, and will decrease with time. In recurring panic disorder, symptoms similar to those observed before treatment may recur either early or late, and they will persist.

While the severity and incidence of withdrawal phenomena appear to be related to dose and duration of treatment, withdrawal symptoms, including seizures, have been reported after only brief therapy with alprazolam at doses within the recommended range for the treatment of anxiety (e.g., 0.75 mg to 4 mg per day). Signs and symptoms of withdrawal are often more prominent after rapid decrease of dosage or abrupt discontinuance. The risk of withdrawal seizures may be increased at doses above 4 mg per day [see Warnings and Precautions (5.4)].

Avoid abrupt discontinuation of alprazolam orally disintegrating tablets, especially in individuals with a history of seizures or epilepsy. It is recommended that all patients on alprazolam orally disintegrating tablets who require a dosage reduction be gradually tapered under close supervision [see Warnings and Precautions ( 5.4) and Dosage and Administration ( 2)].

Psychological dependence is a risk with all benzodiazepines, including alprazolam. The risk of psychological dependence may also be increased at doses greater than 4 mg per day and with longer term use, and this risk is further increased in patients with a history of alcohol or drug abuse. Some patients have experienced considerable difficulty in tapering and discontinuing from alprazolam orally disintegrating tablets, especially those receiving higher doses for extended periods. Addiction-prone individuals should be under careful surveillance when receiving alprazolam orally disintegrating tablets. As with all anxiolytics, repeat prescriptions should be limited to those who are under medical supervision.

10 OVERDOSAGE

10.1 Human Clinical Experience

Manifestations of alprazolam overdosage include somnolence, confusion, impaired coordination, diminished reflexes and coma. Death has been reported in association with overdoses of alprazolam by itself, as it has with other benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with a combination of a single benzodiazepine, including alprazolam, and alcohol; alcohol levels seen in some of these patients have been lower than those usually associated with alcohol-induced fatality.

10.2 Management of Overdose

For the most up to date information on management of alprazolam overdose, contact a certified poison center in your area (1-800-222-1222 or www.poison.org). In case of an overdose, provide supportive care, including close medical supervision and monitoring. Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures.

Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for re-sedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including CONTRAINDICATIONS, WARNINGS and PRECAUTIONS should be consulted prior to use.

11 DESCRIPTION

Alprazolam orally disintegrating tablets, USP contain alprazolam, USP which is a triazolo analog of the 1,4 benzodiazepine class of central nervous system-active compounds.

Alprazolam orally disintegrating tablets, USP are an orally administered formulation of alprazolam which rapidly disintegrates on the tongue and does not require water to aid dissolution or swallowing.

The chemical name of alprazolam is 8-Chloro-1-methyl-6-phenyl-4H-s -triazolo [4,3-α] [1,4] benzodiazepine. The molecular formula is C17 H13 CIN4 and the molecular weight is 308.76.

The structural formula is:

The structural formula of is alprazolam is 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-α] [1,4] benzodiazepine. The molecular formula is C17H13CIN4 and the molecular weight is 308.76.

Alprazolam is a white crystalline powder, which is soluble in methanol or ethanol but which has no appreciable solubility in water at physiological pH.

11.1 Alprazolam Orally Disintegrating Tablets

Each orally disintegrating tablet contains either 0.25 mg, 0.5 mg, 1 mg, or 2 mg of alprazolam, USP and the following inactive ingredients: corn starch, crospovidone, magnesium stearate, mannitol, methacrylic acid copolymer (type C), microcrystalline cellulose, natural and artificial orange flavor, polysorbate 80, sodium lauryl sulfate, sucralose. In addition, the 1 mg and 2 mg tablets contain ferric oxide (yellow 10 synthetic yellow iron oxide).

Product meets USP Dissolution Test 2.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The exact mechanism of action of alprazolam is unknown. Benzodiazepines bind to gamma aminobutyric acid (GABA) receptors in the brain and enhance GABA-mediated synaptic inhibition; such actions may be responsible for the efficacy of alprazolam in anxiety disorder and panic disorder.

12.3 Pharmacokinetics

Absorption

Following oral administration, alprazolam is readily absorbed. The peak plasma concentration is reached about 1.5 to 2 hours after administration of alprazolam given with or without water. When taken with water, mean Tmax occurs about 15 minutes earlier than when taken without water with no change in Cmax or AUC. Plasma levels are proportional to the dose given; over the dose range of 0.5 mg to 3 mg, peak levels of 8 to 37 ng/mL are observed. The elimination half-life of alprazolam is approximately 12.5 hours (range 7.9 to 19.2 hours) after administration of alprazolam in healthy adults.

Food decreased the mean Cmax by about 25% and increased the mean Tmax by 2 hours from 2.2 hours to 4.4 hours after the ingestion of a high-fat meal. Food did not affect the extent of absorption (AUC) or the elimination half-life.

Distribution

In vitro , alprazolam is bound (80 percent) to human serum protein. Serum albumin accounts for the majority of the binding.

Metabolism/Elimination

Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to two major metabolites in the plasma: 4-hydroxyalprazolam and α-hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam. The plasma concentrations of 4-hydroxyalprazolam and α-hydroxyalprazolam relative to unchanged alprazolam concentration were always less than 4%. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0.20 and 0.66, respectively, for 4-hydroxyalprazolam and α-hydroxyalprazolam. Such low concentrations and the 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.

Special Populations

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. A mean half-life of alprazolam of 16.3 hours has been observed in healthy elderly subjects (range: 9.0 to 26.9 hours, n=16) compared to 11.0 hours (range: 6.3 to 15.8 hours, n=16) in healthy adult subjects. In patients with alcoholic liver disease, the half-life of alprazolam ranged between 5.8 and 65.3 hours (mean: 19.7 hours, n=17) as compared to between 6.3 and 26.9 hours (mean=11.4 hours, n=17) in healthy subjects. In an obese group of subjects, the half-life of alprazolam ranged between 9.9 and 40.4 hours (mean=21.8 hours, n=12) as compared to between 6.3 and 15.8 hours (mean=10.6 hours, n=12) in healthy subjects.

Because of its similarity to other benzodiazepines, it is assumed that alprazolam undergoes transplacental passage and that it is excreted in human milk.

Race — Maximal concentrations (Cmax ) and half-life of alprazolam are approximately 15% and 25% higher in Asians compared to Caucasians.

Pediatrics — The pharmacokinetics of alprazolam in pediatric patients have not been studied.

Gender — Gender has no effect on the pharmacokinetics of alprazolam.

Cigarette Smoking — Alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers.

Drug-Drug Interactions

Alprazolam is primarily eliminated by metabolism via cytochrome P450 3A (CYP3A). Most of the interactions that have been documented with alprazolam are with drugs that inhibit or induce CYP3A.

Compounds that are potent inhibitors of CYP3A would be expected to increase plasma alprazolam concentrations. Drug products that have been studied in vivo , along with their effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole, 2.70 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold [see Contraindications ( 4), Warnings and Precautions (5.8), and Drug Interactions ( 7)].

CYP3A inducers would be expected to decrease alprazolam concentrations and this has been observed in vivo. The oral clearance of alprazolam (given in a 0.8 mg single dose) was increased from 0.90 ± 0.21 mL/min/kg to 2.13 ± 0.54 mL/min/kg and the elimination t1/2 was shortened (from 17.1 ± 4.9 to 7.7 ± 1.7 h) following administration of 300 mg/day carbamazepine for 10 days [see Drug Interactions ( 7)]. However, the carbamazepine dose used in this study was fairly low compared to the recommended doses (1000 mg to 1200 mg/day); the effect at usual carbamazepine doses is unknown.

The ability of alprazolam to induce or inhibit human hepatic enzyme systems has not 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.

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