Anxiety Disorder 
Alprazolam shares the actions of other benzodiazepines and is used for the management of anxiety disorders or for the short-term relief of symptoms of anxiety or anxiety associated with depressive symptoms. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The efficacy of alprazolam for long-term use (i.e., longer than 4 months) has not been evaluated. The need for continued therapy with the drug should be periodically reassessed.
Panic Disorder
Alprazolam is used in the management of panic disorder, with or without agoraphobia.107,372,373,374,375,376,378,379,380,381,382,383,384,385,386,387,388,390,391,392,393,394,395,396,397,399,606,607 Efficacy of alprazolam in the management of panic disorder has been established in short-term (for periods up to 4-10 weeks) controlled studies,372,374,375,380,386,387,388,391,394,395,396,606,607 although the drug has been used without apparent loss of efficacy for longer periods (e.g., 8 months or longer) in many patients.372,376,382,607 Following discontinuance of the drug, a relapse of the condition, including a rebound in panic attacks and anxiety, and/or the development of withdrawal frequently occurs.107,372,378,606,607 Additional study is needed to establish the optimum duration of alprazolam therapy in the management of panic disorder, and to determine the most appropriate method of tapered withdrawal of the drug.107,372,385,390,606,607
The potential dependence liability of alprazolam should be considered in weighing the possible risks and benefits of therapy with the drug in this condition.107,372,391 Effective treatment of panic disorder with alprazolam often has required dosages exceeding 4 mg daily,372,386 and spontaneous reporting data suggest that the risk and severity of dependence is increased in patients receiving such dosages for prolonged periods (e.g., longer than 12 weeks).372,606,607 In 2 controlled studies of 6- to 8-weeks' duration in which the patient's ability to discontinue therapy was assessed, 7-29% of patients with panic disorder did not completely taper off of alprazolam therapy.372,606,607 In a controlled postmarketing study, the ability of patients with panic disorder to discontinue alprazolam therapy was reduced in those receiving dosages exceeding 4 mg daily but did not appear to differ between those receiving the drug for 3 months compared with those receiving the drug for 6 months.372,606,607
Administration
Immediate-release preparations of alprazolam (i.e., conventional and orally disintegrating tablets, oral solution concentrate) are administered orally in divided doses. Because concomitant oral administration of grapefruit juice with other similarly metabolized benzodiazepines has been reported to increase the bioavailability of these drugs, caution is advised if grapefruit juice is ingested concomitantly with alprazolam.372,606,607 (See Drug Interactions: Grapefruit Juice under Drug Interactions in the Benzodiazepines General Statement 28:24.08.)
When alprazolam oral concentrate is used, the dose should be added to 30 mL or more of diluent (e.g., water, juices, carbonated or soda-like beverages) or to semi-solid foods (e.g., applesauce, pudding) just before administration.
The orally disintegrating tablets should be administered immediately after the tablet is removed from the container by the patient; if only half a tablet is administered, the unused portion should be discarded immediately since it may not remain stable.607 The orally disintegrating tablet should be removed with a dry hand and placed on the tongue, where it disintegrates rapidly in saliva, and then subsequently can be swallowed with or without water.607 Any cotton that is present in the container when initially opened should be discarded, and the container should be resealed tightly to prevent the introduction of moisture, which might cause tablet disintegration.607 Although peak plasma concentrations are achieved 15 minutes sooner when the orally disintegrating tablets are administered with water, the peak concentration and oral bioavailability are not affected by administration with water.607 Administration of the orally disintegrating tablets with a high-fat meal does not affect the extent of absorption but may delay and reduce peak plasma concentrations of the drug by about 2 hours and 25%, respectively.607 If the orally disintegrating tablets are used in the presence of conditions or in conjunction with drugs that increase gastric pH or cause dry mouth, disintegration or dissolution of the tablets might be slower, potentially resulting in reduced or slower absorption of alprazolam.607
Alprazolam extended-release tablets are administered once daily, preferably in the morning.606 When the extended-release tablets are administered at night rather than in the morning, peak plasma concentrations are about 30% higher and occur about 1 hour sooner.606 The extended-release tablets should be swallowed whole and should not be chewed, crushed, or broken.606 The relative oral bioavailability of alprazolam when administered as extended-release tablets is 100% that of conventional (immediate-release) tablets; however, the rate of GI absorption is slower.606 The slower absorption rate results in a relatively constant plasma concentration of the drug that is maintained between 5-11 hours after dosing.606 Multiple-dose studies indicate that the metabolism and elimination of the drug are similar with the immediate- and extended-release tablets.606 Food affects the rate but not the extent of absorption of alprazolam extended-release tablets.606 Peak plasma concentrations are increased by 25% when alprazolam extended-release tablets are administered within 2 hours after a high-fat meal; time to peak plasma concentrations may be reduced by about one-third if the dose is administered immediately after a meal but may be increased by about one-third if administered 1 hour or more before a meal.606
Dosage
Dosage of alprazolam must be individualized, and the smallest effective dosage should be used (especially in geriatric or debilitated patients and in those with liver disease, low serum albumin, or obesity) to avoid oversedation. If early morning anxiety occurs or emergence of symptoms occurs between doses of an immediate-release preparation in patients previously stabilized, the need for dosage adjustment or maintenance of the same daily dosage but divided and administered at more frequent intervals should be considered.372,607
Anxiety Disorders
Immediate-release Preparations
Optimum dosage for the management of anxiety disorders has only been established for immediate-release preparations of alprazolam (i.e., conventional and orally disintegrating tablets, oral solution concentrate).372,607,608 The extended-release tablets currently are not labeled for use the management of anxiety disorders.606
The usual initial adult dosage of immediate-release alprazolam for the management of anxiety disorders (other than panic disorder) or transient symptoms of anxiety is 0.25-0.5 mg 3 times daily. Dosage may be gradually increased at intervals of 3 or 4 days according to individual requirements and response to a maximum dosage of 4 mg daily, given in divided doses. In geriatric or debilitated patients, immediate-release alprazolam therapy for anxiety should be initiated with 0.25 mg 2 or 3 times daily; if adverse effects occur at this initial dosage, dosage should be decreased. If adverse effects do not occur at this initial dosage, dosage may be gradually increased if necessary according to individual tolerance and response.
When it is necessary to reduce the dosage or discontinue therapy with alprazolam, dosage of the drug should be reduced or withdrawn gradually to prevent the development of withdrawal symptoms.372,607 (See Cautions.) Although studies have not been performed to date to determine the optimal regimen for tapering alprazolam dosage, the manufacturer recommends that dosage of the drug be decreased by no more than 0.5 mg every 3 days.372,607 Some patients may require an even slower dosage reduction,372,607 and some clinicians suggest that more gradual tapering (e.g., decreasing by no more than 0.25 mg every 3-7 days) may be necessary in some patients to prevent symptom recurrence (for the condition being treated) and/or the development of manifestations of withdrawal.107,108,109
Panic Disorder
Immediate-release Preparations
For the management of panic disorder, therapy with immediate-release alprazolam (conventional or orally disintegrating tablets) generally should be initiated at a low dosage to minimize the risk of adverse effects.372,386 Dosage subsequently may be increased until an acceptable therapeutic response is achieved (e.g., substantial reduction in or elimination of panic attacks), intolerable adverse effects occur, or a maximum recommended dosage of 10 mg daily is achieved.372,386 Therapy with immediate-release alprazolam may be initiated in adults at a dosage of 0.5 mg 3 times daily and then increased as necessary at 3- or 4-day intervals in increments of no more than 1 mg daily.372,607 However, slower titration to dosages exceeding 4 mg daily may be advisable so that full expression of the pharmacodynamic effects with a given dosage can occur.372,607
To minimize the risk of interdose symptom emergence, doses of the immediate-release preparation should be distributed as evenly as possible throughout waking hours on a 3- or 4-times-daily schedule.372,607 The optimum duration of therapy is not known, but a carefully supervised tapered discontinuance of therapy can be attempted after a period of extended freedom from attacks.372,607 Unfortunately, current evidence indicates that such tapered discontinuance often is difficult to achieve without recurrence of symptoms and/or manifestations of withdrawal.107,372,378,607
Extended-release Tablets
For the management of panic disorder, the usual adult dosage range for alprazolam extended-release tablets is 3-6 mg once daily.606 Dosage should be individualized for maximum benefit.606 While a dosage of 3-6 mg daily will meet the needs of most patients with panic disorder, some patients will require higher dosages. In such cases, dosage should be increased cautiously to avoid adverse effects.606
For most adults with panic disorder, therapy with alprazolam extended-release tablets may be initiated at a dosage of 0.5-1 mg once daily.606 Thereafter, dosage may be increased according to response at intervals of 3 or 4 days in increments not exceeding 1 mg daily.606 Slower dosage titration may be advisable to allow full expression of the pharmacodynamic effect of the extended-release tablets.606 Dosage generally should be increased until an acceptable therapeutic response is achieved, intolerance occurs, or a maximum dosage of 10 mg once daily is achieved.606
In geriatric patients, in adults with advanced liver disease or another debilitating disease, and in those especially sensitive to the drug, the usual initial dosage of alprazolam extended-release tablets for the management of panic disorder is 0.5 mg once daily.606 If necessary, this dosage may be increased gradually according to patient response and tolerance as described for most adults.606
Maintenance Therapy and Dosage Reduction
The following recommendations for maintenance dosage in adults with panic disorder apply to both immediate- and extended-release alprazolam preparations on a daily basis.372,606,607 However, the dosage should be divided as evenly as possible during waking hours on a 3- or 4-times daily schedule for immediate-release preparations whereas the dosage is given once daily, preferably in the morning, for extended-release tablets.372,606,607
Patients being switched from immediate-release alprazolam therapy to the extended-release tablets can receive the same total daily dosage administered once daily rather than in divided doses.606 If the therapeutic response is not adequate after switching to the same dosage administered once daily, the dosage may be increased in the usual fashion.606
Effective treatment of panic disorder with alprazolam often has required dosages exceeding 4 mg daily in adults.372,386,606,607 Dosage (as immediate-release preparations) generally has averaged 5-6 mg daily, but has ranged from 1-10 mg daily;372,386,607 about 20% of patients required maximum alprazolam dosages exceeding 7 mg daily,372,607 with about one-third of these requiring maximum dosages exceeding 9 mg daily.372,607 An alprazolam dosage of 3-6 mg daily as extended-release tablets generally has been effective, but dosage has ranged from 1-10 mg daily.606 Occasionally, a dosage of 10 mg daily has been required for adequate response.372,386,606,607
For patients receiving dosages exceeding 4 mg daily, periodic reassessment and consideration of dosage reduction is recommended.372,607 In a controlled postmarketing dose-response study, patients receiving alprazolam at dosages exceeding 4 mg daily for 3 months were able to taper their daily maintenance dosage by 50% without apparent loss of clinical benefit.372,607
Reduction of alprazolam dosage must be undertaken under close supervision and must be gradual.372,606,607 If significant withdrawal symptoms develop, the previous dosing schedule should be reinstituted and, only after stabilization, should a less rapid schedule of dosage tapering be attempted.372,606,607 Although not systematically evaluated, a reduction by 0.5 mg daily at 3-day intervals has been suggested, although more gradual reductions may be necessary in some patients.372,606,607 When this suggested tapering schedule was compared with a slower dosage taper, there was no difference in the proportion of patients able to completely discontinue alprazolam, but the slower tapering schedule was associated with fewer withdrawal symptoms.372,606,607 Some patients may prove resistant to all discontinuance regimens.372,606,607
A boxed warning has been included in the prescribing information for all benzodiazepines describing the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions associated with all drugs in this class.900 Abuse and misuse can result in overdose or death, especially when benzodiazepines are combined with other medicines, such as opioid pain relievers, alcohol, or illicit drugs.900 Frequent follow-up with patients receiving benzodiazepines is important.900 Reassess patients regularly to manage their medical conditions and any withdrawal symptoms.900 Clinicians should assess a patient's risk of abuse, misuse, and addiction. 900 Standardized screening tools are available ([Web]).900 To reduce the risk of acute withdrawal reactions, use a gradual dose taper when reducing the dosage or discontinuing benzodiazepines.900 Take precautions when benzodiazepines are used in combination with opioid medications.900
Alprazolam shares the toxic potentials of the benzodiazepines, and the usual precautions of benzodiazepine administration should be observed. (See Cautions in the Benzodiazepines General Statement 28:24.08.)
Seizures,102,103,372,606,607 delirium,102,104 and withdrawal symptoms (similar to those reported following abrupt withdrawal of other benzodiazepines)101,104,372,606,607 have occurred in some patients following rapid dosage reduction104,372,606,607 and/or abrupt discontinuance of alprazolam.101,102,103,372,606,607 In most cases, only a single seizure occurred; however, multiple seizures and status epilepticus also have been reported and may be life-threatening.372,606,607 Withdrawal-related effects appearing after abrupt discontinuance of alprazolam have occurred from 18 hours to 3 days after the last dose of the drug.101,102,103 Seizures resulting from rapid dosage reduction or abrupt withdrawal of alprazolam have occurred in patients receiving usual or higher than recommended dosages of the drug for relatively short periods of time (from 1 week to 4 months).102,103,372,606,607 Seizures also have occurred occasionally in patients apparently tapering dosage gradually.372,606,607 The risk of seizures appears to be greatest 24-72 hours after discontinuance of alprazolam.372,606,607 The use of dosages exceeding 4 mg daily (e.g., those employed for panic disorder) and use of the drug for prolonged periods of time may be associated with an increased frequency and severity of withdrawal symptoms.372,606,607 When it is necessary to reduce the dosage or discontinue therapy with alprazolam, dosage of the drug should be reduced or withdrawn gradually.101,102,111,372,606,607 Patients should be advised not to discontinue the drug abruptly without consulting their physician.372,606,607
Episodes of mania and hypomania have been reported in depressed patients receiving alprazolam.372,606,607
The initial step in alprazolam metabolism is hydroxylation catalyzed by the hepatic cytochrome P-450 (CYP) 3A isoenzyme, and concomitant use of alprazolam with agents that inhibit the CYP3A isoenzyme may result in decreased alprazolam metabolism and clearance and increased plasma alprazolam concentrations.372,606,607 The manufacturers state that caution should be exercised and alprazolam dosage adjustment considered during concomitant use of the drug with some inhibitors of the CYP3A isoenzyme (e.g., nefazodone, fluvoxamine, cimetidine).372,606,607 Other CYP3A inhibitors (e.g., fluoxetine, diltiazem, macrolide antibiotics [i.e., clarithromycin, erythromycin], isoniazid, sertraline, paroxetine, grapefruit juice, amiodarone) may cause clinically important decreases in alprazolam metabolism and clearance and should be used with caution in patients receiving the drug.372,606,607 Concomitant use with some other drugs (propoxyphene, oral contraceptives, ergotamine, cyclosporine, nicardipine, nifedipine) may result in decreases in alprazolam metabolism and clearance; caution is advised if alprazolam is administered with one of these agents.372,606,607
Concomitant use of alprazolam with delavirdine should be avoided because of the potential for delavirdine to decrease metabolism of alprazolam and result in intense or prolonged sedation or respiratory depression.612,623
Because itraconazole and ketoconazole are very potent CYP3A isoenzyme inhibitors that can markedly decrease the metabolism and clearance of alprazolam, the manufacturers state that concomitant use of these drugs with alprazolam is contraindicated.372,606,607 In addition, concomitant use of alprazolam with other azole antifungal agents that are very potent inhibitors of CYP3A should be avoided.372,606,607
For further information about potential drug interactions between benzodiazepines and drugs and foods affecting hepatic microsomal enzymes, see Drug Interactions in the Benzodiazepines General Statement 28:24.08.
Pediatric Precautions
Safety and efficacy of alprazolam have not been established in children younger than 18 years of age.372,606,607
Geriatric Precautions
Clearance of alprazolam is reduced in geriatric patients, and geriatric patients may be particularly sensitive to the effects of benzodiazepines; therefore, the smallest effective dosage of alprazolam should be used in these patients to avoid oversedation and ataxia.372,606,607
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