Alprazolam (Monograph)

Brand names: Niravam, Xanax
Drug class: Benzodiazepines
VA class: CN302
Chemical name: 8-Chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine
Molecular formula: C₁₇H₁₃ClN₄
CAS number: 28981-97-7

Medically reviewed by Drugs.com on Sep 16, 2024. Written by ASHP.

Warning

Concomitant use of benzodiazepines and opiates may result in profound sedation, respiratory depression, coma, and death.⁷⁰⁰ ⁷⁰¹ ⁷⁰³ ⁷⁰⁵ ⁷⁰⁶ ⁷⁰⁷
Reserve concomitant use for patients in whom alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy and monitor closely for respiratory depression and sedation.⁷⁰⁰ ⁷⁰³ (See Specific Drugs and Foods under Interactions.)

A boxed warning has been included in the prescribing information for all benzodiazepines describing risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions.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
Assess a patient’s risk of abuse, misuse, and addiction.⁹⁰⁰ Standardized screening tools are available ([Web]).⁹⁰⁰
To reduce risk of acute withdrawal reactions, use a gradual dose taper when reducing dosage or discontinuing benzodiazepines.⁹⁰⁰ Take precautions when benzodiazepines are used in combination with opioid medications.⁹⁰⁰

Introduction

Benzodiazepine; anxiolytic.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ^b ^c

Uses for Alprazolam

Anxiety Disorders

Management of anxiety disorders or short-term relief of anxiety or anxiety associated with depressive symptoms.³⁷² ⁶⁰⁷ ⁶⁰⁸ ^b ^c

Panic Disorder

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

Cancer Chemotherapy-induced Nausea and Vomiting

Adjunct in the management of nausea and vomiting associated with emetogenic cancer chemotherapy^{† [off-label]}⁴⁹² ⁴⁹³ ⁴⁹⁴ ⁴⁹⁵ ⁴⁹⁶ ⁴⁹⁷ ⁴⁹⁹ ⁵⁰⁰ ⁵⁰¹ ⁵⁰² ⁵⁰³ ⁵⁰⁴ ⁶²⁹ ^b (including cisplatin); ⁶²⁹ ^b currently not recommended as monotherapy.⁶²⁹ ^b

May be useful in the management of anticipatory emesis^{† [off-label]}.⁶²⁹ ^c

Alprazolam Dosage and Administration

General

Periodically reassess usefulness of the drug.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸
When discontinuing therapy or reducing daily dosage, reduce dosage gradually under close supervision.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ If significant withdrawal symptoms develop, reinstitute the previous dosage schedule; attempt a less-rapid schedule of dosage tapering only after stabilization.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ Some patients may be resistant to all discontinuance regimens.³⁷² ⁶⁰⁶ ⁶⁰⁷
The manufacturers recommend that dosage be decreased by ≤0.5 mg every 3 days;³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ some patients may require slower reduction.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸
Some clinicians recommend decreasing the dosage by ≤0.25 mg every 3–7 days.¹⁰⁷ ¹⁰⁸ ¹⁰⁹

Administration

Oral Administration

Immediate-release Preparations

Administer conventional and orally disintegrating tablets and oral concentrate daily in divided doses.³⁷² ⁶⁰⁷ ⁶⁰⁸ ^c

Dilute oral concentrate in ≥30 mL of diluent (e.g., water, juice, carbonated or soda-like beverages) or mix with semisolid foods (e.g., applesauce, pudding) just prior to administration.⁶⁰⁸ ^c

Remove orally disintegrating tablet from protective container with dry hands immediately prior to administration.⁶⁰⁷ Immediately place tablet on tongue, allow it to disintegrate (within a few seconds), then swallow with or without water.⁶⁰⁷ If a half tablet is used, discard the remaining portion because it may not remain stable.⁶⁰⁷

Extended-release Tablets

Administer extended-release tablets daily as a single dose, preferably in the morning.⁶⁰⁶

Swallow extended-release tablets whole; do not chew, crush, or break.⁶⁰⁶

Patients with panic disorder may be switched from conventional tablets to extended-release tablets at the same total daily dosage.⁶⁰⁶ If the response is not sufficient, titrate dosage in a similar manner to initial therapy until an acceptable therapeutic response is achieved.⁶⁰⁶

Dosage

Adults

Anxiety Disorders

Therapy with Conventional or Orally Disintegrating Tablets or Oral Concentrate

Oral

Initially, 0.25–0.5 mg 3 times daily.³⁷² ⁶⁰⁷ ⁶⁰⁸ ^c Increase dosage gradually at intervals of 3 or 4 days according to individual requirements and response; maximum dosage of 4 mg daily given in divided doses.³⁷² ⁶⁰⁷ ⁶⁰⁸ ^c

Panic Disorder

Therapy with Conventional or Orally Disintegrating Tablets

Oral

Dosages >4 mg daily have been required; dosage generally has averaged 5–6 mg daily but has ranged from 1–10 mg daily.³⁷² ³⁸⁶ ⁶⁰⁷

Initiate at low dosage;³⁷² ³⁸⁶ ⁶⁰⁷ increase dosage gradually until an acceptable therapeutic response is achieved, intolerable adverse effects occur, or a maximum dosage of 10 mg daily is achieved.³⁷² ³⁸⁶ ⁶⁰⁷

Initially, 0.5 mg 3 times daily.³⁷² ⁶⁰⁷ Increase dosage as necessary at 3- or 4-day intervals in increments of ≤1 mg daily; slower titration to dosages ≥4 mg daily may be advisable so that full effects of a given dosage can be expressed.³⁷² ⁶⁰⁷

Periodic reassessment and consideration of dosage reduction recommended in patients receiving dosages >4 mg daily.³⁷² ⁶⁰⁷

To minimize risk of symptom emergence between doses, distribute doses evenly 3–4 times daily (while awake).³⁷² ⁶⁰⁷

Therapy with Extended-release Tablets

Oral

Dosage of 3–6 mg daily recommended, but dosage has ranged from 1–10 mg daily.⁶⁰⁶

Initiate at low dosage; increase dosage gradually until an acceptable therapeutic response is achieved, intolerable adverse effects occur, or a maximum dosage of 10 mg daily is achieved.⁶⁰⁶

Initially, 0.5–1 mg daily.⁶⁰⁶ Increase dosage as necessary (based on response) at 3- or 4-day intervals in increments of ≤1 mg daily; slower titration may be advisable so that full effects of a given dosage can be expressed.⁶⁰⁶

Prescribing Limits

Adults

Anxiety Disorders

Oral

Maximum 4 mg daily.³⁷² ⁶⁰⁷ ⁶⁰⁸ ^c

Panic Disorder

Oral

Maximum 10 mg daily.³⁷² ⁶⁰⁶ ⁶⁰⁷

Special Populations

Hepatic Impairment

Prolonged elimination.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ Use the smallest effective dosage.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ^c

Initially, 0.25 mg (as an immediate-release preparation) given 2 or 3 times daily or 0.5 mg (as extended-release tablets) once daily; adjust dosage according to individual tolerance and response.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸

Geriatric or Debilitated Patients

Possible increased sensitivity to benzodiazepines.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ^b Use the smallest effective dosage.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ^c

Cautions for Alprazolam

Contraindications

Known hypersensitivity to alprazolam or other benzodiazepines.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ^b
Concurrent ketoconazole,³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ itraconazole,³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ or delavirdine⁶¹² ⁶²³ therapy. (See Specific Drugs and Foods under Interactions.)
Manufacturers state that alprazolam is contraindicated in patients with acute angle-closure glaucoma but may be administered to patients with open-angle glaucoma who are receiving appropriate therapy;³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ^b however, clinical rationale for this contraindication has been questioned.^b

Warnings/Precautions

Warnings

Concomitant Use with Opiates

Concomitant use of benzodiazepines, including alprazolam, and opiates may result in profound sedation, respiratory depression, coma, and death.⁷⁰⁰ ⁷⁰¹ ⁷⁰³ ⁷⁰⁵ ⁷⁰⁶ ⁷⁰⁷ Substantial proportion of fatal opiate overdoses involve concurrent benzodiazepine use.⁷⁰⁰ ⁷⁰¹ ⁷⁰⁵ ⁷⁰⁶ ⁷⁰⁷ ⁷¹¹

Reserve concomitant use of alprazolam and opiates for patients in whom alternative treatment options are inadequate.⁷⁰⁰ ⁷⁰³ (See Specific Drugs and Foods under Interactions.)

Withdrawal Effects

Rapid dosage reduction or abrupt discontinuance may result in seizures (including status epilepticus),¹⁰² ¹⁰³ ³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ delirium,¹⁰² ¹⁰⁴ or withdrawal symptoms.¹⁰¹ ¹⁰⁴ ³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸

Risk of seizures is greatest 24–72 hours after discontinuance.³⁷² ⁶⁰⁶ ⁶⁰⁷

Use of relatively higher dosages (e.g., those employed for panic disorder) may be associated with an increased frequency and severity of rebound and withdrawal symptoms.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸

Psychiatric Indications

Do not use in patients with depressive neuroses or psychotic reactions in which anxiety is not prominent.^b

Abuse Potential

Abuse potential similar to that of other benzodiazepines and related hypnotics.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸

Patients with a history of drug or alcohol dependence or abuse are at risk of habituation or dependence; use only with careful surveillance in such patients.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸

CNS Effects

Performance of activities requiring mental alertness and physical coordination may be impaired.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ^b ^c

Concurrent use of other CNS depressants may cause additive or potentiated CNS depression.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ (See Concomitant Use with Opiates under Cautions and also see Specific Drugs and Foods under Interactions.)

CYP3A-mediated Drug Interactions

Potential for marked increase in plasma alprazolam concentrations if used concomitantly with a CYP3A inhibitor.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ Avoid concomitant use of potent CYP3A inhibitors (e.g., delavirdine, itraconazole, ketoconazole); use of less potent CYP3A inhibitors requires caution and possible dosage reduction.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ⁶¹² ⁶²³ (See Specific Drugs and Foods under Interactions.)

General Precautions

Suicide

Use with caution in depressed patients; potential for suicidal tendencies.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ^b Prescribe and dispense drug in the smallest feasible quantity.³⁷² ⁶⁰⁶ ^b

Mania

Episodes of mania and hypomania reported in patients with depression.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸

Respiratory Effects

Rare reports of deaths following initiation of therapy in patients with severe pulmonary disease.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸

Use with caution in patients with compromised respiratory function.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ^b

Renal Effects

Weak uricosuric effect; however, no reports of acute renal failure.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸

Specific Populations

Pregnancy

Category D.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸

Lactation

Benzodiazepines generally are distributed into milk; discontinue nursing or the drug.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ^b

Pediatric Use

Safety and efficacy not established in children <18 years of age.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ^c

Geriatric Use

Potential increased sensitivity (increased risk of oversedation and ataxia).³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ^b ^c Initiate therapy at low dosage and adjust carefully.³⁷² ⁶⁰⁶ ^b ^c (See Geriatric or Debilitated Patients under Dosage and Administration.)

Hepatic Impairment

Prolonged elimination.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ Use with caution;³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ^b ^c use smallest effective dosage to avoid oversedation.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ^b ^c (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Use with caution.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ^b

Obese Patients

Use with caution; prolonged elimination reported.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸

Common Adverse Effects

In patients with anxiety disorder: drowsiness, lightheadedness, depression, headache, dry mouth, constipation, diarrhea.³⁷² ⁶⁰⁷ ⁶⁰⁸

Conventional tablets in patients with panic disorder: drowsiness, fatigue/tiredness, impaired coordination, irritability, memory impairment, lightheadedness/dizziness, insomnia, headache, cognitive disorder, dysarthria, anxiety, abnormal involuntary movement, decreased libido, depression, confusional state, decreased salivation, constipation, nausea/vomiting, diarrhea, abdominal distress, nasal congestion, tachycardia, chest pain, blurred vision, sweating, rash, increased appetite, decreased appetite, weight gain, weight loss, micturition difficulties, menstrual disorders.³⁷² ⁶⁰⁷

Extended-release tablets in patients with panic disorder: sedation, somnolence, memory impairment, dysarthria, fatigue, depression, dry mouth.⁶⁰⁶

Drug Interactions

Metabolized by CYP3A.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (altered serum concentrations of alprazolam) with drugs that induce or inhibit CYP3A.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ Avoid concomitant use with potent CYP3A inhibitors.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ with less potent CYP3A inhibitors; alprazolam dosage adjustment may be indicated.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ (See Specific Drugs and Foods under Interactions.)

Drugs Affecting Salivary Flow or Gastric pH

Possible pharmacokinetic interaction (decreased alprazolam absorption) with concomitant use of alprazolam orally disintegrating tablets and drugs that increase gastric pH or decrease salivary flow.⁶⁰⁷

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Amiodarone	Possible increase in plasma alprazolam concentrations³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸	Use with caution³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸
Antidepressants, SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline)	Fluoxetine or fluvoxamine: Increased plasma alprazolam concentrations³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ⁶¹³ Paroxetine: Possible interaction in vitro³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ Sertraline: Possible interaction in vitro; no clinically important interaction in vivo³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸	Fluvoxamine: Use with caution; consider reduction of alprazolam dosage³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ⁶¹³ Fluoxetine, paroxetine, or sertraline: Use with caution³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸
Antidepressants, tricyclics (e.g., imipramine, desipramine)	Possible increase in plasma concentrations of antidepressant³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ^b	Clinical importance unknown³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸
Antifungals, azoles (e.g., itraconazole, ketoconazole)	Increased plasma alprazolam concentrations³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸	Concomitant use of itraconazole or ketoconazole is contraindicated;³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ avoid concomitant use of other azole antifungals that are potent CYP3A inhibitors³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸
Calcium-channel blocking agents (diltiazem, nicardipine, nifedipine)	Possible increase in plasma alprazolam concentrations³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸	Use with caution³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸
Carbamazepine	Possible decrease in plasma alprazolam concentrations³⁷² ⁶⁰⁶ ⁶⁰⁷
Cigarette smoking	Decreased plasma alprazolam concentrations³⁷² ⁶⁰⁶ ⁶⁰⁷ ^b
Cimetidine	Increased plasma alprazolam concentrations³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸	Use with caution; consider reduction of alprazolam dosage³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸
CNS depressants (e.g., sedatives, psychotropic drugs, anticonvulsants, antihistamines, alcohol)	Additive CNS effect³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ^b	Use caution to avoid overdosage⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ^b Avoid alcohol use³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ⁷⁰⁰
Cyclosporine	Possible increase in plasma alprazolam concentrations³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸	Use with caution³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸
Delavirdine	Potential for decreased alprazolam metabolism resulting in intense and prolonged sedation and respiratory depression⁶²³	Concomitant use contraindicated⁶¹² ⁶²³
Digoxin	Digoxin toxicity reported in at least 1 patient²⁰⁹	Monitor carefully and adjust digoxin dosage as necessary²⁰⁹
Disulfiram	Possible decrease in alprazolam clearance²⁰⁰ ²⁰¹	Reduce alprazolam dosage as necessary²⁰⁰
Ergotamine	Possible increase in plasma alprazolam concentrations³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸	Use with caution³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸
Grapefruit juice	Possible increase in plasma alprazolam concentrations³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸	Use with caution³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸
HIV protease inhibitors (e.g., fosamprenavir, ritonavir, saquinavir)	Possible increase in plasma alprazolam concentrations⁶¹⁴ ⁶²⁰ ⁶²²	Clinical importance not determined; consider possible need for alprazolam dosage reduction⁶¹⁴ ⁶²⁰ ⁶²²
Isoniazid	Possible increase in plasma alprazolam concentrations³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸	Use with caution³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸
Macrolides (e.g., clarithromycin, erythromycin)	Possible increase in plasma alprazolam concentrations³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸	Use with caution³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸
Nefazodone	Increased plasma alprazolam concentrations³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸	Use with caution; consider reduction of alprazolam dosage³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸
Opiate agonists and partial agonists	Risk of profound sedation, respiratory depression, coma, or death⁷⁰⁰ ⁷⁰¹ ⁷⁰³ ⁷⁰⁵ ⁷⁰⁶ ⁷⁰⁷	Whenever possible, avoid concomitant use⁷⁰⁸ ⁷⁰⁹ ⁷¹⁰ ⁷¹¹ Opiate analgesics: Use concomitantly only if alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy; monitor closely for respiratory depression and sedation⁷⁰⁰ ⁷⁰³ In patients receiving alprazolam, initiate opiate analgesic, if required, at reduced dosage and titrate based on clinical response⁷⁰⁰ In patients receiving an opiate analgesic, initiate alprazolam, if required, at lower dosage than indicated in the absence of opiate therapy and titrate based on clinical response⁷⁰⁰ Opiate antitussives: Avoid concomitant use⁷⁰⁰ ⁷⁰⁴ Consider offering naloxone to patients receiving benzodiazepines and opiates concomitantly⁷⁰⁹ ⁷¹²
Oral contraceptives	Increased plasma alprazolam concentrations³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸	Use with caution³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸
Warfarin	No effect on PT or plasma warfarin concentrations observed³⁷² ⁶⁰⁶ ⁶⁰⁷

Alprazolam Pharmacokinetics

Absorption

Bioavailability

Readily absorbed following oral administration as conventional or orally disintegrating tablets or oral solution,³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ with peak plasma concentrations achieved within 1–2 hours.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸

When orally disintegrating tablets are taken with water, peak plasma concentrations occur 15 minutes sooner than when taken without water, but actual peak concentration and AUC are unaffected.⁶⁰⁷

Rate of absorption of extended-release tablets is slower than that of conventional tablets, resulting in relatively constant plasma concentrations for 5–11 hours after a dose.⁶⁰⁶

Absolute bioavailability of extended-release tablets is 90%; bioavailability is equivalent to that of conventional tablets.⁶⁰⁶

Absorption rate for extended-release tablets is faster following nighttime versus morning administration.⁶⁰⁶

Food

High-fat meal may alter the rate but not the extent of absorption of orally disintegrating or extended-release tablets.⁶⁰⁶ ⁶⁰⁷

Special Populations

In patients with conditions that increase gastric pH or cause dry mouth, absorption of orally disintegrating tablets may be slower or reduced.⁶⁰⁷

Distribution

Extent

Benzodiazepines are widely distributed into body tissues and cross the blood-brain barrier.^b

Benzodiazepines generally cross the placenta and distribute into milk; because of its similarity to other benzodiazepines, alprazolam is presumed to cross the placenta and to distribute into milk.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ^b

Plasma Protein Binding

Approximately 80%,³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ primarily to albumin.³⁷² ⁶⁰⁶ ⁶⁰⁷

Elimination

Metabolism

Extensively metabolized in the liver by CYP3A4 to metabolites that are inactive or have lower potency than alprazolam.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸

Elimination Route

Alprazolam and metabolites are excreted primarily in urine.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸

Half-life

Approximately 11–12.5 hours for immediate-release preparations;³⁷² ⁶⁰⁷ ⁶⁰⁸ approximately 11–16 hours for extended-release tablets.⁶⁰⁶

Special Populations

In geriatric patients, obese patients, and those with alcoholic liver disease, half-life is increased to approximately 16, 22, and 20 hours, respectively.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ^b

In Asians, half-life is about 25% greater than that in Caucasians.³⁷² ⁶⁰⁶ ⁶⁰⁷

Stability

Storage

Oral

Conventional Tablets

20–25°C.³⁷²

Orally Disintegrating Tablets

20–25°C (may be exposed to 15–30°C).⁶⁰⁷ Protect from moisture.⁶⁰⁷ If a half tablet is used, discard remaining portion because it may not remain stable.⁶⁰⁷ Discard cotton after opening the container and reseal container tightly after each opening to prevent introduction of moisture.⁶⁰⁷

Extended-release Tablets

25°C (may be exposed to 15–30°C).⁶⁰⁶

Solution (Concentrate)

Tight, light-resistant containers at 15–30°C.⁶⁰⁸

Actions

Effects appear to be mediated through the inhibitory neurotransmitter GABA; the site and mechanism of action within the CNS appear to involve a macromolecular complex (GABA_A-receptor-chloride ionophore complex) that includes GABA_A receptors, high-affinity benzodiazepine receptors, and chloride channels.³²⁰ ³⁵⁸ ³⁵⁹ ³⁶⁰ ³⁶¹ ³⁶² ³⁶³ ³⁶⁴ ³⁶⁵ ³⁶⁶ ³⁶⁷ ³⁶⁸ ³⁶⁹ ³⁷⁰

Advice to Patients

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and alcohol consumption.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ Importance of avoiding alcohol-containing beverages or products.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸
Risk of potentially fatal additive effects (e.g., profound sedation, respiratory depression, coma) if used concomitantly with opiates either therapeutically or illicitly.⁷⁰⁰ ⁷⁰³ Avoid concomitant use of opiate antitussives;⁷⁰⁰ ⁷⁰⁴ also avoid concomitant use of opiate analgesics unless use is supervised by clinician.⁷⁰⁰ ⁷⁰³
Importance of taking only as prescribed; do not increase dosage or duration of therapy unless otherwise instructed by a clinician.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸
For patients taking alprazolam orally disintegrating tablets, importance of not removing tablets from the container until just prior to administration; importance of removing tablet from container with dry hands and placing tablet on tongue to dissolve and be swallowed with saliva or water.⁶⁰⁷ Importance of discarding any cotton included in the container and of resealing the container tightly after each opening to prevent introduction of moisture.⁶⁰⁷
For patients taking one-half of an orally disintegrating tablet, importance of immediately discarding the unused portion because of possible instability.⁶⁰⁷
Importance of not abruptly discontinuing therapy; consult clinician about discontinuing use.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸
Potential for drug to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸
Importance of informing clinicians of any behavioral or mental changes, memory impairment, tolerance, or dependence/withdrawal symptoms.⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ^b
Potential for severe emotional and physical dependence in some patients receiving increased dosages for the management of panic disorder.³⁷² ⁶⁰⁶ ⁶⁰⁷ Discontinuance of the drug may be difficult, with increased risk of withdrawal symptoms, including seizures.³⁷² ⁶⁰⁶ ⁶⁰⁷
Importance of informing clinicians about any concomitant illnesses, particularly depression.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸
Importance of informing patients of other important precautionary information.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.³⁷² ⁶⁰⁶ ⁶⁰⁷ ⁶⁰⁸ ^c

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

ALPRAZolam
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Solution, concentrate	1 mg/mL	ALPRAZolam Intensol (C-IV)	Roxane
	Tablets	0.25 mg*	ALPRAZolam Tablets (C-IV)
			Xanax (C-IV; scored)	Pfizer
		0.5 mg*	ALPRAZolam Tablets (C-IV)
			Xanax (C-IV; scored)	Pfizer
		1 mg*	ALPRAZolam Tablets (C-IV)
			Xanax (C-IV; scored)	Pfizer
		2 mg*	ALPRAZolam Tablets (C-IV)
			Xanax (C-IV; multi-scored)	Pfizer
	Tablets, extended-release	0.5 mg	ALPRAZolam Extended-Release Tablets (C-IV)
			Xanax XR (C-IV)	Pfizer
		1 mg	ALPRAZolam Extended-Release Tablets (C-IV)
			Xanax XR (C-IV)	Pfizer
		2 mg	ALPRAZolam Extended-Release Tablets (C-IV)
			Xanax XR (C-IV)	Pfizer
		3 mg	ALPRAZolam Extended-Release Tablets (C-IV)
			Xanax XR (C-IV)	Pfizer
	Tablets, orally disintegrating	0.25 mg	Niravam (C-IV; scored)	Schwarz
		0.5 mg	Niravam (C-IV; scored)	Schwarz
		1 mg	Niravam (C-IV; scored)	Schwarz
		2 mg	Niravam (C-IV; scored)	Schwarz

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

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