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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 26, 2022. Written by ASHP.

Warning

    Concomitant Use with Opiates
  • Concomitant use of benzodiazepines and opiates may result in profound sedation, respiratory depression, coma, and death.

  • 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. (See Specific Drugs and Foods under Interactions.)

    Potential for Abuse, Addiction, and Other Serious Risks
  • A boxed warning has been included in the prescribing information for all benzodiazepines describing risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions.

  • 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.

  • Assess a patient’s risk of abuse, misuse, and addiction. Standardized screening tools are available ([Web]).

  • To reduce risk of acute withdrawal reactions, use a gradual dose taper when reducing dosage or discontinuing benzodiazepines. Take precautions when benzodiazepines are used in combination with opioid medications.

Introduction

Benzodiazepine; anxiolytic.

Uses for Alprazolam

Anxiety Disorders

Management of anxiety disorders or short-term relief of anxiety or anxiety associated with depressive symptoms.

Panic Disorder

Management of panic disorder, with or without agoraphobia.

Cancer Chemotherapy-induced Nausea and Vomiting

Adjunct in the management of nausea and vomiting associated with emetogenic cancer chemotherapy [off-label] (including cisplatin); currently not recommended as monotherapy.

May be useful in the management of anticipatory emesis [off-label].

Alprazolam Dosage and Administration

General

Administration

Oral Administration

Immediate-release Preparations

Administer conventional and orally disintegrating tablets and oral concentrate daily in divided doses.

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.

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

Extended-release Tablets

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

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

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

Dosage

Adults

Anxiety Disorders
Therapy with Conventional or Orally Disintegrating Tablets or Oral Concentrate
Oral

Initially, 0.25–0.5 mg 3 times daily. 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.

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.

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.

Initially, 0.5 mg 3 times daily. 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.

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

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

Therapy with Extended-release Tablets
Oral

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

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.

Initially, 0.5–1 mg daily. 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.

Prescribing Limits

Adults

Anxiety Disorders
Oral

Maximum 4 mg daily.

Panic Disorder
Oral

Maximum 10 mg daily.

Special Populations

Hepatic Impairment

Prolonged elimination. Use the smallest effective dosage.

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.

Geriatric or Debilitated Patients

Possible increased sensitivity to benzodiazepines. Use the smallest effective dosage.

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.

Cautions for Alprazolam

Contraindications

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. Substantial proportion of fatal opiate overdoses involve concurrent benzodiazepine use.

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

Withdrawal Effects

Rapid dosage reduction or abrupt discontinuance may result in seizures (including status epilepticus), delirium, or withdrawal symptoms.

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

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.

Psychiatric Indications

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

Abuse Potential

Abuse potential similar to that of other benzodiazepines and related hypnotics.

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.

CNS Effects

Performance of activities requiring mental alertness and physical coordination may be impaired.

Concurrent use of other CNS depressants may cause additive or potentiated CNS depression. (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. Avoid concomitant use of potent CYP3A inhibitors (e.g., delavirdine, itraconazole, ketoconazole); use of less potent CYP3A inhibitors requires caution and possible dosage reduction. (See Specific Drugs and Foods under Interactions.)

General Precautions

Suicide

Use with caution in depressed patients; potential for suicidal tendencies. Prescribe and dispense drug in the smallest feasible quantity.

Mania

Episodes of mania and hypomania reported in patients with depression.

Respiratory Effects

Rare reports of deaths following initiation of therapy in patients with severe pulmonary disease.

Use with caution in patients with compromised respiratory function.

Renal Effects

Weak uricosuric effect; however, no reports of acute renal failure.

Specific Populations

Pregnancy

Category D.

Lactation

Benzodiazepines generally are distributed into milk; discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established in children <18 years of age.

Geriatric Use

Potential increased sensitivity (increased risk of oversedation and ataxia). Initiate therapy at low dosage and adjust carefully. (See Geriatric or Debilitated Patients under Dosage and Administration.)

Hepatic Impairment

Prolonged elimination. Use with caution; use smallest effective dosage to avoid oversedation. (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Use with caution.

Obese Patients

Use with caution; prolonged elimination reported.

Common Adverse Effects

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

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.

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

Drug Interactions

Metabolized by CYP3A.

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (altered serum concentrations of alprazolam) with drugs that induce or inhibit CYP3A. Avoid concomitant use with potent CYP3A inhibitors. with less potent CYP3A inhibitors; alprazolam dosage adjustment may be indicated. (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.

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Amiodarone

Possible increase in plasma alprazolam concentrations

Use with caution

Antidepressants, SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline)

Fluoxetine or fluvoxamine: Increased plasma alprazolam concentrations

Paroxetine: Possible interaction in vitro

Sertraline: Possible interaction in vitro; no clinically important interaction in vivo

Fluvoxamine: Use with caution; consider reduction of alprazolam dosage

Fluoxetine, paroxetine, or sertraline: Use with caution

Antidepressants, tricyclics (e.g., imipramine, desipramine)

Possible increase in plasma concentrations of antidepressant

Clinical importance unknown

Antifungals, azoles (e.g., itraconazole, ketoconazole)

Increased plasma alprazolam concentrations

Concomitant use of itraconazole or ketoconazole is contraindicated; avoid concomitant use of other azole antifungals that are potent CYP3A inhibitors

Calcium-channel blocking agents (diltiazem, nicardipine, nifedipine)

Possible increase in plasma alprazolam concentrations

Use with caution

Carbamazepine

Possible decrease in plasma alprazolam concentrations

Cigarette smoking

Decreased plasma alprazolam concentrations

Cimetidine

Increased plasma alprazolam concentrations

Use with caution; consider reduction of alprazolam dosage

CNS depressants (e.g., sedatives, psychotropic drugs, anticonvulsants, antihistamines, alcohol)

Additive CNS effect

Use caution to avoid overdosage

Avoid alcohol use

Cyclosporine

Possible increase in plasma alprazolam concentrations

Use with caution

Delavirdine

Potential for decreased alprazolam metabolism resulting in intense and prolonged sedation and respiratory depression

Concomitant use contraindicated

Digoxin

Digoxin toxicity reported in at least 1 patient

Monitor carefully and adjust digoxin dosage as necessary

Disulfiram

Possible decrease in alprazolam clearance

Reduce alprazolam dosage as necessary

Ergotamine

Possible increase in plasma alprazolam concentrations

Use with caution

Grapefruit juice

Possible increase in plasma alprazolam concentrations

Use with caution

HIV protease inhibitors (e.g., fosamprenavir, ritonavir, saquinavir)

Possible increase in plasma alprazolam concentrations

Clinical importance not determined; consider possible need for alprazolam dosage reduction

Isoniazid

Possible increase in plasma alprazolam concentrations

Use with caution

Macrolides (e.g., clarithromycin, erythromycin)

Possible increase in plasma alprazolam concentrations

Use with caution

Nefazodone

Increased plasma alprazolam concentrations

Use with caution; consider reduction of alprazolam dosage

Opiate agonists and partial agonists

Risk of profound sedation, respiratory depression, coma, or death

Whenever possible, avoid concomitant use

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 sedation

In patients receiving alprazolam, initiate opiate analgesic, if required, at reduced dosage and titrate based on clinical response

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 response

Opiate antitussives: Avoid concomitant use

Consider offering naloxone to patients receiving benzodiazepines and opiates concomitantly

Oral contraceptives

Increased plasma alprazolam concentrations

Use with caution

Warfarin

No effect on PT or plasma warfarin concentrations observed

Alprazolam Pharmacokinetics

Absorption

Bioavailability

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

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.

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.

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

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

Food

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

Special Populations

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

Distribution

Extent

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

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.

Plasma Protein Binding

Approximately 80%, primarily to albumin.

Elimination

Metabolism

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

Elimination Route

Alprazolam and metabolites are excreted primarily in urine.

Half-life

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

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.

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

Stability

Storage

Oral

Conventional Tablets

20–25°C.

Orally Disintegrating Tablets

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

Extended-release Tablets

25°C (may be exposed to 15–30°C).

Solution (Concentrate)

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

Actions

Advice to Patients

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.

* 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

AHFS DI Essentials™. © Copyright 2024, Selected Revisions September 26, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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

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