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Alprazolam

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
Brands: Niravam, Xanax

Medically reviewed on November 13, 2017

Warning

    Concomitant Use with Opiates
  • 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.)

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 chemotherapy492 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.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

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 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

Interactions for Alprazolam

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 (GABAA-receptor-chloride ionophore complex) that includes GABAA 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

AHFS DI Essentials. © Copyright 2018, Selected Revisions November 13, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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

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