Alprazolam

Pronunciation

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

Introduction

Benzodiazepine; anxiolytic.b c

Uses for Alprazolam

Anxiety Disorders

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

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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 chemotherapyb (including cisplatin); b currently not recommended as monotherapy.b

May be useful in the management of anticipatory emesis.c

Alprazolam Dosage and Administration

General

  • Periodically reassess usefulness of the drug.

  • When discontinuing therapy or reducing daily dosage, reduce dosage gradually under close supervision. If significant withdrawal symptoms develop, reinstitute the previous dosage schedule; attempt a less-rapid schedule of dosage tapering only after stabilization. Some patients may be resistant to all discontinuance regimens.

  • The manufacturers recommend that dosage be decreased by ≤0.5 mg every 3 days; some patients may require slower reduction.

  • 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.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.c

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.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.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.

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.c

Panic Disorder
Oral

Maximum 10 mg daily.

Special Populations

Hepatic Impairment

Prolonged elimination. Use the smallest effective dosage.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.

Geriatric or Debilitated Patients

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

Cautions for Alprazolam

Contraindications

  • Known hypersensitivity to alprazolam or other benzodiazepines.b

  • Concurrent ketoconazole, itraconazole, or delavirdine 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;b however, clinical rationale for this contraindication has been questioned.b

Warnings/Precautions

Warnings

Withdrawal Effects

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

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.b

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.b c

Concurrent use of other CNS depressants may cause additive or potentiated CNS depression. (See Specific Drugs and Foods under Interactions.)

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.b Prescribe and dispense drug in the smallest feasible quantity.b

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.b

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.b

Pediatric Use

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

Geriatric Use

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

Hepatic Impairment

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

Renal Impairment

Use with caution.b

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.

Interactions for Alprazolam

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. Caution advised if alprazolam is used concomitantly 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 antidepressantb

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 concentrationsb

Cimetidine

Increased plasma alprazolam concentrations

Use with caution; consider reduction of alprazolam dosage

CNS depressants (e.g., opiates or other analgesics, sedatives, psychotropic drugs, anticonvulsants, antihistamines, alcohol)

Additive CNS effectb

Use caution to avoid overdosageb

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., amprenavir, 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

Oral contraceptives

Increased plasma alprazolam concentrations

Use with caution

Propoxyphene

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.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.b

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.b

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

  • 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.

Advice to Patients

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and alcohol consumption. Importance of avoiding alcohol-containing beverages or products.

  • Importance of taking only as prescribed; do not increase dosage or duration of therapy unless otherwise instructed by a clinician.

  • 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. Importance of discarding any cotton included in the container and of resealing the container tightly after each opening to prevent introduction of moisture.

  • For patients taking one-half of an orally disintegrating tablet, importance of immediately discarding the unused portion because of possible instability.

  • Importance of not abruptly discontinuing therapy; consult clinician about discontinuing use.

  • Potential for drug to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing clinicians of any behavioral or mental changes, memory impairment, tolerance, or dependence/withdrawal symptoms.b

  • Potential for severe emotional and physical dependence in some patients receiving increased dosages for the management of panic disorder. Discontinuance of the drug may be difficult, with increased risk of withdrawal symptoms, including seizures.

  • Importance of informing clinicians about any concomitant illnesses, particularly depression.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

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

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.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*

Xanax (C-IV; scored)

Pfizer

0.5 mg*

Xanax (C-IV; scored)

Pfizer

1 mg*

Xanax (C-IV; scored)

Pfizer

2 mg*

Xanax (C-IV; multi-scored)

Pfizer

Tablets, extended-release

0.5 mg

Alprazolam Extended-Release Tablets (C-IV)

Mylan, Sandoz

Xanax XR (C-IV)

Pfizer

1 mg

Alprazolam Extended-Release Tablets (C-IV)

Mylan, Sandoz

Xanax XR (C-IV)

Pfizer

2 mg

Alprazolam Extended-Release Tablets (C-IV)

Mylan, Sandoz

Xanax XR (C-IV)

Pfizer

3 mg

Alprazolam Extended-Release Tablets (C-IV)

Mylan, Sandoz

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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

ALPRAZolam 0.25MG Dispersible Tablets (PAR): 30/$43.99 or 90/$119.97

ALPRAZolam 0.25MG Tablets (GREENSTONE): 30/$11.99 or 90/$15.97

ALPRAZolam 0.5MG 24-hr Tablets (ACTAVIS ELIZABETH): 30/$31.99 or 90/$71.98

ALPRAZolam 0.5MG Tablets (GREENSTONE): 30/$12.99 or 60/$15.97

ALPRAZolam 1MG Dispersible Tablets (PAR): 30/$69.99 or 90/$195.97

ALPRAZolam 1MG Tablets (GREENSTONE): 30/$12.99 or 60/$14.98

ALPRAZolam 2MG Tablets (GREENSTONE): 30/$15.99 or 60/$18.97

ALPRAZolam XR 1MG 24-hr Tablets (GREENSTONE): 30/$69.99 or 90/$196.96

ALPRAZolam XR 2MG 24-hr Tablets (GREENSTONE): 30/$75.99 or 90/$219.97

ALPRAZolam XR 3MG 24-hr Tablets (GREENSTONE): 30/$109.98 or 90/$309.97

Niravam 0.25MG Dispersible Tablets (AZUR PHARMA): 30/$103.58 or 90/$274.17

Niravam 0.5MG Dispersible Tablets (AZUR PHARMA): 30/$136.99 or 90/$361.98

Niravam 1MG Dispersible Tablets (AZUR PHARMA): 30/$178.00 or 90/$490.96

Niravam 2MG Dispersible Tablets (AZUR PHARMA): 30/$255.90 or 90/$710.95

Xanax 0.25MG Tablets (PFIZER U.S.): 30/$56.99 or 90/$144.97

Xanax 0.5MG Tablets (PFIZER U.S.): 30/$64.99 or 90/$179.97

Xanax 1MG Tablets (PFIZER U.S.): 30/$85.99 or 90/$230.98

Xanax 2MG Tablets (PFIZER U.S.): 30/$129.99 or 90/$362.96

Xanax XR 0.5MG 24-hr Tablets (PFIZER U.S.): 30/$98.99 or 90/$282.40

Xanax XR 1MG 24-hr Tablets (PFIZER U.S.): 30/$122.84 or 90/$355.90

Xanax XR 2MG 24-hr Tablets (PFIZER U.S.): 30/$161.68 or 90/$463.03

Xanax XR 3MG 24-hr Tablets (PFIZER U.S.): 30/$229.95 or 90/$658.30

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

101. Noyes R Jr, Clancy J, Coryell WH et al. A withdrawal syndrome after abrupt discontinuance of alprazolam. Am J Psychiatry. 1985; 142:114-6. [IDIS 194746] [PubMed 2857066]

102. Levy AB. Delirium and seizures due to abrupt alprazolam withdrawal: case report. J Clin Psychiatry. 1984; 45:38-9. [IDIS 180244] [PubMed 6141159]

103. Breier A, Charney DS, Nelson JC. Seizures induced by abrupt discontinuance of alprazolam. Am J Psychiatry. 1984; 141:1606-7. [IDIS 193450] [PubMed 6150649]

104. Zipursky RB, Baker RW, Zimmer B. Alprazolam withdrawal delirium unresponsive to diazepam: case report. J Clin Psychiatry. 1985; 46:344-5. [IDIS 204423] [PubMed 2862137]

105. Greenblatt DJ, Shader RI, Abernathy DR. Current status of benzodiazepines (second of two parts). N Engl J Med. 1983; 309:410-6. [IDIS 174051] [PubMed 6135990]

107. Pecknold JC, Swinson RP, Kuch K et al. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. III. Discontinuation effects. Arch Gen Psychiatry. 1988; 45:429-36. [IDIS 241071] [PubMed 3282479]

108. Ayd FJ Jr. Problems associated with alprazolam therapy. Int Drug Ther Newsl. 1988; 23:29-31.

109. Ayd FJ Jr. Discontinuing alprazolam. Int Drug Ther Newsl. 1987; 22:27.

110. Anon. Choice of benzodiazepines. Med Lett Drugs Ther. 1988; 30:26-8. [PubMed 2893246]

111. Fyer AJ, Liebowitz MR, Gorman JM et al. Discontinuation of alprazolam treatment in panic patients. Am J Psychiatry. 1987; 144:303-8. [IDIS 226348] [PubMed 3826428]

b. AHFS drug information 2007. McEvoy GK, ed. Benzodiazepines general statement. Bethesda, MD: American Society of Health-System Pharmacists; 2007:2508-18.

c. AHFS drug information 2007. McEvoy GK, ed. Alprazolam. Bethesda, MD: American Society of Health-System Pharmacists; 2007:2518-9.

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