Alprazolam (Systemic)

Introductory Information
Benzodiazepine; anxiolytic.b, c
Class: 28:24.08 Benzodiazepines; cn302 (VA primary)
Brands*: Niravam, Xanax
*

also available generically

Generic Name: Alprazolam

CAS Number: 28981-97-7
Chemical Name: 8-Chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine
Molecular Formula: C17H13ClN4
Investigational Drug Number: U-31,889

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

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

May be useful in the management of anticipatory emesis

.c

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
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
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

Antidepressants, SSRIs

Interaction
Comments
Possible increase in plasma
Use with caution
alprazolam concentrations
Fluoxetine or fluvoxamine: Fluvoxamine: Use with caution;

(fluoxetine, fluvoxamine,

Increased plasma

consider reduction of alprazolam

paroxetine, sertraline)

alprazolam concentrations

dosage

Paroxetine: Possible

Fluoxetine, paroxetine, or

interaction in vitro

sertraline: Use with caution

Amiodarone

Sertraline: Possible

interaction in vitro; no
clinically important
Antidepressants, tricyclics

interaction in vivo
Possible increase in plasma

(e.g., imipramine,

concentrations of

desipramine)

antidepressantb

Clinical importance unknown

Concomitant use of itraconazole
or ketoconazole is

Antifungals, azoles (e.g.,

Increased plasma

contraindicated; avoid

itraconazole, ketoconazole)

alprazolam concentrations

concomitant use of other azole

antifungals that are potent
CYP3A inhibitors

Calcium-channel blocking
agents (diltiazem, nicardipine,
nifedipine)
Carbamazepine
Cigarette smoking
Cimetidine

Possible increase in plasma

alprazolam concentrations

Use with caution

Possible decrease in plasma

alprazolam concentrations
Decreased plasma
alprazolam concentrationsb
Increased plasma
Use with caution; consider
alprazolam concentrations

reduction of alprazolam dosage

Additive CNS effectb

Use caution to avoid overdosageb

CNS depressants (e.g., opiates

or other analgesics, sedatives,
psychotropic drugs,
anticonvulsants,
antihistamines, alcohol)
Cyclosporine

Possible increase in plasma

alprazolam concentrations
Potential for decreased

Use with caution

alprazolam metabolism
Delavirdine

resulting in intense and

Concomitant use contraindicated

prolonged sedation and

Digoxin
Disulfiram

respiratory depression
Digoxin toxicity reported in Monitor carefully and adjust
at least 1 patient
Possible decrease in

digoxin dosage as necessary

Reduce alprazolam dosage as

Ergotamine
Grapefruit juice
HIV protease inhibitors (e.g.,
amprenavir, fosamprenavir,
ritonavir, saquinavir)
Isoniazid
Macrolides (e.g.,

alprazolam clearance
necessary
Possible increase in plasma
Use with caution
alprazolam concentrations
Possible increase in plasma
Use with caution
alprazolam concentrations
Clinical importance not
Possible increase in plasma determined; consider possible
alprazolam concentrations

reduction
Possible increase in plasma
alprazolam concentrations
Possible increase in plasma

clarithromycin, erythromycin) alprazolam concentrations

Increased plasma
Nefazodone
alprazolam concentrations
Increased plasma
Oral contraceptives
alprazolam concentrations
Increased plasma
Propoxyphene
alprazolam concentrations
No effect on PT or plasma
Warfarin

need for alprazolam dosage

Use with caution

Use with caution
Use with caution; consider
reduction of alprazolam dosage
Use with caution
Use with caution

warfarin concentrations
observed

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
20-25C.

Orally Disintegrating Tablets

20-25C (may be exposed to 15-30C). 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
25C (may be exposed to 15-30C).
Solution (Concentrate)
Tight, light-resistant containers at 15-30C.
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 (GABAAreceptor-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 alcoholcontaining 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 (CIV) drug.c
Alprazolam
Routes Dosage Forms
Oral Solution, concentrate
Tablets

Tablets, extendedrelease

Tablets, orally
disintegrating

Strengths Brand Names

1 mg/mL Alprazolam Intensol (C-IV)
0.25 mg* Xanax (C-IV; scored)
0.5 mg* Xanax (C-IV; scored)
1 mg* Xanax (C-IV; scored)
2 mg* Xanax (C-IV; multi-scored)
Alprazolam Extended-Release
0.5 mg
Tablets (C-IV)
Xanax XR (C-IV)
Alprazolam Extended-Release
1 mg
Tablets (C-IV)
Xanax XR (C-IV)
Alprazolam Extended-Release
2 mg
Tablets (C-IV)
Xanax XR (C-IV)
Alprazolam Extended-Release
3 mg
Tablets (C-IV)
Xanax XR (C-IV)

Manufacturer
Roxane
Pfizer
Pfizer
Pfizer
Pfizer
Mylan,

0.25 mg Niravam (C-IV; scored)

Schwarz

Niravam (C-IV; scored)

Niravam (C-IV; scored)

Schwarz
Schwarz

0.5 mg
1 mg

Sandoz
Pfizer
Mylan,
Sandoz
Pfizer
Mylan,
Sandoz
Pfizer
Mylan,
Sandoz
Pfizer

2 mg
Niravam (C-IV; scored)
Schwarz
* available from one or more manufacturer, distributor, and/or repackager by generic
(nonproprietary) name
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This
pricing information was updated 03/2011. For the most current and up-to-date pricing
information, please visit www.drugstore.com. Actual costs to patients will vary depending on
the use of specific retail or mail-order locations and health insurance copays.
ALPRAZolam 0.25MG Tablets (GREENSTONE): 30/$11.99 or 90/$15.97
ALPRAZolam 0.5MG Tablets (GREENSTONE): 30/$11.99 or 60/$12.97
ALPRAZolam 1MG Tablets (GREENSTONE): 30/$12.99 or 60/$14.98
ALPRAZolam 2MG Tablets (GREENSTONE): 30/$14.99 or 60/$17.97
ALPRAZolam XR 0.5MG 24-hr Tablets (GREENSTONE): 30/$31.99 or 90/$71.97
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 or 90/$490.96
Niravam 2MG Dispersible Tablets (AZUR PHARMA): 30/$255.9 or 90/$710.95
Xanax 0.25MG Tablets (PFIZER U.S.): 30/$53.99 or 90/$136.39
Xanax 0.5MG Tablets (PFIZER U.S.): 30/$61.59 or 90/$167.97
Xanax 1MG Tablets (PFIZER U.S.): 30/$76.54 or 90/$204.96
Xanax 2MG Tablets (PFIZER U.S.): 30/$124.64 or 90/$341.02
Xanax XR 0.5MG 24-hr Tablets (PFIZER U.S.): 30/$96.99 or 90/$268.96
Xanax XR 1MG 24-hr Tablets (PFIZER U.S.): 30/$116.99 or 90/$338.96
Xanax XR 2MG 24-hr Tablets (PFIZER U.S.): 30/$151.99 or 90/$435.97
Xanax XR 3MG 24-hr Tablets (PFIZER U.S.): 30/$216 or 90/$617.96
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; 23:2931.
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.