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Medication Safety Issues
Sound-alike/look-alike issues:
Alprazolam may be confused with alprostadil, lorazepam, triazolam
Xanax® may be confused with Lanoxin®, Tenex®, Tylox®, Xopenex®, Zantac®, Zyrtec®
Pronunciation
(al PRAY zoe lam)
U.S. Brand Names
Generic Available
Yes: Extended release tablet, immediate release tablet
Canadian Brand Names
Pharmacologic Category
Use
Treatment of anxiety disorder (GAD); panic disorder, with or without agoraphobia; anxiety associated with depression
Use: Dental
Preoperative sedation
Use: Unlabeled/Investigational
Anxiety in children
Restrictions
C-IV
Pregnancy Risk Factor
D
Pregnancy Implications
Benzodiazepines have the potential to cause harm to the fetus, particularly when administered during the first trimester. In addition, withdrawal symptoms may occur in the neonate following in utero exposure. Use during pregnancy should be avoided.
Lactation
Enters breast milk/not recommended (AAP rates “of concern”)
Breast-Feeding Considerations
Symptoms of withdrawal, lethargy, and loss of body weight have been reported in infants exposed to alprazolam and/or benzodiazepines while nursing. Breast-feeding is not recommended.
Contraindications
Hypersensitivity to alprazolam or any component of the formulation (cross-sensitivity with other benzodiazepines may exist); narrow-angle glaucoma; concurrent use with ketoconazole or itraconazole; pregnancy
Warnings/Precautions
Concerns related to adverse effects:
• Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• Paradoxical reactions: Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines, particularly in adolescent/pediatric or psychiatric patients.
Disease-related concerns:
• Depression: Use caution in patients with depression, particularly if suicidal risk may be present; episodes of mania or hypomania have occurred in depressed patients treated with alprazolam.
• Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use (generally >10 days).
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Impaired gag reflux: Use with caution in patients with an impaired gag reflux.
• Renal impairment: Use with caution in patients with renal impairment or predisposition to urate nephropathy; has weak uricosuric properties.
• Respiratory disease: Use with caution in patients with respiratory disease.
Concurrent drug therapy issues:
• CNS depressants/psychoactive medications: Use with caution in patients receiving other CNS depressants or psychoactive medication; effects with other sedative drugs or ethanol may be potentiated.
• High potential for interactions: Use with caution in patients taking strong CYP3A4 inhibitors, moderate or strong CYP3A4 inducers and major CYP3A4 substrates (see Drug Interactions); consider alternative agents that avoid or lessen the potential for CYP-mediated interactions.
Special populations:
• Debilitated patients: Use with caution in debilitated patients.
• Elderly: Use with caution in the elderly; benzodiazepines have been associated with falls and traumatic injury.
• Fall risk: Use with extreme caution in patients who are at risk of falls; benzodiazepines have been associated with falls and traumatic injury.
• Obese patients: Use with caution in obese patients; may have prolonged action when discontinued.
Other warnings/precautions:
• Appropriate use: Does not have analgesic, antidepressant, or antipsychotic properties.
• Breakthrough anxiety: At the end of dosing interval, breakthrough anxiety may occur.
• Withdrawal: Rebound or withdrawal symptoms, including seizures, may occur 18 hours to 3 days following abrupt discontinuation or large decreases in dose (more common in patients receiving >4 mg/day or prolonged treatment). Use caution when reducing dose or withdrawing therapy; decrease slowly and monitor for withdrawal symptoms. Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy.
Adverse Reactions
>10%:
Central nervous system: Abnormal coordination, cognitive disorder, depression, drowsiness, fatigue, irritability, lightheadedness, memory impairment, sedation, somnolence
Gastrointestinal: Appetite increased/decreased, constipation, salivation decreased, weight gain/loss, xerostomia
Genitourinary: Micturition difficulty
Neuromuscular & skeletal: Dysarthria
1% to 10%:
Cardiovascular: Hypotension
Central nervous system: Agitation, attention disturbance, confusion, depersonalization, derealization, disorientation, disinhibition, dizziness, dream abnormalities, fear, hallucinations, hypersomnia, nightmares, seizure, talkativeness
Dermatologic: Dermatitis, pruritus, rash
Endocrine & metabolic: Libido decreased/increased, menstrual disorders
Gastrointestinal: Salivation increased
Genitourinary: Incontinence
Hepatic: Bilirubin increased, jaundice, liver enzymes increased
Neuromuscular & skeletal: Arthralgia, ataxia, myalgia, paresthesia
Ocular: Diplopia
Respiratory: Allergic rhinitis, dyspnea
<1% (Limited to important or life-threatening): Amnesia, falls
Postmarketing and/or case reports: Galactorrhea, gynecomastia, hepatic failure, hepatitis, hyperprolactinemia, Stevens-Johnson syndrome
Drug Interactions
Substrate of CYP3A4 (major)
CNS depressants: Sedative effects and/or respiratory depression may be additive with CNS depressants. Includes ethanol, barbiturates, opioid analgesics, and other sedative agents; monitor for increased effect.
CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of alprazolam. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.
CYP3A4 inhibitors: May increase the levels/effects of alprazolam. Example inhibitors include azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, telithromycin, and verapamil. Contraindicated with itraconazole and ketoconazole.
Fluoxetine: May increase plasma concentrations/effects of alprazolam.
Oral contraceptives: May increase serum levels/effects of alprazolam.
Theophylline: May partially antagonize some of the effects of benzodiazepines; monitor for decreased response; may require higher doses for sedation.
Tricyclic antidepressants: Plasma concentrations of imipramine and desipramine have been reported to be increased 31% and 20%, respectively, by concomitant administration; monitor.
Ethanol/Nutrition/Herb Interactions
Cigarette smoking: May decrease alprazolam concentrations up to 50%.
Ethanol: Avoid ethanol (may increase CNS depression).
Food: Alprazolam serum concentration is unlikely to be increased by grapefruit juice because of alprazolam's high oral bioavailability. The Cmax of the extended release formulation is increased by 25% when a high-fat meal is given 2 hours before dosing. Tmax is decreased 30% when food is given immediately prior to dose. Tmax is increased by 30% when food is given ?1 hour after dose.
Herb/Nutraceutical: St John's wort may decrease alprazolam levels. Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).
Storage
Orally-disintegrating tablet: Store at room temperature of 20°C to 25°C (68°F to 77°F). Protect from moisture. Seal bottle tightly and discard any cotton packaged inside bottle.
Mechanism of Action
Binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system, including the limbic system, reticular formation. Enhancement of the inhibitory effect of GABA on neuronal excitability results by increased neuronal membrane permeability to chloride ions. This shift in chloride ions results in hyperpolarization (a less excitable state) and stabilization.
Pharmacodynamics/Kinetics
Onset of action: Immediate release and extended release formulations: 1 hour
Duration of action: Immediate release: 5.1 ± 1.7 hours; Extended release: 11.3 ± 4.2 hours
Absorption: Extended release: Slower relative to immediate release formulation resulting in a concentration that is maintained 5-11 hours after dosing
Distribution: Vd: 0.9-1.2 L/kg; enters breast milk
Protein binding: 80%; primarily to albumin
Metabolism: Hepatic via CYP3A4; forms two active metabolites (4-hydroxyalprazolam and ?-hydroxyalprazolam)
Bioavailability: 90%
Half-life elimination:
Adults: 11.2 hours (immediate release range: 6.3-26.9; extended release range: 10.7-15.8)
Elderly: 16.3 hours (range: 9-26.9 hours)
Alcoholic liver disease: 19.7 hours (range: 5.8-65.3 hours)
Obesity: 21.8 hours (range: 9.9-40.4 hours)
Time to peak, serum: Immediate release: 1-2 hours; Extended release: ?9 hours; decreased by 1 hour following bedtime dosing compared to morning dosing
Excretion: Urine (as unchanged drug and metabolites)
Dosage
Oral: Note: Treatment >4 months should be re-evaluated to determine the patient's continued need for the drug
Children: Anxiety (unlabeled use): Immediate release: Initial: 0.005 mg/kg/dose or 0.125 mg/dose 3 times/day; increase in increments of 0.125-0.25 mg, up to a maximum of 0.02 mg/kg/dose or 0.06 mg/kg/day (0.375-3 mg/day)
Adults:
Anxiety: Immediate release: Effective doses are 0.5-4 mg/day in divided doses; the manufacturer recommends starting at 0.25-0.5 mg 3 times/day; titrate dose upward; usual maximum: 4 mg/day. Patients requiring doses >4 mg/day should be increased cautiously. Periodic reassessment and consideration of dosage reduction is recommended.
Anxiety associated with depression: Immediate release: Average dose required: 2.5-3 mg/day in divided doses
Ethanol withdrawal (unlabeled use): Immediate release: Usual dose: 2-2.5 mg/day in divided doses
Panic disorder:
Immediate release: Initial: 0.5 mg 3 times/day; dose may be increased every 3-4 days in increments ?1 mg/day. Mean effective dosage: 5-6 mg/day; many patients obtain relief at 2 mg/day, as much as 10 mg/day may be required
Extended release: 0.5-1 mg once daily; may increase dose every 3-4 days in increments ?1 mg/day (range: 3-6 mg/day)
Switching from immediate release to extended release: Patients may be switched to extended release tablets by taking the total daily dose of the immediate release tablets and giving it once daily using the extended release preparation.
Preoperative sedation: 0.5 mg in evening at bedtime and 0.5 mg 1 hour before procedure
Dose reduction: Abrupt discontinuation should be avoided. Daily dose may be decreased by 0.5 mg every 3 days, however, some patients may require a slower reduction. If withdrawal symptoms occur, resume previous dose and discontinue on a less rapid schedule.
Elderly: Initial: 0.125-0.25 mg twice daily; increase by 0.125 mg/day as needed. The smallest effective dose should be used. Note: Elderly patients may be more sensitive to the effects of alprazolam including ataxia and oversedation. The elderly may also have impaired renal function leading to decreased clearance. Titrate gradually, if needed.
Immediate release: Initial: 0.25 mg 2-3 times/day
Extended release: Initial: 0.5 mg once daily
Dosing adjustment in renal impairment: No guidelines for adjustment; use caution
Dosing adjustment in hepatic impairment: Reduce dose by 50% to 60% or avoid in cirrhosis
Dental Usual Dosing
Preoperative sedation: Adults: Oral: 0.5 mg in evening at bedtime and 0.5 mg 1 hour before procedure
Administration: Oral
Immediate release preparations: Can be administered sublingually with comparable onset and completeness of absorption.
Extended release tablet: Should be taken once daily in the morning; do not crush, break, or chew.
Orally-disintegrating tablets: Using dry hands, place tablet on top of tongue. If using one-half of tablet, immediately discard remaining half (may not remain stable). Administration with water is not necessary.
Monitoring Parameters
Respiratory and cardiovascular status
Patient Education
Take exactly as directed; do not increase dose or frequency. Drug may cause physical and/or psychological dependence. Avoid alcohol and do not take other prescription or OTC medications (especially pain medications, sedatives, antihistamines, or hypnotics) without consulting prescriber. Do not stop medication or reduce dosage abruptly without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may experience drowsiness, lightheadedness, impaired coordination, dizziness, or blurred vision (use caution when driving or engaging in hazardous tasks until response to drug is known); nausea, vomiting, or dry mouth (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); constipation (increased exercise, fluids, fruit, and fiber may help); altered sexual drive or ability (reversible); or photosensitivity (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight). Report persistent CNS effects (eg, confusion, depression, increased sedation, excitation, headache, agitation, insomnia or nightmares, dizziness, fatigue, impaired coordination, changes in personality, or changes in cognition); changes in urinary pattern; muscle cramping, weakness, tremors, or rigidity; ringing in ears or visual disturbances; chest pain, palpitations, or rapid heartbeat; excessive perspiration; excessive GI symptoms (eg, cramping, constipation, vomiting, anorexia); or worsening of condition. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication; use appropriate contraceptive measures as recommended by your prescriber. Breast-feeding is not recommended.
Geriatric Considerations
Considered to be a benzodiazepine of choice in elderly due to the short duration of action.
Additional Information
Not intended for management of anxieties and minor distresses associated with everyday life. Treatment longer than 4 months should be re-evaluated to determine the patient's need for the drug. Patients who become physically dependent on alprazolam tend to have a difficult time discontinuing it; withdrawal symptoms may be severe. To minimize withdrawal symptoms, taper dosage slowly; do not discontinue abruptly. Abrupt discontinuation after sustained use (generally >10 days) may cause withdrawal symptoms.
Anesthesia and Critical Care Concerns/Other Considerations
Chronic use of this agent may increase the perioperative benzodiazepine dose needed to achieve desired effect. Patients who become physically dependent on alprazolam tend to have a difficult time discontinuing it; withdrawal symptoms may be severe. To minimize withdrawal symptoms, taper dosage slowly; do not discontinue abruptly. Abrupt discontinuation after sustained use (generally >10 days) may cause withdrawal symptoms.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Significant xerostomia and changes in salivation (normal salivary flow resumes upon discontinuation)
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Child/Adolescent Considerations
Children <18 years: Anxiety: Dose not established; investigationally, in children 7-16 years of age (n=13), initial doses of 0.005 mg/kg or 0.125 mg/dose were given 3 times/day for situational anxiety; increments of 0.125-0.25 mg were used to increase doses to maximum of 0.02 mg/kg/dose or 0.06 mg/kg/day; a range of 0.375-3 mg/day was needed.
Note: A more recent study in 17 children (8-17 years of age) with overanxious disorder or avoidant disorders used initial daily doses of 0.25 mg for children <40 kg and 0.5 mg for those >40 kg. The dose was titrated at 2-day intervals to a maximum of 0.04 mg/kg/day. Required doses ranged from 0.5-3.5 mg/day (mean: 1.6 mg/day). Based on clinical global ratings, alprazolam appeared to be better than placebo, however, this difference was not statistically significant; further studies are needed (Simeon, 1992).
Simeon JG, Ferguson HB, Knott V, et al, “Clinical, Cognitive, and Neurophysiological Effects of Alprazolam in Children and Adolescents With Overanxious and Avoidant Disorders,” J Am Acad Child Adolesc Psychiatry, 1992, 31(1):29-33.
Mental Health: Comment
There are two subtypes of GABA receptors (GABA-A and GABA-B) and three different benzodiazepine receptors (Bz1, Bz2, and Bz3). Benzodiazepine receptors and effects appear to be linked to the GABA-A receptors. Benzodiazepines do not bind to GABA-B receptors. The role of GABA-B receptors is unclear. Benzodiazepines have no specificity for benzodiazepine receptor subtypes.
Alprazolam is a short half-life benzodiazepine. Duration of action after a single dose is determined by redistribution rather than metabolism. Tolerance develops to the sedative, hypnotic, and anticonvulsant effects. It does not develop to the anxiolytic or skeletal muscle-relaxing effects. Psychological and physical dependence may occur with prolonged use of benzodiazepines. The onset of withdrawal symptoms is usually seen on the first day without drug and lasts 5-7 days in patients receiving short half-life benzodiazepines, whereas, the onset occurs after 5 days with a duration of 10-14 days after abrupt discontinuance of long half-life benzodiazepines. Risk factors for abuse include alcohol abuse, personality disorders in the patient or the patient's parent(s).
With the exception of a slower absorption rate, the extended release dosage form of alprazolam displays similar bioavailability and pharmacokinetics to the immediate release dosage form. The slower absorption rate results in a concentration that is maintained between 5-11 hours after dosing. The rate of absorption of benzodiazepines has been linked to abuse potential and side effect burden (sedation and cognitive impairment). The extended release dosage form may have less abuse potential and side effects relative to the immediate release dosage form.
Nursing: Physical Assessment/Monitoring
Assess other medications patient may be taking for effectiveness and interactions. Assess for signs of CNS depression. Assess for history of addiction; long-term use can result in dependence, abuse, or tolerance; periodically evaluate need for continued use. For inpatient use, institute safety measures and monitor effectiveness and adverse reactions. For outpatients, monitor therapeutic effectiveness and adverse reactions at beginning of therapy and periodically with long-term use. Taper dosage slowly when discontinuing. Assess knowledge/teach patient appropriate use, interventions to reduce side effects, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, oral [concentrate]:
Alprazolam Intensol®: 1 mg/mL (30 mL) [alcohol free, dye free, sugar free; contains propylene glycol]
Tablet: 0.25 mg, 0.5 mg, 1 mg, 2 mg
Xanax®: 0.25 mg, 0.5 mg, 1 mg, 2 mg
Tablet, extended release: 0.5 mg, 1 mg, 2 mg, 3 mg
Xanax XR®: 0.5 mg, 1 mg, 2 mg, 3 mg
Tablet, orally disintegrating [scored]:
Niravam™: 0.25 mg, 0.5 mg, 1 mg, 2 mg [orange flavor]
Pricing: U.S. (www.drugstore.com)
Tablet, 24-hour (Alprazolam)
0.5 mg (30): $31.99
1 mg (30): $69.99
2 mg (30): $76.00
Tablet, 24-hour (Xanax XR)
0.5 mg (30): $77.69
1 mg (30): $99.11
2 mg (30): $128.72
3 mg (30): $193.07
Tablet, orally-disintegrating (Niravam)
0.25 mg (30): $40.94
0.5 mg (30): $50.39
1 mg (30): $61.99
2 mg (30): $104.99
Tablets (Alprazolam)
0.25 mg (30): $11.99
0.5 mg (30): $11.99
1 mg (30): $11.99
2 mg (30): $13.99
Tablets (Xanax)
0.25 mg (30): $44.09
0.5 mg (30): $51.44
1 mg (30): $65.09
2 mg (30): $105.99
References
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Bernstein GA, Garfinkel BD, and Borchardt CM, “Comparative Studies of Pharmacotherapy for School Refusal,” J Am Acad Child Adolesc Psychiatry, 1990, 29(5):773-81.
Cano-Munoz JL, Montejo-Iglesias ML, Yanez-Saez RM, et al, “Possible Serotonin Syndrome Following the Combined Administration of Clomipramine and Alprazolam,” J Clin Psychiatry, 1995, 56(3):122.
Crome P and Ali C, “Clinical Features and Management of Self Poisoning With Newer Antidepressants,” Med Toxicol Adverse Drug Exp, 1986, 1(6):411-20.
Fawcett JA and Kravitz HM, “Alprazolam: Pharmacokinetics, Clinical Efficacy, and Mechanism of Action,” Pharmacotherapy, 1982, 2(5):243-54.
Freeman EW, Rickels K, Sondheimer SJ, et al, “A Double-Blind Trial of Oral Progesterone, Alprazolam, and Placebo in Treatment of Severe Premenstrual Syndrome,” JAMA, 1995, 274(1):51-7.
Greenblatt DJ, Divoll M, Abernethy DR, et al, “Alprazolam Kinetics in the Elderly: Relation to Antipyrine Disposition,” Arch Gen Psychiatry, 1983, 40(3):287-90.
McCormick SR, Nielsen J, and Jatlow PI, “Alprazolam Overdose, Clinical Findings and Serum Concentrations in Two Cases,” J Clin Psychiatry, 1985, 46(6):247-8.
Mokhlesi B, Leikin JB, Murray P, et al, “Adult Toxicology in Critical Care: Part II: Specific Poisonings,” Chest, 2003, 123(3):897-922.
Moulin CH, Rolachon A, Cohard M, et al, “Fulminant Hepatitis Secondary to Alprazolam,” Therapie, 1994, 49(4):362-3.
Mumford GK, Evans SM, Fleishaker JC, et al, “Alprazolam Absorption Kinetics Affects Abuse Liability,” Clin Pharmacol Ther, 1995, 57(3):356-65.
Noyes R Jr, DuPont RL Jr, Pecknold JC, et al, “Alprazolam in Panic Disorder and Agoraphobia: Results From a Multicenter Trial. II. Patient Acceptance, Side Effects, and Safety,” Arch Gen Psychiatry, 1988, 45(5):423-8.
Pfefferbaum B, Overall JE, Boren HA, et al, “Alprazolam in the Treatment of Anticipatory and Acute Situational Anxiety in Children With Cancer,” J Am Acad Child Adolesc Psychiatry, 1987, 26(4):532-5.
Prischl F, Donner A, Grimm G, et al, “Value of Flumazenil in Benzodiazepine Self-Poisoning,” Med Toxicol Adverse Drug Exp, 1988, 3(4):334-9.
Reidenberg MM, Levy M, Warner H, et al, “Relationship Between Diazepam Dose, Plasma Level, Age, and Central Nervous System Depression,” Clin Pharmacol Ther, 1978, 23(4):371-4.
Rickels K, “Alprazolam Extended-Release in Panic Disorder,” Expert Opin Pharmacother, 2004, 5(7):1599-611.
Sheehan DV, Sheehan KH, and Raj BA, “The Speed of Onset of Action of Alprazolam-XR Compared to Alprazolam-CT in Panic Disorder,” Psychopharmacol Bull, 2007, 40(2):63-81.
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Simeon JG, Ferguson HB, Knott V, et al, “Clinical, Cognitive, and Neurophysiological Effects of Alprazolam in Children and Adolescents With Overanxious and Avoidant Disorders,” J Am Acad Child Adolesc Psychiatry, 1992, 31(1):29-33.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2008
Content last modified May 2008
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