Alprazolam

Pronunciation

(al PRAY zoe lam)

U.S. Brand Names

Alprazolam Intensol®; Xanax®; Xanax XR®

Generic Available

Yes: Immediate release tablet

Canadian Brand Names

Alti-Alprazolam; Apo-Alpraz®; Gen-Alprazolam; Novo-Alprazol; Nu-Alprax; Xanax®; Xanax TS™

Use

Treatment of anxiety disorder (GAD); panic disorder, with or without agoraphobia; anxiety associated with depression

Use - Unlabeled/Investigational

Anxiety in children

Restrictions

C-IV

Pregnancy Risk Factor

Pregnancy Implications

Lactation

Enters breast milk/not recommended (AAP rates "of concern")

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

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). Dose reductions or tapering must be approached with extreme caution. Breakthrough anxiety may occur at the end of dosing interval. Use with caution in patients receiving concurrent CYP3A4 inhibitors, particularly when these agents are added to therapy. Has weak uricosuric properties, use with caution in renal impairment or predisposition to urate nephropathy. Use with caution in elderly or debilitated patients, patients with hepatic disease (including alcoholics), renal impairment, or obese patients.

Causes CNS depression (dose-related) resulting in sedation, dizziness, confusion, or ataxia which may impair physical and mental capabilities. Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Use with caution in patients receiving other CNS depressants or psychoactive agents. Effects with other sedative drugs or ethanol may be potentiated. Benzodiazepines have been associated with falls and traumatic injury and should be used with extreme caution in patients who are at risk of these events (especially the elderly). Use with caution in patients with respiratory disease or impaired gag reflex.

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. May cause physical or psychological dependence - use with caution in patients with a history of drug dependence. Acute withdrawal, including seizures, may be precipitated in patients after administration of flumazenil to patients receiving long-term benzodiazepine therapy.

Benzodiazepines have been associated with anterograde amnesia. Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines, particularly in adolescent/pediatric or psychiatric patients. Does not have analgesic, antidepressant, or antipsychotic properties.

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 of alprazolam during pregnancy should be avoided. In addition, symptoms of withdrawal, lethargy, and loss of body weight have been reported in infants exposed to alprazolam and/or benzodiazepines while nursing; use during breast-feeding is not recommended.

Adverse Reactions

>10%:

Central nervous system: Depression, drowsiness, dysarthria, fatigue, headache, irritability, lightheadedness, memory impairment, sedation

Endocrine & metabolic: Libido decreased, menstrual disorders

Gastrointestinal: Appetite increased/decreased, salivation decreased, weight gain/loss, xerostomia

1% to 10%:

Cardiovascular: Hypotension

Central nervous system: Abnormal coordination, akathisia, attention disturbance, confusion, derealization, disorientation, disinhibition, dizziness, hypersomnia, nightmares, vertigo

Dermatologic: Dermatitis, pruritus, rash

Endocrine & metabolic: Libido increased

Gastrointestinal: Diarrhea, dyspepsia, salivation increased, vomiting

Genitourinary: Incontinence, micturition difficulty, sexual dysfunction

Neuromuscular & skeletal: Arthralgia, ataxia, muscle cramps, muscle twitching, myalgia, paresthesia, rigidity, tremor

Ophthalmic: Blurred vision

Otic: Tinnitus

Respiratory: Allergic rhinitis, dyspnea, nasal congestion

Miscellaneous: Diaphoresis

<1% (Limited to important or life-threatening): Amnesia, falls, hypotension, photosensitivity, seizure, syncope, tachycardia, urticaria

Postmarketing and/or case reports: Gynecomastia, hepatic failure, hepatitis, hyperprolactinemia, Stevens-Johnson syndrome

Overdosage/Toxicology

Symptoms of overdose include somnolence, confusion, coma, and diminished reflexes. Treatment for benzodiazepine overdose is supportive. Flumazenil has been shown to selectively block the binding of benzodiazepines to CNS receptors, resulting in a reversal of benzodiazepine-induced sedation; however, its use may not reverse respiratory depression.

Drug Interactions

Substrate of CYP3A4 (major)

CNS depressants: Sedative effects and/or respiratory depression may be additive with CNS depressants. Includes ethanol, barbiturates, narcotic 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, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil. Contraindicated with itraconazole and ketoconazole.

Levodopa: Therapeutic effects may be diminished in some patients following the addition of a benzodiazepine; limited/inconsistent data.

Oral contraceptives: May decrease the clearance of some benzodiazepines (those which undergo oxidative metabolism); monitor for increased benzodiazepine effect.

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 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).

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

Distribution: Vd: 0.9-1.2 L/kg; enters breast milk

Protein binding: 80%

Metabolism: Hepatic via CYP3A4; forms 2 active metabolites (4-hydroxyalprazolam and -hydroxyalprazolam)

Bioavailability: 90%

Half-life elimination:

Adults: 11.2 hours (range: 6.3-26.9)

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: 1-2 hours

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; maximum: 4 mg/day

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; 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.

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: 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. The smallest effective dose should be used. 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 hepatic impairment: Reduce dose by 50% to 60% or avoid in cirrhosis

Administration

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.

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. 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 barrier contraceptive measures as recommended by your prescriber. Breast-feeding is not recommended.

Nursing Implications

Assist with ambulation during beginning therapy, raise bed rails and keep room partially illuminated at night; monitor for CNS and respiratory depression

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; not intended for management of anxieties and minor distresses associated with everyday life. Treatment >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.

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.

Dosage Forms

Solution, oral (Alprazolam Intensol®): 1 mg/mL (30 mL)

Tablet (Xanax®): 0.25 mg, 0.5 mg, 1 mg, 2 mg

Tablet, extended release (Xanax XR®): 0.5 mg, 1 mg, 2 mg, 3 mg

References

"American Academy of Pediatrics Committee on Drugs. The Transfer of Drugs and Other Chemicals Into Human Milk," Pediatrics , 2001, 108(3):776-89.

Ballenger JC, Burrows GD, DuPont RL Jr, et al, "Alprazolam in Panic Disorder and Agoraphobia: Results From a Multicenter Trial. I. Efficacy in Short-term Treatment," Arch Gen Psychiatry , 1988, 45(5):413-22.

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 Tial. 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.

Simeon JG and Ferguson HB, "Alprazolam Effects in Children With Anxiety Disorders," Can J Psychiatry , 1987, 32(7):570-4.

International Brand Names

Adax® (CL, EC); Afobam® (PL); Alcelam® (TH); Alganax® (ID); Alkrazil® (GT); Alnax® (TH); Alplax® (AR); Alpralid® (IL); Alpraphar® (BE); Alprastad® (AT); Alpraz® (BE, LU); Alprazig® (IT); Alprazolam ABC® (IT); Alprazolam AbZ® (DE); Alprazolam AL® (DE); Alprazolam Arcana® (AT); Alprazolam® (AT, CL, CO, RO); Alprazolam AZU® (DE); Alprazolam Bayvit® (ES); Alprazolam BC® (BE); Alprazolam Cinfa® (ES); Alprazolam Denver® (AR); Alprazolam Doc® (IT); Alprazolam Edigen® (ES); Alprazolam EG® (BE, IT); Alprazolam Esteve® (ES); Alprazolam Fabra® (AR); Alprazolam Geminis® (ES); Alprazolam Generics® (FI); Alprazolam GNR® (IT); Alprazolam Hexan® (IT); Alprazolam Kern® (ES); Alprazolam L.CH.® (CL); Alprazolam Luar® (AR); Alprazolam Mabo® (ES); Alprazolam Merck® (ES, IT, PT); Alprazolam MK® (CR, DO, GT, HN, PA, SV); Alprazolam NM Pharma® (SE); Alprazolam Normon® (ES); Alprazolam PCD® (DK); Alprazolam Pharmacia® (DK); Alprazolam Pharmagenus® (ES); Alprazolam Pliva® (ES); Alprazolam Qualix® (ES); Alprazolam-ratiopharm® (AT, BE, DE, DK, ES, IT); Alprazolam Sandoz® (DE); Alprazolam Stada® (SE); Alprazolam Tarbis® (ES); Alprazolam-TEVA® (DE, IT); Alprazomed® (BE); Alprazomerck® (PL); Alprocontin® (IN); Alprox® (DK, FI, HU, IE, IL, PL, RO, RU); Alti-Alprazolam (CA); Alviz® (ID); Alzam® (MX, ZA); Alzolam® (BD, RU); Anpress® (TH); Ansiopax® (CL); Anxirid® (ZA); Anzion® (TH); Apo-Alpraz® (CA, HU, SG, TR); Apraz® (BR); Azaxol® (CY); Azor® (ZA); Becede® (AR); Bestrol® (AR); Calmax® (IE); Calmlet® (ID); Cassadan® (DE); Constan® (JP); CPL Alliance Alprazolam® (ZA); Daclor® (DO); Dixin® (CO); Dizolam Atlantic® (TH); Dizolam® (SG); Docalprazo® (BE); Duazolam® (DO); Es-3 (DO); Frixitas® (ID); Frontal® (BR, IT); Frontin® (CZ, HU, PL, RO, RU); Gen-Alprazolam (CA); Gerax® (IE); Grifoalpram® (CL); Helex® (CZ, HR, RO, RU, SI); Huma-Alprazol® (HU); Ibizolam® (IT); Kalma® (AU); Krama® (AR); Ksalol® (YU); Librazolam® (EC); Marzolan® (TH); Meprax® (DO); Merck-Alprazolam® (ZA); Mialin® (IT); Neurol® (CZ, PL, RU); Nirvan® (CO); Novo-Alprazol (CA); Nu-Alprax (CA); Pazolam® (PT); Pharnak® (TH); Prazam® (CL, PT); Prazin® (EG, JO, KW, LB, SY); Prenadona® (AR); Prinox® (AR); PTA® (AR); Retan® (AR); Sanerva® (CL); Siampraxol® (TH); Tafil® (CR, DE, DK, GT, HN, MX, PA, SV); Tensium® (AR); Tensivan® (CO); Thiprazolan® (AR); Topazolam® (BE); Trankimazin® (ES); Tranquinal® (AR, CR, GT, PA, SV); Tricalma® (CL); Tricalma Retard® (CL); Unilan® (PT); Valeans® (IT); Xanacine® (TH); Xanagis® (IL); Xanax® (AR, AU, BE, BG, CA, CH, CO, CZ, DE, FR, GB, HK, HR, HU, ID, IE, IL, IT, LU, NL, NZ, PL, PT, RO, RU, SG, SI, TH, TR, YU); Xanax TS™ (CA); Xanor® (AT, FI, NO, SE); Xiemed® (TH); Zacetin® (SG); Zaxan® (YU); Zolarem® (RO, YU); Zomiren® (PL); Zopax® (ZA); Zotran® (CL); Zypraz® (ID)

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