General Articles

Alprazolam

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®

U.S. BRAND NAMES — Alprazolam Intensol®; Niravam™ ; Xanax XR®; Xanax®

PHARMACOLOGIC CATEGORY
Benzodiazepine

DOSING: ADULTS — Note: Treatment >4 months should be re-evaluated to determine the patient’s continued need for the drug

Anxiety: Oral: 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: Oral: Immediate release: Average dose required: 2.5-3 mg/day in divided doses

Ethanol withdrawal (unlabeled use): Oral: Immediate release: Usual dose: 2-2.5 mg/day in divided doses

Panic disorder: Oral:
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: Oral: 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.

DOSING: PEDIATRIC

(For additional information see “Alprazolam: Pediatric drug information”)
Anxiety (unlabeled use): Oral: 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). See “Dose Reduction” comment in adult dosing.

Note: Treatment >4 months should be re-evaluated to determine the patient’s continued need for the drug.

DOSING: ELDERLY — Initial: 0.125-0.25 mg twice daily; increase by 0.125 mg/day as needed. The smallest effective dose should be used.
Immediate release: Initial 0.25 mg 2-3 times/day
Extended release: Initial: 0.5 mg once daily

DOSING: RENAL IMPAIRMENT — No guidelines for adjustment; use caution.

DOSING: HEPATIC IMPAIRMENT — Oral: Reduce dose by 50% to 60% or avoid in cirrhosis.

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]: 0.25 mg, 0.5 mg, 1 mg, 2 mg
Niravam™ : 0.25 mg, 0.5 mg, 1 mg, 2 mg [orange flavor]

DOSAGE FORMS: CONCISE
Solution, oral [concentrate]:
Alprazolam Intensol®: 1 mg/mL

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]: 0.25 mg, 0.5 mg, 1 mg, 2 mg
Niravam™ : 0.25 mg, 0.5 mg, 1 mg, 2 mg

GENERIC EQUIVALENT AVAILABLE — Yes: Excludes oral solution

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.

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.

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

USE – UNLABELED / INVESTIGATIONAL — Anxiety in children

ADVERSE REACTIONS SIGNIFICANT
>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

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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, galactorrhea, gynecomastia, hepatic failure, hepatitis, hyperprolactinemia, Stevens-Johnson syndrome 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 CYP

3A4 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.

RESTRICTIONS — C-IV

METABOLISM / TRANSPORT EFFECTS — Substrate of CYP3A4 (major)

DRUG INTERACTIONS
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification

Aprepitant: May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification

CarBAMazepine: May increase the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Cimetidine: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Clozapine: Benzodiazepines may enhance the adverse/toxic effect of Clozapine. Risk D: Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

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CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Disulfiram: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Fluconazole: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification

Fosaprepitant: May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Specifically, the active metabolite aprepitant is likely responsible for this effect. Risk C: Monitor therapy

Grapefruit Juice: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification

Isoniazid: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Macrolide Antibiotics: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Exceptions: Azithromycin; Dirithromycin [Off Market]; Spiramycin. Risk D: Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce dosage of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification

Nefazodone: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification

Oral Contraceptive (Estrogens): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Oral Contraceptive (Progestins): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Protease Inhibitors: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Management: Amprenavir, atazanavir, darunavir, indinavir, nelfinavir, ritonavir, and tipranavir are contraindicated with midazolam and triazolam according to each protease inhibitor’s prescribing information. Risk D: Consider therapy modification

Proton Pump Inhibitors: May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Exceptions: Lansoprazole; Pantoprazole; Rabeprazole. Risk C: Monitor therapy

Rifamycin Derivatives: May increase the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification

Selective Serotonin Reuptake Inhibitors: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Exceptions: Citalopram; Escitalopram; PARoxetine; Sertraline. Risk C: Monitor therapy

St Johns Wort: May increase the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Risk D: Consider therapy modification

Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Risk C: Monitor therapy

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).

PREGNANCY RISK FACTOR — D (show table)

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.

PRICING — (data from drugstore.com)
Concentrate (ALPRAZolam Intensol)
1 mg/mL (30): $67.03

Tablet, 24-hour (ALPRAZolam)
0.5 mg (30): $31.99
1 mg (30): $69.99
2 mg (30): $76.00
3 mg (30): $109.98

Tablet, 24-hour (Xanax XR)
0.5 mg (30): $81.58
1 mg (30): $104.06
2 mg (30): $135.16
3 mg (30): $202.73

Tablet, orally-disintegrating (Niravam)
0.25 mg (30): $86.32
0.5 mg (30): $104.93
1 mg (30): $135.40
2 mg (30): $213.26

Tablets (ALPRAZolam)
0.25 mg (

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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): $48.29
0.5 mg (30): $54.01
1 mg (30): $68.34
2 mg (30): $111.29

MONITORING PARAMETERS — Respiratory and cardiovascular status

CANADIAN BRAND NAMES — Alti-Alprazolam; Apo-Alpraz®; Apo-Alpraz® TS; Gen-Alprazolam; Novo-Alprazol; Nu-Alprax; Xanax TS™ ; Xanax®

INTERNATIONAL BRAND NAMES — Aceprax (PY, UY); Actazolam (ID); Afobam (PL); Alcelam (TH); Alganax (ID); Alnax (TH); Alpaz (PE); Alplax (AR); Alpralid (IL); Alpraline (MY); Alpram (KP); Alpranax (MY); Alprax (AU, HK, IN, TH); Alpraz (LU); Alprazomerck (PL); Alprocontin (IN); Alprox (HU, IL, PL); Altrox (PH); Alviz (ID); Alzam (MX, ZA); Alzax (KP); Alzolam (IN); Anax (TH); Anpress (TH); Apo-Alpraz (SG); Apraz (BR); Aprazo (TW); Azor (ZA); Cassadan (DE); Constan (JP); Daclor (DO); Dixin (CO); Farmapram (MX); Feprax (ID); Frontal (BR); Frontin (HU, PL); Helex (HR); Irizz. (MX); Kalma (AU); Kinax (TW); Marzolam (TH); Neupax (MX); Neurol (PL); Pacyl (IN); Pharnax (TH); Prazol (AE, BH, CY, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Prazovex (MY); Prinox (AR); Solanax (JP); Soxietas (ID); Tafil (CR, DE, DK, DO, GT, HN, MX, NI, PA, SV, VE); Tafil D (MU); Tazun (MX); Tensivan (CO); Trankimazin Retard (ES); Tranquinal (BR, DO, EC, GT, HN, NI, PA, PE, PY, SV, UY); Tricalma (CN); Valeans (IT); Xanacine (TH); Xanagis (IL); Xanax (AE, AR, AU, BB, BE, BF, BG, BH, BJ, BM, BS, BZ, CH, CI, CO, CY, CZ, DE, EC, EE, EG, ET, FR, GB, GH, GM, GN, GR, GY, HK, HN, HR, HU, IE, IL, IQ, IR, IT, JM, JO, KE, KW, LB, LR, LU, LY, MA, ML, MR, MU, MW, MY, NE, NG, NL, OM, PE, PK, PL, PT, QA, SA, SC, SD, SL, SN, SR, SY, TH, TN, TT, TW, TZ, UG, YE, ZA, ZM, ZW); Xanax SR (SG); Xanax XR (IL, TH, TW); Xanor (AT, FI, NO, PH, SE, ZA); Xanor XR (PH); Zacetin (KP); Zamhexal (AU); Zanapam (AE, BH, CY, EG, IL, IQ, IR, JO, KP, KW, LB, LY, OM, QA, SA, SY, YE); Zolam (IN); Zolarem (AE, BF, BH, BJ, CI, CY, EG, ET, GH, GM, GN, IL, IQ, IR, JO, KE, KW, LB, LR, LY, MA, ML, MR, MU, MW, NE, NG, OM, QA, SA, SC, SD, SL, SN, SY, TN, TZ, UG, YE, ZA, ZM, ZW); Zolastin (ID); Zoldac (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZA, ZM, ZW); Zomiren (PL); Zopax (ZA); Zotran (CN); Zypraz (ID); Zyren (KP)

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: 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 alpha-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)

PATIENT INFORMATION — Avoid alcohol and other CNS depressants; avoid activities needing good psychomotor coordination until CNS effects are known; drug may cause physical or psychological dependence; avoid abrupt discontinuation after prolonged use; do not crush, break, or chew extended release tablets


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