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

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 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.

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

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 (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

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

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 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.

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

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 (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

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

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 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.

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

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 (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

Alpha-1 proteinase inhibitor

U.S. BRAND NAMES — Aralast; Aralast NP; Prolastin®; Zemaira®

PHARMACOLOGIC CATEGORY
Antitrypsin Deficiency Agent
Blood Product Derivative

DOSING: ADULTS — Alpha1-antitrypsin deficiency: I.V.: 60 mg/kg once weekly

DOSING: ELDERLY — Refer to adult dosing.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, powder for reconstitution [preservative free]:
Aralast, Aralast NP: 500 mg, 1000 mg [contains sodium ≤ 230 mEq/L and polysorbate 80; packaged with diluent]
Prolastin®: 500 mg, 1000 mg [contains sodium 100-210 mEq/L and sucrose; packaged with diluent]
Zemaira®: 1000 mg [contains sodium 81 mEq/1000 mg; packaged with diluent]

DOSAGE FORMS: CONCISE
Injection, powder for reconstitution [preservative free]:
Aralast, Aralast NP, Prolastin®: 500 mg, 1000 mg
Zemaira®: 1000 mg

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — For I.V. infusion only; reduce rate or temporarily discontinue infusion if adverse effects occur. Infuse at ~0.08 mL/kg/minute; actual rate may be increased or decreased based on patient response. Emergency equipment (including epinephrine) should be available during infusion. Do not mix with other agents or solutions.

USE — Replacement therapy in congenital alpha1-antitrypsin deficiency with clinical emphysema

ADVERSE REACTIONS SIGNIFICANT
>10%: Hepatic: ALT increased (11%; ~4 times ULN), AST increased (11%; ~4 times ULN)

1% to 10%:
Central nervous system: Headache (≤ 7%)
Neuromuscular & skeletal: Musculoskeletal discomfort (7%)
Respiratory: Pharyngitis (2%)

<1% (Limited to important or life-threatening): Allergic reactions, asthma, back pain, bilateral pulmonary infiltrates, bloating, bronchitis, chest pain, chills, cough increased, dizziness, dyspnea, fever <102ºF (delayed up to 12 hours after treatment), flu-like syndrome, hypotension, leukocytosis, lightheadedness, pain, peripheral edema, pruritus, rash, rhinitis, sinusitis, somnolence, tachycardia, vasodilation, viral infection, vision abnormal. Severe reactions (anaphylaxis) may occur in patients with anti-IgA antibody.

CONTRAINDICATIONS — Hypersensitivity to any component of the formulation or other A1-PI products; selective IgA deficiency with known anti-IgA antibody

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Anaphylaxis/hypersensitivity reactions: Hypersensitivity and anaphylactic reactions can occur; immediate treatment (including epinephrine 1:1000) should be available. Severe anaphylaxis may occur in patients with anti-IgA antibody; use in patients with selective IgA deficiency with known anti-IgA antibody is contraindicated

Disease-related concerns: Fluid overload: Use with caution in patients at risk for fluid overload. Hepatitis B: May consider hepatitis B immunization.

Special populations: Pediatrics: Safety and efficacy have not been established in children.

Dosage form specific issues: Human plasma: Product of human plasma; may potentially contain infectious agents which could transmit disease. Screening of donors, as well as testing and/or inactivation or removal of certain viruses, reduces the risk. Infections thought to be transmitted by this product should be reported to the manufacturer.

DRUG INTERACTIONS — There are no known significant interactions.

PREGNANCY RISK FACTOR — C (show table)

PREGNANCY IMPLICATIONS — Reproduction studies have not been conducted.

LACTATION — Excretion in breast milk unknown/use caution

DIETARY CONSIDERATIONS — Sodium content of 1 L after reconstitution:

Aralast, Aralast NP: ≤ 230 mEq/L

Prolastin®: 100-210 mEq/L

Zemaira®: 81 mEq/1000 mg

MONITORING PARAMETERS — Alpha1-PI serum levels; lung function; vital signs during infusion

CANADIAN BRAND NAMES — Prolastin®

INTERNATIONAL BRAND NAMES — Prolastin (CA)

MECHANISM OF ACTION — Alpha1-antitrypsin (AAT) is the principle protease inhibitor in serum. Its major physiologic role is to render proteolytic enzymes (secreted during inflammation) inactive. A decrease in AAT, as seen in congenital AAT deficiency, leads to increased elastic damage in the lung, causing emphysema.

PHARMACODYNAMICS / KINETICS
Distribution: Vd: ~3.5 L

Half-life elimination: Metabolic: 5.9 days (Aralast)

Time to peak, serum: ~1 hour; threshold levels achieved after 3 weeks

PATIENT INFORMATION — This medication is given by injection only.

Alosetron

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Lotronex® may be confused with Lovenox®, Protonix®

International issues:
Lotronex® may be confused with Lotanax® which is a brand name for terfenadine in the Czech Republic

MEDICATION GUIDE — An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088624.pdf, must be dispensed with this medication for each new outpatient prescription and refill.

U.S. BRAND NAMES — Lotronex®

PHARMACOLOGIC CATEGORY
Selective 5-HT3 Receptor Antagonist

DOSING: ADULTS — IBS: Female: Oral: Initial: 0.5 mg twice daily for 4 weeks, with or without food; if tolerated, but response is inadequate, may be increased after 4 weeks to 1 mg twice daily. If response is inadequate after 4 weeks of 1 mg twice-daily dosing, discontinue treatment.
Note: Discontinue immediately if constipation or signs/symptoms of ischemic colitis occur. Do not reinitiate in patients who develop ischemic colitis.

DOSING: ELDERLY — Refer to adult dosing. Dosage adjustment is not required; however, postmarketing experience suggests that elderly patients may be at greater risk for complications of constipation.

DOSING: RENAL IMPAIRMENT — The need for dosage adjustment has not been defined (due to limited information on activity of metabolites).

DOSING: HEPATIC IMPAIRMENT — In mild-to-moderate dysfunction (Child-Pugh score ≤ 9), use caution. Contraindicated in severe hepatic dysfunction (Child-Pugh score ≥ 10).

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet:
Lotronex®: 0.5 mg, 1 mg

DOSAGE FORMS: CONCISE
Tablet:
Lotronex®: 0.5 mg, 1 mg

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — May be administered with or without food; however, when administered with food, absorption may be reduced by approximately 25%.

USE — Treatment of women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have failed to respond to conventional therapy

ADVERSE REACTIONS SIGNIFICANT
>10%: Gastrointestinal: Constipation (dose related; 29%)

2% to 10%: Gastrointestinal: Abdominal discomfort and pain (7%), nausea (6%), gastrointestinal discomfort and pain (5%), abdominal distention (2%), hemorrhoids (2%), regurgitation and reflux (2%)

≤ 1% (Limited to important or life-threatening): Allergic skin reactions, alopecia, anxiety, arrhythmia, bilirubin level changes, bladder inflammation, bone pain, breathing disorder, cholecystitis, cognitive function disorders, confusion, cramps, colitis, depression, dermatitis, diaphoresis, diverticulitis, dyspepsia, extrasystoles, fatigue, fluid disturbances, gastroenteritis, GI impaction, GI intussusception, GI lesions, GI motility decreased, GI obstructions, GI perforation, GI spasms, GI ulceration, headache, hematoma, hemorrhage, hepatitis, hyperacidity, hyper-/hypoglycemia, hypertension, hypnagogic effects, hypoesthesia, hypothalamus/pituitary dysfunction, ileus, ischemic colitis, memory effects, muscle pain/stiffness, occult stools, pain, proctitis, rash, RBC/hemoglobin defects, sedation, sexual dysfunction, skeletal pain, small bowel mesenteric ischemia, tachyarrhythmia, temperature regulation impairment, tremor, ulcerative colitis, urinary frequency, urticaria

CONTRAINDICATIONS — Do not start treatment in patients who are constipated. Hypersensitivity to alosetron or any component of the formulation; history of severe or chronic constipation or sequelae from constipation; history of ischemic colitis, intestinal obstruction, stricture, toxic megacolon, gastrointestinal perforation and/or adhesions; diverticulitis, current or history of Crohn's disease, or ulcerative colitis; severe hepatic impairment; history of impaired intestinal circulation, thrombophlebitis, or hypercoagulable state; patients unable to understand or comply with "Patient-Physician" agreement; concomitant administration with fluvoxamine

WARNINGS / PRECAUTIONS
Boxed warnings: Appropriate use: See "Other warnings/precautions" below. Constipation: See "Concerns related to adverse effects" below. Ischemic colitis: See "Concerns related to adverse effects" below. Patient-Physician agreement: See "Other warnings/precautions" below.

Concerns related to adverse effects: Constipation: [U.S. Boxed Warning]: Discontinue immediately in patients who develop constipation; serious complications of constipation have been infrequently reported (obstruction, ileus, perforation, impaction, toxic megacolon, secondary ischemia). Constipation is a frequent, dose-related side effect; risk for complications from constipation may be increased in elderly, debilitated patients, or with concurrent use of other medications which decrease GI motility. Nonsevere constipation may be managed by temporarily interrupting therapy. Do not initiate in patients with constipation. Do not initiate in patients with constipation. Ischemic colitis: [U.S. Boxed Warning]: Acute ischemic colitis has been reported during treatment. Discontinue and evaluate immediately in patients who experience rectal bleeding or a sudden worsening of abdominal pain, and do not restart therapy if ischemic colitis is diagnosed.

Disease-related concerns: Hepatic impairment: Use caution in mild-to-moderate hepatic impairment (Child-Pugh score ≤ 9); contraindicated in severe impairment (Child-Pugh score ≥ 10).

Special populations: Elderly: Use with caution in the elderly due to increased risk of complications from constipation. Males: Safety and efficacy have not been established in males. Pediatrics: Safety and efficacy have not been established in children.

Other warnings/precautions: Appropriate use: [U.S. Boxed Warning]: Only indicated for women with severe diarrhea-predominant irritable bowel syndrome with inadequate response to conventional therapy. Patient-Physician agreement: [U.S. Boxed Warning]: Should only be prescribed by physicians enrolled in the Prometheus' Prescribing Program for Lotronex®. Patients must read and sign a "Patient-Physician" agreement before receiving the initial prescription.

RESTRICTIONS — Only physicians enrolled in Prometheus' Prescribing Program for Lotronex® may prescribe this medication. Program stickers must be affixed to all prescriptions; no phone, fax, or computerized prescriptions are permitted with this program.

METABOLISM / TRANSPORT EFFECTS — Substrate of CYP1A2 (major), 2C9 (minor), 3A4 (minor); Inhibits CYP1A2 (weak), 2E1 (weak)

DRUG INTERACTIONS
Apomorphine: Antiemetics (5HT3 Antagonists) may enhance the hypotensive effect of Apomorphine. Risk X: Avoid combination

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy

CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Risk D: Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Alosetron. Risk C: Monitor therapy

Fluvoxamine: May decrease the metabolism of Alosetron. Risk X: Avoid combination

Rifamycin Derivatives: May increase the metabolism of Antiemetics (5HT3 Antagonists). Risk C: Monitor therapy

ETHANOL / NUTRITION / HERB INTERACTIONS — Food: When administered with food, absorption may be reduced by ~25%.

PREGNANCY RISK FACTOR — B (show table)

PREGNANCY IMPLICATIONS — There are no adequate and well-controlled studies in pregnant women. Alosetron should be used in pregnant women only if clearly needed.

LACTATION — Excretion in breast milk unknown/use caution

BREAST-FEEDING CONSIDERATIONS — Animal studies indicate that alosetron and/or metabolites are excreted in breast milk. It is not known if alosetron in excreted in human milk. Caution should be used in administering alosetron to a nursing woman.

DIETARY CONSIDERATIONS — May be taken with or without food.

PRICING — (data from drugstore.com)
Tablets (Lotronex)
1 mg (30): $428.32

MECHANISM OF ACTION — Alosetron is a potent and selective antagonist of a subtype of the serotonin 5-HT3 receptor. 5-HT3 receptors are ligand-gated ion channels extensively distributed on enteric neurons in the human gastrointestinal tract, as well as other peripheral and central locations. Activation of these channels affect the regulation of visceral pain, colonic transit, and gastrointestinal secretions. In patients with irritable bowel syndrome, blockade of these channels may reduce pain, abdominal discomfort, urgency, and diarrhea.

PHARMACODYNAMICS / KINETICS
Distribution: Vd: 65-95 L

Protein binding: 82%

Metabolism: Extensive hepatic metabolism. Alosetron is metabolized by CYP2C9, 3A4, and 1A2. Thirteen metabolites have been detected in the urine. Biological activity of these metabolites in unknown.

Bioavailability: Mean: 50% to 60% (range: 30% to >90%); decreased with food (25%)

Half-life elimination: 1.5 hours for alosetron

Time to peak: 1 hour after oral administration

Excretion: Urine (73%) and feces (24%); 7% as unchanged drug (1% feces, 6% urine)

PATIENT INFORMATION — Take with or without food. Do not take if you are frequently constipated; constipation is a side effect associated with this medication and can lead to serious complications. Stop taking this medication and call your prescriber if you become constipated, or if you have sudden worsening of abdominal pain, severe constipation, or blood in your stool. Do not continue taking the medication until you have spoken with your prescriber; if after stopping the medication, constipation does not resolve, call your prescriber again. Notify your prescriber if you are pregnant, plan on becoming pregnant, or if you are breast-feeding.