Estazolam

Pronunciation

Class: Benzodiazepines
VA Class: CN302
Chemical Name: 8-Chloro-6-phenyl-4H -[1,2,4]triazolo[4,3-a][1,4]benzodiazepine
Molecular Formula: C16H11ClN4
CAS Number: 29975-16-4

Introduction

Benzodiazepine, sedative and hypnotic.e

Uses for Estazolam

Insomnia

Short-term management of insomnia characterized by difficulty in falling asleep, nocturnal awakenings, and/or early morning awakening.e Has been used effectively for periods of up to 12 weeks in duration.

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Decreases sleep latency, increases the duration of sleep, and decreases the number of nocturnal awakenings.e

Estazolam Dosage and Administration

General

  • Use only when able to get a full night’s sleep of sleep before being active again.e

  • Avoid prolonged administration. Generally limit hypnotic therapy to 7–10 days.e

  • Avoid abrupt discontinuance in patients who have received prolonged therapy (e.g., 6 weeks) because of potential for precipitating withdrawal manifestations and rebound insomnia. Gradually taper dosage, particularly in patients with a seizure history.e (See Withdrawal Effects under Cautions.)

Administration

Oral Administration

Administer at bedtime.e

Dosage

Individualize dosage; use smallest effective dosage.

Adults

Insomnia
Oral

Initially, 1 mg at bedtime.e

If drug is well-tolerated, gradually increase dosage to 2 mg if needed.e

Special Populations

Hepatic Impairment

No specific dosage recommendations.e

Renal Impairment

No specific dosage recommendations.e

Geriatric or Debilitated Patients

Use smallest effective dosage. In small or debilitated geriatric patients, initially, 0.5 mg at bedtime.e

Cautions for Estazolam

Contraindications

  • Known hypersensitivity to estazolam or any ingredient in the formulation. c

  • Pregnancy.e f

  • Concomitant use of ketoconazole or itraconazole.e (See Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; use contraindicated during pregnancy.b e f If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.b e f

Adequate Patient Evaluation

Insomnia may be a manifestation of an underlying physical and/or psychiatric disorder; carefully evaluate patient before providing symptomatic treatment.b e

Worsening of insomnia or emergence of new abnormal thinking or behavior may indicate the presence of an underlying psychiatric and/or medical condition.b

Complex Sleep-related Behaviors

Potential risk of complex sleep-related behaviors such as sleep-driving (i.e., driving while not fully awake after ingesting a sedative-hypnotic drug with no memory of the event), making phone calls, or preparing and eating food while asleep.c e

CNS Depression

Performance of activities requiring mental alertness and physical coordination may be impaired.e Risk of residual daytime sedation and impaired performance.e

Concurrent use of other CNS depressants may cause additive or potentiated CNS depression.e (See Specific Drugs under Interactions.)

Adverse Psychiatric Events

Abnormal thinking and behavioral changes (e.g., aggressiveness, uncharacteristic extroversion, excitement, bizarre behavior, agitation, hallucinations, depersonalization, amnesia) may occur unpredictably in patients receiving benzodiazepines.b e

Some adverse effects appear to be dose related; use the lowest effective dose.a

Withdrawal Effects

Abrupt discontinuance may result in symptoms of withdrawal (similar to barbiturates or alcohol).b e

Interactions

Concomitant use with drugs that are potent inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole) is contraindicated.e Concomitant use with lesser inhibitors of CYP3A4 (e.g., nefazodone, fluvoxamine, cimetidine, diltiazem, isoniazid, macrolide antibiotics) requires particular caution.e (See Specific Drugs under Interactions.)

Sensitivity Reactions

Potential risk of anaphylaxis and angioedema; may occur even with the first dose of drug.c

General Precautions

Respiratory Effects

Possible dose-related respiratory depression, especially in patients with compromised respiratory function.b e Monitor patients with compromised respiratory function.e

Suicide

Use with caution in depressed patients; potential for suicidal tendencies.e Prescribe and dispense drug in the smallest feasible quantity.e

Specific Populations

Pregnancy

Category X. e f (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Benzodiazepines generally are distributed into milk.b Estazolam is distributed into milk in rats; not known whether the drug is distributed into human milk.e f Use not recommended in nursing women.e

Pediatric Use

Safety and efficacy not established in children <18 years of age.e

Geriatric Use

Potential increased sensitivity to dose related adverse effects (e.g., oversedation, dizziness, confusion, ataxia); use low initial dosage and monitor closely, especially in small or debilitated elderly patients. e

Hepatic Impairment

Potential increased sensitivity to adverse CNS effects (e.g., oversedation, dizziness, confusion, ataxia); use with caution and monitor closely.b e

Renal Impairment

Potential increased sensitivity to adverse CNS effects (e.g., oversedation, dizziness, confusion, ataxia); use with caution and monitor closely.b e

Common Adverse Effects

Somnolence, hypokinesia, dizziness, abnormal coordination.e

Interactions for Estazolam

Metabolized principally by CYP3A4.e

Does not inhibit CYP isoenzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, or 3A in vitro.e Pharmacokinetic interactions with drugs metabolized by these isoenzymes unlikely.e Not known whether estazolam induces drug metabolizing enzymes.e

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: potential pharmacokinetic interaction (increased plasma estazolam concentrations).e Concomitant use with potent CYP3A inhibitors is contraindicated.e Use less potent CYP3A inhibitors with caution; estazolam dosage reduction may be indicated (see table).e

Inducers of CYP3A4: potential pharmacokinetic interaction (decreased plasma estazolam concentrations).e

Specific Drugs

Drug

Interaction

Comments

Antifungals, azoles (fluconazole, itraconazole, ketoconazole)

Increased estazolam plasma concentrationsb e

Concomitant use of itraconazole and ketoconazole contraindicatede

Barbiturates

Possible decreased plasma estazolam concentrationsc

Additive CNS depressant effectse

Use concomitantly with cautionb

Calcium-channel blocking agents (diltiazem, nicardipine, nifedipine, verapamil)

Possible decreased clearance of estazolam and increased plasma estazolam concentrations e

Use with caution; consider estazolam dosage reductione

Carbamazepine

Possible decreased plasma estazolam concentrationsb e

Cigarette smoking

Possible decreased sedative effect due to increased clearance of estazolame

Cimetidine

Possible decreased clearance of estazolam and increased plasma estazolam concentrations e

Use with caution; consider estazolam dosage reductione

CNS depressants (e.g., alcohol, anticonvulsants, antihistamines, narcotics, psychotropic agents, sedatives)

Additive CNS depressant effectse

Avoid concomitant use of alcohol;e use other CNS depressants with cautionb

Fluoxetine

Pharmacokinetic interactions unlikelye

Fluvoxamine

Possible decreased clearance of estazolam and increased plasma estazolam concentrations e

Use with caution; consider estazolam dosage reductione

Isoniazid

Possible decreased clearance of estazolam and increased plasma estazolam concentrations e

Use with caution; consider estazolam dosage reductione

Macrolide antibiotics

Possible decreased clearance of estazolam and increased plasma estazolam concentrations e

Use with caution; consider estazolam dosage reductione

MAO inhibitors

Additive CNS depressant effectse

Nefazodone

Possible decreased clearance of estazolam and increased plasma estazolam concentrations e

Use with caution; consider estazolam dosage reductione

Phenytoin

Possible decreased plasma estazolam concentrationsb e

Rifampin

Possible decreased plasma estazolam concentrationsb e

Estazolam Pharmacokinetics

Absorption

Bioavailability

Rapidly and well absorbed following oral administration, with peak plasma concentration achieved within 2 hours.e

Food

Effect of food on GI absorption not determined.

Distribution

Extent

Benzodiazepines are widely distributed into body tissues and cross the blood-brain barrier.b

Benzodiazepines generally cross the placenta and are distributed into milk;b f not known whether estazolam crosses the placenta or distributes into milk.f

Plasma Protein Binding

93%.e

Elimination

Metabolism

Rapidly and extensively metabolized in the liver, principally to 4-hydroxy-estazolam and 1-oxo-estazolam.e

Elimination Route

Excreted in urine (91%) mainly as inactive metabolites and in feces (4%).

Half-life

14–19 hours (range: 10–24 hours) following single or multiple doses.e f

Special Population

In smokers, clearance of estazolam is increased compared with nonsmokers.e

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at 20–25°C. e

Actions

  • Effects appear to be mediated through the inhibitory neurotransmitter GABA; the sites and mechanisms of action within the CNS appear to involve a macromolecular complex (GABAA-receptor-chloride ionophore complex) that includes GABAA receptors, high-affinity benzodiazepine receptors, and chloride channels.

Advice to Patients

  • Provide patient a copy of the manufacturer’s patient information.c e

  • Potential for drug to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.e

  • Importance of informing clinicians of any behavioral or mental changes, memory impairment, sleep driving, tolerance, or dependence/withdrawal symptoms.c e

  • Importance of informing clinicians about any concomitant illnesses (e.g., respiratory disorders, depression).e

  • Risk of anaphylactoid or hypersensitivity reactions.c

  • Importance of taking only as prescribed; do not increase dosage or duration of therapy unless otherwise instructed by a clinician.e

  • Importance of not consuming alcoholic beverages.e

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed;e f necessity for clinicians to advise women to avoid pregnancy during therapy.e

  • Importance of informing patients of other precautionary information.a (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.e

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Estazolam

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

1 mg*

Estazolam Tablets ( C-IV)

Par, Teva, Watson

2 mg*

Estazolam Tablets ( C-IV)

Par, Teva, Watson

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Estazolam 1MG Tablets (WATSON LABS): 30/$24.99 or 60/$46.99

Estazolam 2MG Tablets (WATSON LABS): 30/$27.97 or 60/$51.93

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 1, 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

a. AHFS drug information 2007. McEvoy GK, ed.Estazolam. Bethesda, MD: American Society of Health-System Pharmacists; 2007:pages [2525-2526].

b. AHFS drug information 2007. McEvoy GK, ed. Benzodiazepines General Statement. Bethesda, MD: American Society of Health-System Pharmacists, 2007 pages [2508-2518]

c. Food and Drug Administration. Prosom (estazolam) tablets. [March 14, 2007: Abbott Laboratories] MedWatch drug labeling changes. Rockville, MD; April 2007. From FDA websites () and ().

e. Watson Pharma. Estazolam tablet prescribing and patient information. Corona, CA; 2008 Jan.

f. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2005: 593-4.

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