Drug 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

Medically reviewed by Drugs.com on Sep 26, 2022. Written by ASHP.

Introduction

Benzodiazepine, sedative and hypnotic.

Uses for Estazolam

Insomnia

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

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

Estazolam Dosage and Administration

General

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

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

• 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. (See Withdrawal Effects under Cautions.)

Administration

Oral Administration

Administer at bedtime.

Dosage

Individualize dosage; use smallest effective dosage.

Adults

Insomnia

Oral

Initially, 1 mg at bedtime.

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

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations.

Geriatric or Debilitated Patients

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

Cautions for Estazolam

Contraindications

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

• Pregnancy.

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

Warnings/Precautions

Warnings

Concomitant Use with Opiates

Concomitant use of benzodiazepines, including estazolam, and opiates may result in profound sedation, respiratory depression, coma, and death. Substantial proportion of fatal opiate overdoses involve concurrent benzodiazepine use.

Reserve concomitant use of estazolam and opiates for patients in whom alternative treatment options are inadequate. (See Specific Drugs under Interactions.)

Fetal/Neonatal Morbidity and Mortality

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

Adequate Patient Evaluation

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

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

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.

CNS Depression

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

Concurrent use of other CNS depressants may cause additive or potentiated CNS depression. (See Concomitant Use with Opiates under Cautions and also 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.

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

Withdrawal Effects

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

CYP3A-mediated Drug Interactions

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

Sensitivity Reactions

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

General Precautions

Respiratory Effects

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

Suicide

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

Specific Populations

Pregnancy

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

Lactation

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

Pediatric Use

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

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.

Hepatic Impairment

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

Renal Impairment

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

Common Adverse Effects

Somnolence, hypokinesia, dizziness, abnormal coordination.

Drug Interactions

Metabolized principally by CYP3A4.

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

Drugs Affecting Hepatic Microsomal Enzymes

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

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

Specific Drugs

Estazolam Pharmacokinetics

Absorption

Bioavailability

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

Food

Effect of food on GI absorption not determined.

Distribution

Extent

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

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

Plasma Protein Binding

93%.

Elimination

Metabolism

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

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.

Special Population

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

Stability

Storage

Oral

Tablets

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

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 (GABA_A-receptor-chloride ionophore complex) that includes GABA_A receptors, high-affinity benzodiazepine receptors, and chloride channels.

Advice to Patients

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

• Risk of potentially fatal additive effects (e.g., profound sedation, respiratory depression, coma) if used concomitantly with opiates either therapeutically or illicitly. Avoid concomitant use of opiate antitussives; also avoid concomitant use of opiate analgesics unless use is supervised by clinician.

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

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

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

• Risk of anaphylactoid or hypersensitivity reactions.

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

• Importance of not consuming alcoholic beverages.

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

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

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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

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

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