section name header

Introduction

VA Class:CN302

AHFS Class:

Generic Name(s):

Chemical Name:

Molecular Formula:

Associated Monographs

Estazolam is a benzodiazepine.400,402,407,412

Uses

Estazolam shares the actions of other benzodiazepines and is used as a hypnotic agent in the short-term management of insomnia, reportedly for periods of up to 12 weeks.400,405,409,417,418,419,420,421,422,423,447 Benzodiazepines generally are preferred to other hypnotics for the management of insomnia because of their short- and intermediate-term efficacy and relative safety.320

The choice of a specific benzodiazepine must be individualized according to patient response and tolerance, taking into consideration pharmacokinetic and pharmacodynamic characteristics of the drug, patient age and other characteristics, and the underlying sleep disorder being treated.215 Benzodiazepines with an intermediate elimination half-life, such as estazolam, appear to be more likely than those with a relatively long half-life, but less likely than those with a short half-life, to result in transient rebound insomnia after discontinuance and in pharmacodynamic tolerance and adaptation to the hypnotic effect during continued therapy.215,252,259,400,418,419,420,421,422,423 Benzodiazepines with a short or intermediate half-life may be less likely than long-acting benzodiazepines to result in residual daytime sedative effects and in impaired psychomotor and mental performance during continued therapy.215,252,259,400,418,419,420,421,422,423 Prolonged use of hypnotics usually is not indicated and should be undertaken only on further evaluation of the patient.400,401 The possibility that insomnia may be a manifestation of an underlying condition for which there may be a more specific treatment should be considered.400

For additional information on the use of benzodiazepines in the management of insomnia, see Uses: Anxiety and Insomnia, in the Benzodiazepines General Statement 28:24.08.

Dosage and Administration

[Section Outline]

Administration !!navigator!!

Estazolam is administered orally at bedtime.400,416,417,418,419,420,421,422,423

Dosage !!navigator!!

Dosage of estazolam must be individualized, and the smallest effective dosage should be used400 (especially in geriatric or debilitated patients).400,405 Prolonged administration of estazolam should be avoided.400

The usual initial adult dose of estazolam is 1 mg at bedtime, although some adults may require an initial 2-mg dose.400,416,417,418,419,420,421,422,423 In small, debilitated, and/or geriatric patients, an initial dose of 0.5 mg may be appropriate;400,405 however, limited evidence suggests that this dose may be only marginally effective in many geriatric patients,400,405,409 and the drug can be initiated in healthy geriatric patients at the 1-mg dose.400,447 After individual response has been determined, the dose may be increased gradually to 2 mg if needed.401 As with other benzodiazepines, abrupt withdrawal of estazolam therapy should be avoided since manifestations of withdrawal, including rebound insomnia, may be precipitated.400,429 If estazolam is to be discontinued after prolonged therapy (e.g., 6 weeks), the dosage should be tapered gradually.429

Cautions

[Section Outline]

Precautions !!navigator!!

A boxed warning has been included in the prescribing information for all benzodiazepines describing the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions associated with all drugs in this class.900 Abuse and misuse can result in overdose or death, especially when benzodiazepines are combined with other medicines, such as opioid pain relievers, alcohol, or illicit drugs.900 Frequent follow-up with patients receiving benzodiazepines is important.900 Reassess patients regularly to manage their medical conditions and any withdrawal symptoms.900 Clinicians should assess a patient's risk of abuse, misuse, and addiction. 900 Standardized screening tools are available ([Web]).900 To reduce the risk of acute withdrawal reactions, use a gradual dose taper when reducing the dosage or discontinuing benzodiazepines.900 Take precautions when benzodiazepines are used in combination with opioid medications.900

Estazolam shares the toxic potentials of the benzodiazepines, and the usual precautions of benzodiazepine administration should be observed.400,419 (See Cautions in the Benzodiazepines General Statement 28:24.08.)

Hydroxylation of estazolam to form 4-hydroxyestazolam is catalyzed by the hepatic cytochrome P-450 (CYP) 3A isoenzyme, and concomitant use of estazolam with drugs (e.g., some azole antifungals agents, nefazodone, erythromycin, fluvoxamine) that inhibit this isoenzyme system may result in decreased estazolam metabolism and clearance and increased plasma estazolam concentrations.625 Although specific drug interaction studies are not available, the manufacturer states that caution should be exercised and estazolam dosage adjustment considered during concomitant use of the drug with CYP3A inhibitors (e.g., nefazodone, fluvoxamine, cimetidine, diltiazem, isoniazid, some macrolide antibiotics).625 Because itraconazole and ketoconazole are very potent CYP3A isoenzyme inhibitors, the manufacturer states that concomitant use of these drugs with estazolam is contraindicated.625

For further information about potential interactions between benzodiazepines and drugs and foods affecting hepatic microsomal enzymes, see Drug Interactions in the Benzodiazepines General Statement 28:24.08.

Pediatric Precautions !!navigator!!

Safety and efficacy of estazolam in children younger than 18 years of age have not been established.400

Geriatric Precautions !!navigator!!

In premarketing clinical studies, the adverse event profile of estazolam in geriatric individuals did not differ substantially from that observed in younger adults,400,405,409 but greater sensitivity of some geriatric individuals cannot be ruled out;447 in these studies, approximately 18% of patients were 60 years of age or older (range: 60-83 years old).447 In addition, because elimination of the drug may be prolonged in geriatric individuals400,402,405,427 and because this age group generally is at increased risk from adverse nervous system effects of drugs, including benzodiazepines,215,221,222,224,252,253,256,259,297,427 estazolam dosage should be adjusted carefully in geriatric individuals.400,405 (See Dosage and Administration: Dosage.)

Mutagenicity and Carcinogenicity !!navigator!!

No evidence of estazolam-induced mutagenicity was observed in the following test systems: Ames microbial mutagen test, DNA repair in Bacillus subtilis , in vivo cytogenetics in mice and rats, or the dominant lethal test in mice.400

No evidence of carcinogenesis was observed in rats given oral estazolam dosages up to 10 mg/kg daily for 2 years.400,415

Pregnancy, Fertility, and Lactation !!navigator!!

Pregnancy

Benzodiazepines can cause fetal harm when administered to pregnant women (see Cautions: Pregnancy and Lactation, in the Benzodiazepines General Statement 28:24.08),400,428 and those used solely as hypnotics, such as estazolam, are contraindicated during pregnancy.400,428 The safety of estazolam during labor or delivery has not been established.400

Fertility

Reproduction studies in male and female rats given estazolam in doses up to 30 times the usual human dose revealed no evidence of impaired fertility.400

Lactation

It is not known whether estazolam is distributed into milk in humans;400 however, estazolam and/or its metabolites are distributed into milk in rats.400,450 Because of the potential for serious adverse reactions to estazolam in nursing infants if it were distributed, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.400

Other Information

[Section Outline]

Pharmacology

Estazolam shares the actions of other benzodiazepines.400,402,405 The exact sites and modes of action of benzodiazepines have not been fully elucidated,320 but the effects of the drugs appear to be mediated through the inhibitory neurotransmitter γ-aminobutyric acid (GABA).320,365,366,367,368,369 Specific binding sites with high affinity for benzodiazepines have been detected in the CNS,320,358,359,360,361,362,363,364,365,366,367,368,369,370 and the affinity of these sites for the drugs is enhanced by both GABA and chloride.320 The sites and actions of benzodiazepines within the CNS appear to involve a macromolecular (oligomer, possibly a tetramer) complex (GABAA-receptor-chloride ionophore complex) that includes GABAA receptors (GABA recognition sites), high-affinity benzodiazepine receptors, and chloride channels,320,358,359,360,361,362,363,364,365,366,367,368,369,370,448,449 although precise relationships between the sites of action of benzodiazepines and GABA-regulated (-gated) chloride channels remain to be more fully elucidated.320,365 Allosteric interactions of central benzodiazepine receptors with GABAA receptors and subsequent opening of chloride channels appear to be involved in eliciting the CNS effects of the drugs; the benzodiazepine receptors act as modulatory sites on the complex.320,358,359,360,361,362,363,364,365,366,367,368,369,370,448,449 Some evidence suggests that benzodiazepine receptor sites are heterogeneous, with at least 2 major CNS subtypes (type 1 [BZ1] and type 2 [BZ2] benzodiazepine receptors) being described to date.365,448,449 While quazepam and 2-oxoquazepam (an active metabolite), like halazepam (no longer commercially available in the US) but unlike other currently available benzodiazepines, exhibit relative selectivity for type 1 receptors,448 it has not been determined if estazolam or its metabolites400,402,403,404 exhibit relative selectivity for either type 1 or 2 receptors.404 Although the clinical importance, if any, of receptor selectivity remains to be established, some evidence suggests that such selectivity may be responsible for the reduced ataxic effect of some benzodiazepines (e.g., quazepam) observed in animal studies (type 1 receptor selectivity);365 the possibility that the spectrum of other benzodiazepine-induced effects may be narrowed by such selectivity also has been suggested.

For further information on the pharmacology of estazolam, see the Benzodiazepines General Statement 28:24.08.

Pharmacokinetics

Absorption !!navigator!!

Estazolam is rapidly and reportedly well absorbed from the GI tract following oral administration. 400,402,403,404,407 The absolute bioavailability of estazolam in humans has not been determined to date, although the oral bioavailability of the drug in mice reportedly averaged 98% when administered as tablets dissolved in 0.5% carboxymethylcellulose.404 The effect of food on GI absorption of the drug has not been determined.447

Considerable interindividual variation in plasma concentrations attained with a given dose of estazolam has been reported.400,402,403,407 In a limited number of healthy adults, peak plasma estazolam concentrations averaging 99-103 ng/mL were achieved approximately 0.5-1.6 hours after a single, 2-mg oral dose of the drug as tablets or solution.403,407 In healthy men who received a single, 4-mg oral dose of the drug as tablets, peak plasma concentrations averaged 194 ng/mL at 1-3 hours after the dose.404 Peak plasma concentrations and elimination half-lives after single doses of estazolam are similar to those after multiple dosing, suggesting a linear, dose-independent pharmacokinetic profile for the drug.402,404,407

Distribution !!navigator!!

Estazolam reportedly is distributed widely into most body tissues and fluids.401 Limited evidence from animal studies indicates that the drug and at least one of its metabolites, 1-oxo-estazolam, readily cross the blood-brain barrier.404,414 Estazolam reportedly is 93% protein bound at concentrations ranging from 30-1000 ng/mL.401,447

It is not known whether estazolam crosses the placenta or is distributed into milk in humans;400,450 however, the drug and/or its metabolites readily cross the placenta and are distributed into milk in animals.400,450 Generally, benzodiazepines and their metabolites readily cross the placenta, and the drugs and their metabolites also are distributed into milk.

Elimination !!navigator!!

Plasma concentrations of estazolam appear to decline in a biphasic manner, with a half-life in the initial distribution phase of approximately 17 minutes following single oral doses of the drug.402 The terminal elimination half-life averages 14-19 hours (range: 10-24 hours) following single or multiple doses.401,402,403,404,407 The terminal elimination half-life in healthy geriatric adults reportedly is similar to that in healthy young adults following single oral doses.400,405,409,447

Estazolam is rapidly and extensively metabolized in the liver.401,402,403,404 Plasma concentrations of the drug's principal metabolites, 4-hydroxyestazolam and 1-oxo-estazolam, are low or undetectable;400,402,403,404 these metabolites have little to no pharmacologic activity in humans.403,404 Estazolam is excreted in both urine and feces, principally as inactive metabolites.400,403 Unchanged drug accounts for less than 5% of a dose excreted in urine.400,404 Following oral administration of radiolabeled estazolam in healthy adults, approximately 91% of a dose was excreted in urine (87%) and feces (4%) over a 5-day period.404

Chemistry and Stability

Chemistry !!navigator!!

Estazolam is a benzodiazepine.400,402,407,412 The drug occurs as a white, odorless powder that is soluble in alcohol and practically insoluble in water.401,413

Stability !!navigator!!

Estazolam tablets should be stored in well-closed containers at temperatures less than 30°C.400 When stored as directed, estazolam tablets are stable for 3 years following the date of manufacture.401

Additional Information

For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, chronic toxicity, acute toxicity, drug interactions, laboratory test interferences, and dosage and administration of estazolam, see the Benzodiazepines General Statement 28:24.08.

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.

Estazolam is subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.400

Estazolam

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

1 mg*

Estazolam Tablets (C-IV)

2 mg*

Estazolam Tablets (C-IV)

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

Copyright

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions September 26, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

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