Estazolam

Description

DESCRIPTION Estazolam, a triazolobenzodiazepine derivative, is an oral hypnotic agent. Estazolam occurs as a fine, white, odorless powder that is soluble in alcohol and practically insoluble in water. The chemical name for estazolam is 8-chloro-6-phenyl-4 H -s-triazolo[4,3-α][1,4]benzodiazepine. The structural formula is represented as follows: C 16 H 11 ClN 4 Each tablet, for oral administration, contains either 1 mg or 2 mg of estazolam, USP. In addition, each tablet contains the following inactive ingredients: 1 mg tablets - corn starch, lactose monohydrate, pregelatinized starch, and stearic acid; 2 mg tablets - corn starch, FD&C Red #40 aluminum lake, FD&C Yellow #6 aluminum lake, lactose monohydrate, pregelatinized starch, and stearic acid.

What Is Estazolam Used For?

INDICATIONS AND USAGE Estazolam is indicated for the short-term management of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings. Both outpatient studies and a sleep laboratory study have shown that estazolam administered at bedtime improved sleep induction and sleep maintenance (see CLINICAL PHARMACOLOGY ). Because insomnia is often transient and intermittent, the prolonged administration of estazolam is generally neither necessary nor recommended. Since insomnia may be a symptom of several other disorders, the possibility that the complaint may be related to a condition for which there is a more specific treatment should be considered. There is evidence to support the ability of estazolam to enhance the duration and quality of sleep for intervals up to 12 weeks (see CLINICAL PHARMACOLOGY ).

Dosage and Administration

DOSAGE AND ADMINISTRATION The recommended initial dose for adults is 1 mg at bedtime; however, some patients may need a 2 mg dose. In healthy elderly patients, 1 mg is also the appropriate starting dose, but increases should be initiated with particular care. In small or debilitated older patients, a starting dose of 0.5 mg, while only marginally effective in the overall elderly population, should be considered. Discontinuation or Dosage Reduction of Estazolam To reduce the risk of withdrawal reactions, use a gradual taper to discontinue estazolam or reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly (see WARNINGS, Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE, Dependence ).

Side Effects (Adverse Reactions)

ADVERSE REACTIONS Commonly Observed The most commonly observed adverse events associated with the use of estazolam, not seen at an equivalent incidence among placebo-treated patients were somnolence, hypokinesia, dizziness, and abnormal coordination. Associated with Discontinuation of Treatment Approximately 3% of 1277 patients who received estazolam in U.S. premarketing clinical trials discontinued treatment because of an adverse clinical event. The only event commonly associated with discontinuation, accounting for 1.3% of the total, was somnolence. Incidence in Controlled Clinical Trials The table below enumerates adverse events that occurred at an incidence of 1% or greater among patients with insomnia who received estazolam in 7-night, placebo-controlled trials. Events reported by investigators were classified into standard dictionary (COSTART) terms to establish event frequencies. Event frequencies reported were not corrected for the occurrence of these events at baseline. The frequencies were obtained from data pooled across six studies: estazolam, N = 685; placebo, N = 433. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice in which patient characteristics and other factors differ from those that prevailed in these six clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigators involving related drug products and uses, since each group of drug trials was conducted under a different set of conditions. However, the cited figures provide the physician with a basis of estimating the relative contribution of drug and nondrug factors to the incidence of side effects in the population studied. INCIDENCE OF ADVERSE EXPERIENCES IN PLACEBO-CONTROLLED CLINICAL TRIALS (Percentage of Patients Reporting) Body System/Adverse Event Events reported by at least 1% of estazolam patients. Estazolam (N = 685) Placebo (N = 433) Body as a Whole Headache 16 27 Asthenia 11 8 Malaise 5 5 Lower extremity pain 3 2 Back pain 2 2 Body pain 2 2 Abdominal pain 1 2 Chest pain 1 1 Digestive System Nausea 4 5 Dyspepsia 2 2 Musculoskeletal System Stiffness 1 - Nervous System Somnolence 42 27 Hypokinesia 8 4 Nervousness 8 11 Dizziness 7 3 Coordination abnormal 4 1 Hangover 3 2 Confusion 2 - Depression 2 3 Dream abnormal 2 2 Thinking abnormal 2 1 Respiratory System Cold symptoms 3 5 Pharyngitis 1 2 Skin and Appendages Pruritus 1 - Other Adverse Events During clinical trials, some of which were not placebo-controlled, estazolam was administered to approximately 1300 patients. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing adverse events, similar types of untoward events must be grouped into a smaller number of standardized event categories. In the tabulations that follow, a standard COSTART dictionary terminology has been used to classify reported adverse events. The frequencies presented, therefore, represent the proportion of the 1277 individuals exposed to estazolam who experienced an event of the type cited on at least one occasion while receiving estazolam. All reported events are included except those already listed in the previous table, those COSTART terms too general to be informative, and those events where a drug cause was remote. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in less than 1/1000 patients. It is important to emphasize that, although the events reported did occur during treatment with estazolam, they were not...

Drug Interactions

Drug Interactions The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABA A sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation. If estazolam is given concomitantly with other drugs acting on the central nervous system, careful consideration should be given to the pharmacology of all agents. The action of the benzodiazepines may be potentiated by anticonvulsants, antihistamines, alcohol, barbiturates, monoamine oxidase inhibitors, narcotics, phenothiazines, psychotropic medications, or other drugs that produce CNS depression. Smokers have an increased clearance of benzodiazepines as compared to nonsmokers; this was seen in studies with estazolam (see CLINICAL PHARMACOLOGY ). While no in vivo drug-drug interaction studies were conducted between estazolam and inducers of CYP3A, compounds that are potent CYP3A inducers (such as carbamazepine, phenytoin, rifampin, and barbiturates) would be expected to decrease estazolam concentrations. Estazolam Interaction with Drugs That Inhibit Metabolism via Cytochrome P450 3A (CYP3A) The metabolism of estazolam to the major circulating metabolite 4-hydroxy-estazolam and the metabolism of other triazolobenzodiazepines is catalyzed by CYP3A. Consequently, estazolam should be avoided in patients receiving ketoconazole and itraconazole, which are very potent inhibitors of CYP3A (see CONTRAINDICATIONS ). With drugs inhibiting CYP3A to a lesser, but still significant degree, estazolam should be used only with caution and consideration of appropriate dosage reduction. The following are examples of drugs known to inhibit the metabolism of other related benzodiazepines, presumably through inhibition of CYP3A: nefazodone, fluvoxamine, cimetidine, diltiazem, isoniazide, and some macrolide antibiotics. Drug interaction with fluoxetine A multiple-dose study was conducted to assess the effect of fluoxetine 20 mg BID on the pharmacokinetics of estazolam 2 mg QHS after seven days. The pharmacokinetics of estazolam (C max and AUC) were not affected during multiple-dose fluoxetine, suggesting no clinically significant pharmacokinetic interaction. Estazolam Interaction with Other Drugs That are Metabolized by Cytochrome P450 (CYP) At clinically relevant concentrations, in vitro studies indicate that estazolam (0.6µM) was not inhibitory towards the major cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A. Therefore, based on these in vitro data, estazolam is very unlikely to inhibit the biotransformation of other drugs metabolized by these CYP...

Contraindications

CONTRAINDICATIONS Estazolam is contraindicated with ketoconazole and itraconazole, since these medications significantly impair oxidative metabolism mediated by CYP3A (see WARNINGS and PRECAUTIONS, Drug Interactions ).

Pregnancy and Breastfeeding

Pregnancy Advise pregnant females that use of estazolam late in pregnancy can results in sedation (respiratory, depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS: Pregnancy ). Instruct patients to inform their healthcare provider if they are pregnant. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to estazolam during pregnancy (see Precautions, Pregnancy ). Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including estazolam, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/. Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS: Clinical Considerations ). Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia and sedation in...

Nursing Mothers There are no data on the presence of estazolam in human milk. Estazolam is present in animal milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. There are reports that sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. The effects of estazolam on milk production are unknown. Because of estazolam's long half-life, the potential for estazolam to accumulate in breast milk, and the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed infants, advise patients that breastfeeding is not recommended during treatment with estazolam.

Overdosage

OVERDOSAGE Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal (see WARNINGS: Dependence and Withdrawal Reactions ). Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage. In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management. Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g. tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of potentially life-threatening condition (e.g. status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information. Consider contacting a poison center...

How Supplied

HOW SUPPLIED Estazolam tablets 1 mg are available as white, oval, convex tablet, bisected and debossed "m" and "073" on one side, bisected and plain on the other side. Packaged in bottles of 100 (NDC 75907-028-01). Estazolam tablets 2 mg are available as pale orange, oval, convex tablet, bisected and debossed "m" and "074" on one side, plain on the other side. Packaged in bottles of 100 (NDC 75907-029-01). Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).