rescribe a lower initial dose of the opioid and titrate based upon clinical response. advise both patients and caregivers about the risks of respiratory depression and sedation when estazolam is used with opioids. advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see precautions , drug interactions ). abuse, misuse, and addiction the use of benzodiazepines, including estazolam, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death (see drug abuse and dependence , abuse ) . before prescribing estazolam and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). use of estazolam, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of estazolam along with monitoring for signs and symptoms of abuse, misuse, and addiction. prescribe the lowest effective dosage; avoid or minimize concomitant use of cns depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. if a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate. dependence and withdrawal reactions to reduce the risk of withdrawal reactions, use a gradual taper to discontinue estazolam or reduce the dosage (a patient-specific plan should be used to taper the dose) (see dosage and administration , discontinuation or dosage reduction of estazolam ). patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use. acute withdrawal reactions the continued use of benzodiazepines, including estazolam, may lead to clinically significant physical dependence. abrupt discontinuation or rapid dosage reduction of estazolam after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) (see drug abuse and dependence , dependence ) . protracted withdrawal syndrome in some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months (see drug abuse and dependence , dependence ). because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. the failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. such findings have emerged during the course of treatment with sedative-hypnotic drugs. because some of the important adverse effects of sedative-hypnotics appear to be dose-related (see precautions and dosage and administration ), it is important to use the smallest possible effective dose, especially in the elderly. complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported. these events can occur in sedative-hypnotic-naïve as well as in sedative-hypnotic-experienced persons. although behaviors such as sleep driving may occur with sedative-hypnotics alone at therapeutic doses, the use of alcohol and other cns depressants with sedative-hypnotics appears to increase the risk of such behaviors, as does the use of sedative-hypnotics at doses exceeding the maximum recommended dose. due to the risk to the patient and the community, discontinuation of sedative-hypnotics should be strongly considered for patients who report a “sleep-driving” episode. other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. as with sleep-driving, patients usually do not remember these events. because sedative-hypnotics can cause drowsiness and a decreased level of consciousness, patients, particularly the elderly, are at higher risk of falls. severe anaphylactic and anaphylactoid reactions rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including estazolam. some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. some patients have required medical therapy in the emergency department. if angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. patients who develop angioedema after treatment with estazolam should not be rechallenged with the drug. estazolam, like other benzodiazepines, has cns depressant effects. for this reason, patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness, such as operating machinery or driving a motor vehicle, after ingesting the drug, including potential impairment of the performance of such activities that may occur the day following ingestion of estazolam. patients should also be cautioned about possible combined effects with alcohol and other cns depressant drugs. as with all benzodiazepines, amnesia, paradoxical reactions (e.g., excitement, agitation, etc.), and other adverse behavioral effects may occur unpredictably. 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, isoniazid, and some macrolide antibiotics. 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. neonatal sedation and withdrawal syndrome use of estazolam late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate (see precautions: pregnancy ) . monitor neonates exposed to estazolam during pregnancy or labor for signs of sedation and monitor neonates exposed to estazolam during pregnancy for signs of withdrawal; manage these neonates accordingly.

requencies 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) estazolam placebo body system/adverse event* (n=685) (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 -- * events reported by at least 1% of estazolam patients. 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 necessarily caused by it. body as a whole - infrequent: allergic reaction, chills, fever, neck pain, upper extremity pain; rare: edema, jaw pain, swollen breast. cardiovascular system - infrequent: flushing, palpitation; rare: arrhythmia, syncope. digestive system - frequent: constipation, dry mouth; infrequent: decreased appetite, flatulence, gastritis, increased appetite, vomiting; rare: enterocolitis, melena, ulceration of the mouth. endocrine system - rare: thyroid nodule. hematologic and lymphatic system - rare: leukopenia, purpura, swollen lymph nodes. metabolic/nutritional disorders - infrequent: thirst; rare: increased sgot, weight gain, weight loss. musculoskeletal system - infrequent: arthritis, muscle spasm, myalgia; rare: arthralgia. nervous system - frequent: anxiety; infrequent: agitation, amnesia, apathy, emotional lability, euphoria, hostility, paresthesia, seizure, sleep disorder, stupor, twitch; rare: ataxia, circumoral paresthesia, decreased libido, decreased reflexes, hallucinations, neuritis, nystagmus, tremor. minor changes in eeg patterns, usually low-voltage fast activity, have been observed in patients during estazolam therapy or withdrawal and are of no known clinical significance. respiratory system - infrequent: asthma, cough, dyspnea, rhinitis, sinusitis; rare: epistaxis, hyperventilation, laryngitis. skin and appendages - infrequent: rash, sweating, urticaria; rare: acne, dry skin. special senses - infrequent: abnormal vision, ear pain, eye irritation, eye pain, eye swelling, perverse taste, photophobia, tinnitus; rare: decreased hearing, diplopia, scotomata. urogenital system - infrequent: frequent urination, menstrual cramps, urinary hesitancy, urinary urgency, vaginal discharge/itching; rare: hematuria, nocturia, oliguria, penile discharge, urinary incontinence. postintroduction reports - voluntary reports of non-u.s. postmarketing experience with estazolam have included rare occurrences of photosensitivity, stevens-johnson syndrome, and agranulocytosis. because of the uncontrolled nature of these spontaneous reports, a causal relationship to estazolam treatment has not been determined. to report suspected adverse reactions, contact actavis at 1-888-838-2872 or fda at 1-800-fda-1088 or www.fda.gov/medwatch .

single dose of estazolam was recovered in the urine as metabolites. less than 5% of a 2 mg dose of estazolam was excreted unchanged in the urine, with only 4% of the dose appearing in the feces. the principal urinary excretion product is an unidentified metabolite, presumed to be a metabolic product of 4-hydroxy-estazolam, accounting for at least 27% of the administered dose. 4-hydroxy-estazolam is the major metabolite in plasma, with concentrations approaching 12% of those of the parent eight hours after administration. urinary 4-hydroxy-estazolam and 1-oxo-estazolam account for 11.9% and 4.4% of the dose respectively. in vitro studies with human liver microsomes indicate that the biotransformation of estazolam to the major circulating metabolite 4-hydroxy-estazolam is mediated by cytochrome p450 3a (cyp3a). while 4-hydroxy-estazolam and the lesser metabolite, 1-oxo-estazolam, have some pharmacologic activity, their low potencies and low concentrations preclude any significant contribution to the hypnotic effect of estazolam. elimination the range of estimates for the mean elimination half-life of estazolam varied from 10 to 24 hours. radiolabel mass balance studies indicate that the main route of excretion is via the kidneys. after 5 days, 87% of the administered radioactivity was excreted in human urine. less than 4% of the dose was excreted unchanged. eleven metabolites were found in urine. four metabolites were identified as 1-oxo-estazolam, 4’-hydroxy-estazolam, 4-hydroxy-estazolam, and benzophenone, as free metabolites and glucuronides. the predominant metabolite in urine (17% of the administered dose) has not been identified, but is likely to be a metabolite of 4-hydroxy-estazolam. special populations in a small study (n=8) using various doses in older subjects (59 to 68 years), peak estazolam concentrations were found to be similar to those observed in younger subjects with a mean elimination half-life of 18.4 hours (range 13.5 to 34.6 hours). the influence of hepatic or renal impairment on the pharmacokinetics of estazolam has not been studied. pediatrics the pharmacokinetics of estazolam have not been studied in pediatric patients. race the influence of race on the pharmacokinetics of estazolam has not been studied. gender the gender-effect on the pharmacokinetics of estazolam has not been investigated. cigarette smoking the clearance of benzodiazepines is accelerated in smokers compared to nonsmokers, and there is evidence that this occurs with estazolam. this decrease in half-life, presumably due to enzyme induction by smoking, is consistent with other drugs with similar hepatic clearance characteristics. in all subjects and at all doses, the mean elimination half-life appeared to be independent of the dose. drug-drug interaction the metabolism of estazolam to the major circulating metabolite 4-hydroxy-estazolam is catalyzed by cyp3a. while no in vivo drug-drug interaction studies were conducted between estazolam and inhibitors/inducers of cyp3a, compounds that are potent cyp3a inhibitors (such as ketoconazole, itraconazole, nefazodone, fluvoxamine, and erythromycin) would be expected to increase plasma estazolam concentrations and cyp3a inducers (such as carbamazepine, phenytoin, rifampin and barbiturates) would be expected to decrease estazolam concentrations. 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. the ability of estazolam to induce or inhibit human enzyme systems the results from in vitro human liver microsomal studies suggest that at therapeutic concentrations, estazolam has no significant inhibitory effect on the major human cytochrome p450 enzyme activities (i.e., cyp1a2, cyp2a6, cyp2c9, cyp2c19, cyp2d6, cyp2e1, and cyp3a). the ability of estazolam to induce human hepatic enzyme systems has not been determined. pharmacodynamics postulated relationship between elimination rate of benzodiazepine hypnotics and their profile of common untoward effects: the type and duration of hypnotic effects and the profile of unwanted effects during administration of benzodiazepine drugs may be influenced by the biologic half-life of administered drug and any active metabolites formed. if half-lives are long, drug or metabolites may accumulate during periods of nightly administration and may be associated with impairments of cognitive and/or motor performance during waking hours; the possibility of interaction with other psychoactive drugs or alcohol will be increased. in contrast, if half-lives are short, drug and metabolites will be cleared before the next dose is ingested, and carry-over effects related to excessive sedation or cns depression should be minimal or absent. however, during nightly use for an extended period, pharmacodynamic tolerance or adaptation to some effects of benzodiazepine hypnotics may develop. if the drug has a short elimination half-life, it is possible that a relative deficiency of the drug or its active metabolites (i.e., in relationship to the receptor site) may occur at some point in the interval between each night’s use. this sequence of events may account for two clinical findings reported to occur after several weeks of max nightly use of rapidly eliminated benzodiazepine hypnotics, namely, increased wakefulness during the last third of the night and increased daytime anxiety in selected patients.

eep medications, estazolam was superior to placebo in subjective measures of sleep induction and maintenance. in a 12 week, double-blind, parallel-group trial including a comparison of estazolam 2 mg and placebo in adult outpatients with chronic insomnia, estazolam was superior to placebo in subjective measures of sleep induction (latency) and maintenance (duration, number of awakenings, total wake time during sleep) at week 2, but produced consistent improvement over 12 weeks only for sleep duration and total wake time during sleep. following withdrawal at week 12, rebound insomnia was seen at the first withdrawal week, but there was no difference between drug and placebo by the second withdrawal week in all parameters except latency, for which normalization did not occur until the fourth withdrawal week. adult outpatients with chronic insomnia were evaluated in a sleep laboratory trial comparing four doses of estazolam (0.25, 0.5, 1 and 2 mg) and placebo, each administered for 2 nights in a crossover design. the higher estazolam doses were superior to placebo in most eeg measures of sleep induction and maintenance, especially at the 2 mg dose, but only for sleep duration in subjective measures of sleep.