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Estazolam
Overview
What is Estazolam?
Estazolam, USP, 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--triazolo[4,3-α][1,4]benzodiazepine. The molecular formula is CHClN and its molecular weight is 294.75. The structural formula is represented as follows:
Each tablet, for oral administration, contains either 1 mg or 2 mg of estazolam, USP. In addition, each tablet contains the following inactive ingredients: docusate sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium starch glycolate and stearic acid. The 2 mg tablets also contain FD&C Red #40 aluminum lake.
What does Estazolam look like?
What are the available doses of Estazolam?
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What should I talk to my health care provider before I take Estazolam?
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How should I use Estazolam?
Estazolam tablets, USP are 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 ).
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 ).
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.
What interacts with Estazolam?
Benzodiazepines may cause fetal damage when administered during pregnancy. An increased risk of congenital malformations associated with the use of diazepam and chlordiazepoxide during the first trimester of pregnancy has been suggested in several studies. Transplacental distribution has resulted in neonatal CNS depression and also withdrawal phenomena following the ingestion of therapeutic doses of a benzodiazepine hypnotic during the last weeks of pregnancy.
Estazolam is contraindicated in pregnant women. If there is a likelihood of the patient becoming pregnant while receiving estazolam she should be warned of the potential risk to the fetus and instructed to discontinue the drug prior to becoming pregnant. The possibility that a woman of childbearing potential is pregnant at the time of institution of therapy should be considered.
Estazolam is contraindicated with ketoconazole and itraconazole, since these medications significantly impair oxidative metabolism mediated by CYP3A (see and ).
What are the warnings of Estazolam?
Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses.
Concomitant use of benzodiazepines, including estazolam, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe estazolam concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of estazolam than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking estazolam, prescribe 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 Drug Interactions).
Because sleep disturbances may be presenting manifestations of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. 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 and ), 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.
Severe Anaphylactic and Anaphylactoid Reactions
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.
There have been reports of withdrawal signs and symptoms of the type associated with withdrawal from CNS depressant drugs following the rapid decrease or the abrupt discontinuation of benzodiazepines (see ).
Estazolam Interaction with Drugs that Inhibit Metabolism via Cytochrome P450 3A (CYP3A):
While no 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.
What are the precautions of Estazolam?
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Elderly or debilitated patients and those with impaired renal or hepatic function should be cautioned about these risks and advised to monitor themselves for signs of excessive sedation or impaired conditions.
Estazolam appears to cause dose-related respiratory depression that is ordinarily not clinically relevant at recommended doses in patients with normal respiratory function. However, patients with compromised respiratory function may be at risk and should be monitored appropriately. As a class, benzodiazepines have the capacity to depress respiratory drive; there are insufficient data available, however, to characterize their relative potency in depressing respiratory drive at clinically recommended doses.
As with other benzodiazepines, estazolam should be administered with caution to patients exhibiting signs or symptoms of depression. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional overdosage is more common in this group of patients; therefore, the least amount of drug that is feasible should be prescribed for the patient at any one time.
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Information for Patients:
There have been reports of people getting out of bed after taking a sedative-hypnotic and driving their cars while not fully awake, often with no memory of the event. If a patient experiences such an episode, it should be reported to his or her doctor immediately, since “sleep-driving” can be dangerous. This behavior is more likely to occur when sedativehypnotics are taken with alcohol or other central nervous system depressants (see ). 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.
To assure the safe and effective use of estazolam, the following information and instructions should be given to patients:
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Laboratory Tests:
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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 ).
While no 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 ). 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.
Drug Interaction with Fluoxetine:
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Carcinogenesis, Mutagenesis, Impairment of Fertility:
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Fertility in male and female rats was not affected by doses up to 30 times the usual recommended human dose.
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- Teratogenic Effects: Pregnancy Category X (see ).
- Nonteratogenic Effects: The child born of a mother taking benzodiazepines may be at some risk for withdrawal symptoms during the postnatal period. Neonatal flaccidity has been reported in an infant born of a mother who received benzodiazepines during pregnancy.
Pregnancy:
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Labor and Delivery:
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Nursing Mothers:
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Pediatric Use:
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Geriatric Use:
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What are the side effects of Estazolam?
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.
| Body System/Adverse Event | 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 necessarily caused by it.
Body as a Whole
Cardiovascular System
Digestive System
Endocrine System
Hematologic and Lymphatic System
Metabolic/Nutritional Disorders
Musculoskeletal System
Nervous System
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
Skin and Appendages
Special Senses
Urogenital System
Postintroduction Reports
What should I look out for while using Estazolam?
Benzodiazepines may cause fetal damage when administered during pregnancy. An increased risk of congenital malformations associated with the use of diazepam and chlordiazepoxide during the first trimester of pregnancy has been suggested in several studies. Transplacental distribution has resulted in neonatal CNS depression and also withdrawal phenomena following the ingestion of therapeutic doses of a benzodiazepine hypnotic during the last weeks of pregnancy.
Estazolam is contraindicated in pregnant women. If there is a likelihood of the patient becoming pregnant while receiving estazolam she should be warned of the potential risk to the fetus and instructed to discontinue the drug prior to becoming pregnant. The possibility that a woman of childbearing potential is pregnant at the time of institution of therapy should be considered.
Estazolam is contraindicated with ketoconazole and itraconazole, since these medications significantly impair oxidative metabolism mediated by CYP3A (see and
).
Concomitant use of benzodiazepines, including estazolam, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe estazolam concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of estazolam than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking estazolam, prescribe 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 Drug Interactions).
Because sleep disturbances may be presenting manifestations of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. 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 and ), 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.
What might happen if I take too much Estazolam?
As with other benzodiazepines, experience with estazolam indicates that manifestations of overdosage include somnolence, respiratory depression, confusion, impaired coordination, slurred speech, and ultimately, coma. Patients have recovered from overdosage as high as 40 mg. As in the management of intentional overdose with any drug, the possibility should be considered that multiple agents may have been taken.
Gastric evacuation, either by the induction of emesis, lavage, or both, should be performed immediately. Maintenance of adequate ventilation is essential. General supportive care, including frequent monitoring of the vital signs and close observation of the patient, is indicated. Fluids should be administered intravenously to maintain blood pressure and encourage diuresis. The value of dialysis in treatment of benzodiazepine overdose has not been determined. The physician may wish to consider contacting a Poison Control Center for up-to-date information on the management of hypnotic drug product overdose.
Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation, and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The complete flumazenil package insert including , , and should be consulted prior to use.
How should I store and handle Estazolam?
Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature].Estazolam tablets, USP 1 mg are white, scored, diamond shaped compressed tablets imprinted with on one side of the tablet and on the other side with on the left side of the score and 1 on the right side of the score, supplied in bottles of 100.Estazolam tablets, USP 2 mg are dark pink, scored, diamond shaped compressed tablets imprinted with on one side of the tablet and on the other side with on the left side of the score and 2 on the right side of the score, supplied in bottles of 100.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.Manufactured by: Watson Pharma Private Limited Verna, Salcette Goa 403 722 INDIA Distributed by: Actavis Pharma, Inc.Parsippany, NJ 07054 USA Revised: September 2016227194-1Estazolam tablets, USP 1 mg are white, scored, diamond shaped compressed tablets imprinted with on one side of the tablet and on the other side with on the left side of the score and 1 on the right side of the score, supplied in bottles of 100.Estazolam tablets, USP 2 mg are dark pink, scored, diamond shaped compressed tablets imprinted with on one side of the tablet and on the other side with on the left side of the score and 2 on the right side of the score, supplied in bottles of 100.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.Manufactured by: Watson Pharma Private Limited Verna, Salcette Goa 403 722 INDIA Distributed by: Actavis Pharma, Inc.Parsippany, NJ 07054 USA Revised: September 2016227194-1Estazolam tablets, USP 1 mg are white, scored, diamond shaped compressed tablets imprinted with on one side of the tablet and on the other side with on the left side of the score and 1 on the right side of the score, supplied in bottles of 100.Estazolam tablets, USP 2 mg are dark pink, scored, diamond shaped compressed tablets imprinted with on one side of the tablet and on the other side with on the left side of the score and 2 on the right side of the score, supplied in bottles of 100.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.Manufactured by: Watson Pharma Private Limited Verna, Salcette Goa 403 722 INDIA Distributed by: Actavis Pharma, Inc.Parsippany, NJ 07054 USA Revised: September 2016227194-1Estazolam tablets, USP 1 mg are white, scored, diamond shaped compressed tablets imprinted with on one side of the tablet and on the other side with on the left side of the score and 1 on the right side of the score, supplied in bottles of 100.Estazolam tablets, USP 2 mg are dark pink, scored, diamond shaped compressed tablets imprinted with on one side of the tablet and on the other side with on the left side of the score and 2 on the right side of the score, supplied in bottles of 100.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.Manufactured by: Watson Pharma Private Limited Verna, Salcette Goa 403 722 INDIA Distributed by: Actavis Pharma, Inc.Parsippany, NJ 07054 USA Revised: September 2016227194-1Estazolam tablets, USP 1 mg are white, scored, diamond shaped compressed tablets imprinted with on one side of the tablet and on the other side with on the left side of the score and 1 on the right side of the score, supplied in bottles of 100.Estazolam tablets, USP 2 mg are dark pink, scored, diamond shaped compressed tablets imprinted with on one side of the tablet and on the other side with on the left side of the score and 2 on the right side of the score, supplied in bottles of 100.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.Manufactured by: Watson Pharma Private Limited Verna, Salcette Goa 403 722 INDIA Distributed by: Actavis Pharma, Inc.Parsippany, NJ 07054 USA Revised: September 2016227194-1Estazolam tablets, USP 1 mg are white, scored, diamond shaped compressed tablets imprinted with on one side of the tablet and on the other side with on the left side of the score and 1 on the right side of the score, supplied in bottles of 100.Estazolam tablets, USP 2 mg are dark pink, scored, diamond shaped compressed tablets imprinted with on one side of the tablet and on the other side with on the left side of the score and 2 on the right side of the score, supplied in bottles of 100.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.Manufactured by: Watson Pharma Private Limited Verna, Salcette Goa 403 722 INDIA Distributed by: Actavis Pharma, Inc.Parsippany, NJ 07054 USA Revised: September 2016227194-1Estazolam tablets, USP 1 mg are white, scored, diamond shaped compressed tablets imprinted with on one side of the tablet and on the other side with on the left side of the score and 1 on the right side of the score, supplied in bottles of 100.Estazolam tablets, USP 2 mg are dark pink, scored, diamond shaped compressed tablets imprinted with on one side of the tablet and on the other side with on the left side of the score and 2 on the right side of the score, supplied in bottles of 100.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.Manufactured by: Watson Pharma Private Limited Verna, Salcette Goa 403 722 INDIA Distributed by: Actavis Pharma, Inc.Parsippany, NJ 07054 USA Revised: September 2016227194-1Estazolam tablets, USP 1 mg are white, scored, diamond shaped compressed tablets imprinted with on one side of the tablet and on the other side with on the left side of the score and 1 on the right side of the score, supplied in bottles of 100.Estazolam tablets, USP 2 mg are dark pink, scored, diamond shaped compressed tablets imprinted with on one side of the tablet and on the other side with on the left side of the score and 2 on the right side of the score, supplied in bottles of 100.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.Manufactured by: Watson Pharma Private Limited Verna, Salcette Goa 403 722 INDIA Distributed by: Actavis Pharma, Inc.Parsippany, NJ 07054 USA Revised: September 2016227194-1
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Absorption
Estazolam tablets have been found to be equivalent in absorption to an orally administered solution of estazolam. In healthy subjects who received up to three times the recommended dose of estazolam, peak estazolam plasma concentrations occurred within two hours after dosing (range 0.5 to 6 hours) and were proportional to the administered dose, suggesting linear pharmacokinetics over the dosage range tested.
Distribution
Independent of concentration, estazolam in plasma is 93% protein bound.
Metabolism
Estazolam is extensively metabolized. Only two metabolites (1-oxo-estazolam and 4-hydroxy-estazolam) were detected in human plasma up to 18 hours.
The pharmacologic activity of estazolam is primarily from the parent drug. The elimination of the parent drug takes place via hepatic metabolism of estazolam to hydroxylated and other metabolites that are eliminated largely in the urine both free and conjugated. In humans, greater than 70% of a 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. 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.
Non-Clinical Toxicology
Benzodiazepines may cause fetal damage when administered during pregnancy. An increased risk of congenital malformations associated with the use of diazepam and chlordiazepoxide during the first trimester of pregnancy has been suggested in several studies. Transplacental distribution has resulted in neonatal CNS depression and also withdrawal phenomena following the ingestion of therapeutic doses of a benzodiazepine hypnotic during the last weeks of pregnancy.Estazolam is contraindicated in pregnant women. If there is a likelihood of the patient becoming pregnant while receiving estazolam she should be warned of the potential risk to the fetus and instructed to discontinue the drug prior to becoming pregnant. The possibility that a woman of childbearing potential is pregnant at the time of institution of therapy should be considered.
Estazolam is contraindicated with ketoconazole and itraconazole, since these medications significantly impair oxidative metabolism mediated by CYP3A (see and ).
Concomitant use of benzodiazepines, including estazolam, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe estazolam concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of estazolam than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking estazolam, prescribe 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 Drug Interactions).
Because sleep disturbances may be presenting manifestations of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. 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 and ), 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.
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 ).
While no 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.
General:
Elderly or debilitated patients and those with impaired renal or hepatic function should be cautioned about these risks and advised to monitor themselves for signs of excessive sedation or impaired conditions.
Estazolam appears to cause dose-related respiratory depression that is ordinarily not clinically relevant at recommended doses in patients with normal respiratory function. However, patients with compromised respiratory function may be at risk and should be monitored appropriately. As a class, benzodiazepines have the capacity to depress respiratory drive; there are insufficient data available, however, to characterize their relative potency in depressing respiratory drive at clinically recommended doses.
As with other benzodiazepines, estazolam should be administered with caution to patients exhibiting signs or symptoms of depression. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional overdosage is more common in this group of patients; therefore, the least amount of drug that is feasible should be prescribed for the patient at any one time.
Commonly Observed:
Associated with Discontinuation of Treatment:
Incidence in Controlled Clinical Trials:
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
Cardiovascular System
Digestive System
Endocrine System
Hematologic and Lymphatic System
Metabolic/Nutritional Disorders
Musculoskeletal System
Nervous System
Respiratory System
Skin and Appendages
Special Senses
Urogenital System
Postintroduction Reports
To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-272-5525 or FDA at 1-800-FDA-1088 or .
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
While we update our database periodically, we cannot guarantee it is always updated to the latest version.
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).