Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1159
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PROSOM (Tablet)
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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.
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ProSom (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���4H���s���triazolo[4,3-��] [1,4]benzodiazepine.
The empirical formula is CHClN. The
structural formula is represented as follows: ProSom tablets are scored and contain either
1 mg or 2 mg of estazolam.<br/>Inactive Ingredients: Colloidal silicon dioxide, lactose, povidone, stearic
acid, and sodium starch glycolate. In addition,
the 2 mg tablets contain FD&C Red No. 40.
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Pharmacokinetics:<br/>Absorption: ProSom 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 ProSom, peak
estazolam plasma concentrations occurred within two hours after dosing (range
0.5 to 6.0 hours) and were proportionalto the administered dose, suggesting
linear pharmacokinetics over the dosage range tested.<br/>Distribution: Independent of concentration, estazolam in plasma
is 93% protein bound.<br/>Metabolism: Estazolam is extensively metabolized. Only two
metabolites (1-oxo-estazolam&4���hydroxy���estazolam)
were detected in human plasma up to 18 hrs. 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. 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 ProSom.<br/>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.<br/>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.<br/>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.<br/>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 (Cand
AUC) were not affected during multiple-dose fluoxetine, suggesting no clinically
significant pharmacokinetic interaction.<br/>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.<br/>Pharmacodynamics:<br/>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
eliminationhalf-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 nightly use of rapidly eliminated benzodiazepine hypnotics,
namely, increased wakefulness during the last third of the night and increased
daytime anxiety in selected patients.
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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. ProSom is contraindicated
in pregnant women. If there is a likelihood of the patient becoming pregnant
while receiving ProSom 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 WARNINGS and PRECAUTIONS
- Drug Interactions).
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ProSom tablets are scored tablets supplied as: ProSom Tablets 1 mg white tablets bearing the Abbott
logo and UC (Abbo-Code). Bottles of 100 (NDC 0074-3735-13) ProSom Tablets 2 mg pink tablets bearing the Abbott logo
and UD (Abbo-Code). Bottles of 100 (NDC 0074-3736-13).<br/>Recommended Storage: Store below 86��F (30��C).
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As with other benzodiazepines, experience with ProSom
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 prescriber should be aware of a risk of seizure in association
with flumazenil treatment, particularly in long���term benzodiazepine
users and in cyclic antidepressant overdose. The complete flumazenil
package insert including CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS should be consulted prior to use.
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estazolam
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PROSOM (Tablet)
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Commonly Observed: The most commonly observed adverse events associated
with the use of ProSom, not seen at an equivalent incidence among placebo-treated
patients were somnolence, hypokinesia, dizziness, and abnormal coordination.<br/>Associated with Discontinuation of Treatment: Approximately 3% of 1277 patients who received ProSom
in US 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.<br/>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
ProSom 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:ProSom, 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 ofconditions.
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.<br/>Other Adverse Events: During clinical trials conducted by Abbott, some
of which were not placebo���controlled, ProSom 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. Thefrequencies presented, therefore, represent the proportion
of the 1277 individuals exposed to ProSom who experienced an event of the
type cited on at least one occasion while receiving ProSom. 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 ProSom, they were not necessarily caused by
it.<br/>Body as a Whole:<br/>Cardiovascular System:<br/>Digestive System:<br/>Endocrine System:<br/>Hematologic and Lymphatic System:<br/>Metabolic/Nutritional Disorders:<br/>Musculoskeletal System:<br/>Nervous System:<br/>Respiratory System:<br/>Skin and Appendages:<br/>Special Senses:<br/>Urogenital System:<br/>Postintroduction Reports: Voluntary reports of non-US 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.
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ProSom, 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 ProSom. 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 DRUG ABUSE AND DEPENDENCE ).<br/>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. 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.
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ProSom (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 ProSom administered at bedtime
improved sleep induction and sleep maintenance (see CLINICAL
PHARMACOLOGY). Because insomnia is
often transient and intermittent, the prolonged administration of ProSom 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 ProSom to enhance
the duration and quality of sleep for intervals up to 12 weeks (see CLINICAL PHARMACOLOGY).
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PROSOM
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