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Central nervous system agents of the 1,4-benzodiazepine class presumably exert their effects by binding to stereo-specific receptors at several sites within the central nervous system (CNS). Their exact mechanism of action is unknown.
In a sleep laboratory study, DORAL® (quazepam tablets) Tablets significantly decreased sleep latency and total wake time, and significantly increased total sleep time and percent sleep time, for one or more nights. Quazepam 15 mg was effective on the first night of administration. Sleep latency, total wake time and wake time after sleep onset were still decreased and percent sleep time was still increased for several nights after the drug was discontinued. Percent slow wave sleep was decreased, and REM sleep was essentially unchanged. No transient sleep disturbance, such as “rebound insomnia,” was observed after withdrawal of the drug in sleep laboratory studies in 12 patients using 15 mg doses.
In outpatient studies, DORAL® (quazepam tablets) Tablets improved all subjective measures of sleep including sleep induction time, duration of sleep, number of nocturnal awakenings, occurrence of early morning awakening, and sleep quality. Some effects were evident on the first night of administration of DORAL® (quazepam tablets) Tablets (sleep induction time, number of nocturnal awakenings, and duration of sleep). Residual medication effects (“hangover”) were minimal.
Quazepam is rapidly (absorption half-life of about 30 minutes) and well absorbed from the gastrointestinal tract. The peak plasma concentration of quazepam is approximately 20 ng/mL after a 15 mg dose and is obtained at about 2 hours. Quazepam, the active parent compound, is extensively metabolized in the liver; two of the plasma metabolites are 2-oxoquazepam and N-desalkyl-2-oxoquazepam. All three compounds show pharmacological central nervous system activity in animals.
Following administration of 14C-quazepam, approximately 31% of the dose appears in the urine and 23% in the feces over a five-day period; only trace amounts of unchanged drug are present in the urine.
The mean elimination half-life of quazepam and 2-oxoquazepam is 39 hours and that of N-desalkyl-2oxoquazepam is 73 hours. Steady-state levels of quazepam and 2-oxoquazepam are attained by the seventh daily dose and that of N-desalkyl-2-oxoquazepam by the thirteenth daily dose.
The pharmacokinetics of quazepam and 2-oxoquazepam in geriatric subjects are comparable to those seen in young adults; as with desalkyl metabolites of other benzodiazepines, the elimination half-life of N-desalkyl-2oxoquazepam in geriatric patients is about twice that of young adults.
The degree of plasma protein binding for quazepam and its two major metabolites is greater than 95%. The absorption, distribution, metabolism, and excretion of benzodiazepines may be altered in various disease states including alcoholism, impaired hepatic function, and impaired renal function.
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. When half-lives are long, drug or metabolites may accumulate during periods of nightly administration and 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 enhanced. 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 half-life of elimination, 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 the appearance of increased signs of daytime anxiety in selected patients.
Quazepam crosses the placental barrier of mice. Quazepam, 2-oxoquazepam and N-desalkyl-2oxoquazepam are present in breast milk of lactating women, but the total amount found in the milk represents only about 0.1% of the administered dose.
(see also PRECAUTIONS: DRUG INTERACTIONS)
In vitro inhibition studies conducted to assess the potential of quazepam to inhibit CYP2B6, CYP2C8 and CYP2E1 at relevant clinical Cmax concentrations (0.15 μM = 58 ng/mL) demonstrate quazepam is a CYP2B6 mechanism based inhibitor. Increased plasma concentrations of drugs that are substrates of CYP2B6 may result if coadministered with DORAL®. Quazepam does not inhibit CYP2C8 and CYP2E1.
Last reviewed on RxList: 4/30/2010
This monograph has been modified to include the generic and brand name in many instances.
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