Benzodiazepines, including QUAZEPAM, produce additive CNS depressant effects when co-administered with ethanol or other CNS depressants (e.g. psychotropic medications, anticonvulsants, antihistamines). Downward dose adjustment of QUAZEPAM and/or concomitant CNS depressants may be necessary because of additive effects.
Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Administration of benzodiazepines immediately prior to or during childbirth can result in a syndrome of hypothermia, hypotonia, respiratory depression, and difficulty feeding. In addition, infants born to mothers who have taken benzodiazepines during the later stages of pregnancy can develop dependence, and subsequently withdrawal, during the postnatal period. Although administration of quazepam to pregnant animals did not indicate a risk for adverse effects on morphological development at clinically relevant doses, data for other benzodiazepines suggest the possibility of adverse developmental effects (long-term effects on neurobehavioral and immunological function) in animals following prenatal exposure to benzodiazepines. QUAZEPAM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Developmental toxicity studies of quazepam in mice at doses up to 400 times the human dose (15 mg) revealed no major drug-related malformations. Minor fetal skeletal variations that occurred were delayed ossification of the sternum, vertebrae, distal phalanges and supraoccipital bones, at doses approximately 70 and 400 times the human dose. A developmental toxicity study of quazepam in New Zealand rabbits at doses up to approximately 130 times the human dose demonstrated no effect on fetal morphology or development of offspring.
Quazepam and its metabolites are excreted in human milk. Caution should be exercised when administering QUAZEPAM to a nursing woman.
Safety and effectiveness in pediatric patients have not been established.
QUAZEPAM may cause confusion and over-sedation in the elderly. Elderly patients generally should be started on a low dose of QUAZEPAM and observed closely.
Elderly and debilitated patients may be more sensitive to benzodiazepines, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
A double-blind controlled sleep laboratory study (N=30) compared the effects of quazepam 7.5 mg and 15 mg to that of placebo over a period of 7 days. Both the 7.5 mg and 15 mg doses appeared to be well tolerated. Caution must be used in interpreting this data due to the small size of the study.
Quazepam is classified as a Schedule IV controlled substance by federal regulation.
Addiction-prone individuals (e.g. history of drug addiction or alcoholism) should be under careful surveillance when receiving QUAZEPAM because of increased risk of abuse and dependence. Benzodiazepine withdrawal symptoms can occur following discontinuation of QUAZEPAM [see Warnings and Precautions (5.2)].
Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug and/or administration of an antagonist. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time. Tolerance may occur to both the desired and undesired effects of drugs and may develop at different rates for different effects.
Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common.
Contact a poison control center for up-to-date information on the management of benzodiazepine overdose.
Manifestations of QUAZEPAM overdose include somnolence, confusion, and coma. General supportive measures should be employed, along with immediate gastric lavage. Dialysis is of limited value. Flumazenil may be useful, but can contribute to the appearance of neurological symptoms including convulsions. Hypotension may be treated by appropriate medical intervention. Animal experiments suggest that forced diuresis or hemodialysis are of little value in treating QUAZEPAM overdose. As with the management of intentional overdose with any drug, the possibility of multiple drug ingestion should be considered.
QUAZEPAM contains quazepam, a trifluoroethyl benzodiazepine hypnotic agent, having the chemical name 7-chloro-5- (o-fluoro-phenyl)-1,3-dihydro-1-(2,2,2- trifluoroethyl)-2H-1,4-benzodiazepine-2-thione and the following structural formula:
Quazepam has the empirical formula C17H11ClF4N2S, and a molecular weight of 386.8. It is a white crystalline compound, soluble in ethanol and insoluble in water. Each QUAZEPAM Tablet contains 15 mg of quazepam. The inactive ingredients for QUAZEPAM Tablets include cellulose, corn starch, FD&C Yellow No. 6 Al Lake, lactose, magnesium stearate, silicon dioxide, and sodium lauryl sulfate.
Quazepam, like other central nervous system agents of the 1,4-benzodiazepine class, presumably exerts its effects by binding to stereo-specific receptors at several sites within the central nervous system (CNS). The exact mechanism of action is unknown.
Absorption: 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 occurs at about 2 hours.
Metabolism: 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 CNS depressant activity.
Distribution: The degree of plasma protein binding for quazepam and its two major metabolites is greater than 95%.
Elimination: Following administration of 14 C-quazepam, 31% of the dose appeared in the urine and 23% in the feces over five days; only trace amounts of unchanged drug were present in the urine.
The mean elimination half-life of quazepam and 2-oxoquazepam is 39 hours and that of N-desalkyl-2-oxoquazepam 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.
Special Populations: Geriatrics: 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-2-oxoquazepam in geriatric patients is about twice that of young adults.
Bupropion (a CYP2B6 substrate): Co-administration of a single dose of 150 mg Bupropion Hydrochloride XL with steady state quazepam did not significantly affect the AUC and Cmax of bupropion or its primary metabolite, hydroxybupropion.
Carcinogenesis Quazepam showed no evidence of carcinogenicity in oral carcinogenicity studies in mice and hamsters.
Mutagenesis Quazepam was negative in the bacterial reverse mutation (Ames) assay and equivocal in the mouse lymphoma tk assay.
Impairment of Fertility Reproduction studies in mice conducted with quazepam at doses equal to 60 and 180 times the human dose of 15 mg produced slight reductions in fertility rate. Similar reductions in fertility rate have been reported in mice dosed with other benzodiazepines, and is believed to be related to the sedative effects of these drugs at high doses.
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