Insomnia
Quazepam shares the actions of other benzodiazepines and is used as a hypnotic agent in the short-term management of insomnia for periods up to 4 weeks in duration. Benzodiazepines generally are preferred to other hypnotics for the management of insomnia because of their short- and intermediate-term efficacy and relative safety.
The choice of a specific benzodiazepine must be individualized according to patient response and tolerance, taking into consideration pharmacokinetic and pharmacodynamic characteristics of the drug, patient age and other characteristics, and the underlying sleep disorder being treated. Benzodiazepines with a relatively long elimination half-life, such as quazepam, appear to be less likely than those with a relatively short half-life to result in transient rebound insomnia after discontinuance and in pharmacodynamic tolerance and adaptation to the hypnotic effect during continued therapy but may be more likely to result in residual daytime sedative effects and in impaired psychomotor and mental performance during continued therapy, although partial tolerance to these effects can occur. Prolonged use of hypnotics usually is not indicated and should be undertaken only on further evaluation of the patient. The possibility that insomnia may be a manifestation of an underlying condition for which there may be a more specific treatment should be considered.
For additional information on the use of benzodiazepines in the management of insomnia, see Uses: Anxiety and Insomnia in the Benzodiazepines General Statement 28:24.08.
Administration 
Quazepam is administered orally at bedtime.
Dosage
Dosage of quazepam must be individualized, and the smallest effective dosage should be used (especially in geriatric or debilitated patients). Prolonged administration of quazepam should be avoided. Because of the drug's long elimination half-life, intermittent therapy (e.g., every second or third night) may be possible without substantial risk of rebound insomnia in some patients.
The usual adult dose of quazepam is 15 mg; a dose of 7.5 mg may be adequate for some patients. While a quazepam dose of 30 mg occasionally has been used, this dose is associated with an increased risk of daytime sedation. In geriatric or debilitated patients, an initial dose of 7.5 or 15 mg should be used; in patients receiving 15 mg initially, reduction of the dose after the first one or two nights of therapy should be attempted. In patients who have received prolonged (e.g., even for periods as brief as 6 weeks) quazepam therapy, abrupt discontinuance of the drug should be avoided since manifestations of withdrawal can be precipitated; if the drug is to be discontinued in such patients, it is recommended that dosage be gradually tapered.
Precautions
A boxed warning has been included in the prescribing information for all benzodiazepines describing the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions associated with all drugs in this class.900 Abuse and misuse can result in overdose or death, especially when benzodiazepines are combined with other medicines, such as opioid pain relievers, alcohol, or illicit drugs.900 Frequent follow-up with patients receiving benzodiazepines is important.900 Reassess patients regularly to manage their medical conditions and any withdrawal symptoms.900 Clinicians should assess a patient's risk of abuse, misuse, and addiction. 900 Standardized screening tools are available ([Web]).900 To reduce the risk of acute withdrawal reactions, use a gradual dose taper when reducing the dosage or discontinuing benzodiazepines.900 Take precautions when benzodiazepines are used in combination with opioid medications.900
Quazepam shares the toxic potentials of the benzodiazepines, and the usual precautions of benzodiazepine administration should be observed. (See Cautions in the Benzodiazepines General Statement 28:24.08.)
Pediatric Precautions
Safety and efficacy of quazepam in children younger than 18 years of age have not been established.
Geriatric Precautions
Oral quazepam doses of 7.5 or 15 mg generally have been well tolerated during short-term use in geriatric patients. In several short-term studies employing such doses, ataxia and morning hangover did not occur more frequently with quazepam than with placebo. However, because elimination of the drug may be prolonged in geriatric patients and because this age group generally is at increased risk from adverse nervous system effects of drugs, including benzodiazepines, quazepam dosage should be adjusted carefully in geriatric patients. (See Dosage and Administration: Dosage.)
Mutagenicity and Carcinogenicity
No evidence of quazepam-induced mutagenicity was observed in the Ames microbial mutagen test, with or without metabolic activation; results were equivocal in a mammalian mutagenicity assay using L5178Y/TK± mouse lymphoma cells.
No evidence of carcinogenesis was observed in mice or hamsters receiving quazepam orally.
Pregnancy, Fertility, and Lactation
Pregnancy
Benzodiazepines can cause fetal harm when administered to pregnant women (see Cautions: Pregnancy and Lactation in the Benzodiazepines General Statement 28:24.08), and those used solely as hypnotics, such as quazepam, are contraindicated during pregnancy. The safety of quazepam during labor or delivery has not been established.
Fertility
Reproduction studies in mice given quazepam doses equivalent to 60-180 times the human dose of 15 mg indicate that the drug produces a slight reduction in pregnancy rate. A similar reduction in pregnancy rates in mice has been observed with high dosages of other benzodiazepines and is believed to be related to the sedative effects of the drugs.
Lactation
Quazepam and its metabolites are distributed into milk in humans. (See Pharmacokinetics: Distribution.) Therefore, use of the drug in nursing woman is not recommended.
Pharmacology
Quazepam shares the actions of other benzodiazepines. The exact sites and modes of action of benzodiazepines have not been fully elucidated, but the effects of the drugs appear to be mediated principally through the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Specific binding sites with high affinity for benzodiazepines have been detected in the CNS, and the affinity of these sites for the drugs is enhanced by both GABA and chloride. The sites and actions of benzodiazepines within the CNS appear to involve a macromolecular (oligomer or possibly a tetramer) complex (GABAA-receptor-chloride ionophore complex) that includes GABAA receptors (GABA recognition sites), high-affinity benzodiazepine receptors, and chloride channels, although precise relationships between the sites of action of benzodiazepines and GABA-regulated (-gated) chloride channels remain to be more fully elucidated. Allosteric interactions of central benzodiazepine receptors with GABAA receptors and subsequent opening of chloride channels appears to be involved in eliciting the CNS effects of the drugs; the benzodiazepine receptors act as modulatory sites on the complex. Some evidence suggests that benzodiazepine receptor sites are heterogeneous, with at least 2 CNS subtypes (type 1 [BZ1] and type 2 [BZ2] benzodiazepine receptors) being described to date. While quazepam and 2-oxoquazepam (an active metabolite), like halazepam (another 1- N -trifluoroethyl derivative [no longer commercially available in the US]) but unlike other currently available benzodiazepines, exhibit relative selectivity for type 1 receptors (2-oxoquazepam is the most potent and selective of the three), the clinical importance, if any, of this finding remains to be established. Some evidence suggests that such selectivity may be responsible for the reduced ataxic effect of quazepam observed in animal studies; the possibility that the spectrum of other benzodiazepine-induced effects may be narrowed by such selectivity also has been suggested.
For further information on the pharmacology of quazepam, see the Benzodiazepines General Statement 28:24.08.
Pharmacokinetics
Absorption
Quazepam is rapidly and reportedly well absorbed from the GI tract following oral administration. Although the manufacturer states that oral bioavailability of the drug is approximately 80%, the absolute bioavailability in humans has not been determined to date. In addition, the drug has been shown to undergo extensive first-pass metabolism following oral administration in animals. Food does not appear to affect GI absorption of quazepam.
Peak plasma concentrations of quazepam and a principal active metabolite, 2-oxoquazepam, average approximately 20-30 or 13.5-18 ng/mL, respectively, and are achieved 1-3 hours following oral administration of single or multiple (at steady state) 15-mg doses of quazepam as tablets. Area under the plasma concentration-time curve (AUC), peak plasma concentration, and time-to-peak plasma concentration for unchanged drug and 2-oxoquazepam following a single 15-mg oral dose are similar in geriatric adults and in younger adults. GI absorption of quazepam is delayed slightly and AUCs of quazepam, 2-oxoquazepam, and N -desalkyl-2-oxoquazepam (another major metabolite) are increased slightly when the drug is administered at bedtime compared with administration in the morning, but such differences are unlikely to be clinically important.
Distribution
Quazepam is widely distributed into most body tissues and fluids. In animals, highest concentrations are achieved in liver and kidneys; 24 hours after administration, concentrations in liver, kidney, epididymal fat, pituitary, and prostate exceed those in plasma. The apparent volume of distribution of quazepam in healthy human adults reportedly averages 5 L/kg when the drug is administered at bedtime and 8.6 L/kg when administered in the morning. Evidence from animal studies indicates that the drug and its metabolites readily cross the blood-brain barrier, and it has been suggested that both quazepam and 2-oxoquazepam, which are highly lipophilic, distribute rapidly into the CNS and that N -desalkyl-2-oxoquazepam, which is less lipophilic, distributes more slowly. In animals, hypnotic activity (assessed by inhibition of electroconvulsive shock-induced seizures) closely parallels CNS concentrations of quazepam and 2-oxoquazepam; the contribution of N -desalkyl-2-oxoquazepam is less well defined. Quazepam and its metabolites are more than 95% protein bound.
Quazepam and its metabolites cross the placenta in mice and, near term (i.e., on the 18th day of gestation), are present in fetal plasma at concentrations similar to those in maternal plasma. Fetal accumulation of the drug does not appear to occur.
Quazepam and its metabolites are distributed into milk in humans. Following oral administration of a 15-mg dose of the drug in lactating women, total recovery in milk of quazepam, 2-oxoquazepam, and N -desalkyl-2-oxoquazepam during the following 48 hours averaged 0.11% of the administered dose. Milk-to-plasma AUC ratios averaged 4.19, 2.02, and 0.091 for the drug and these metabolites, respectively.
Elimination
Quazepam is rapidly and extensively metabolized in the liver to 2-oxoquazepam and N -desalkyl-2-oxoquazepam ( N -desalkylflurazepam), both of which have pharmacologic activity reportedly similar to that of quazepam. Plasma concentrations of quazepam and these metabolites decline in a biphasic manner, with half-lives in the initial distribution phase (t½α) of approximately 1.7, 2.9, and 27.8 hours, respectively, following single oral doses and 1.9, 2, and 57 hours, respectively, following multiple oral doses in healthy young adults. The elimination half-lives (t½β) of both quazepam and 2-oxoquazepam in healthy young adults average approximately 39-40 hours (range: 25-41 hours for quazepam) following single or multiple oral doses; in healthy geriatric adults, the elimination half-life appears to be somewhat prolonged for quazepam (e.g., 53 hours) but not for 2-oxoquazepam (e.g., 43 hours). The elimination half-life of N -desalkyl-2-oxoquazepam averages about 70-75 hours in healthy young adults following single or multiple oral doses but, in healthy geriatric adults, may be more than twice that (e.g., 190 hours). The total body clearance of quazepam reportedly is 890 mL/minute.
N -Desalkyl-2-oxoquazepam, which is formed via N -dealkylation of 2-oxoquazepam, is metabolized further via conjugation with glucuronic acid or via hydroxylation and subsequent glucuronide formation. 2-Oxoquazepam also undergoes hydroxylation to 3-hydroxy-2-oxoquazepam and subsequent glucuronide formation, which appears to be the principal metabolic pathway for urinary excretion.
Quazepam is excreted slowly in both urine and feces, principally as glucuronide conjugates of inactive metabolites; only trace amounts of the drug are excreted unchanged. Following oral administration of radiolabeled quazepam in healthy adults, approximately 54% of a dose is excreted in urine (31%) and feces (23%) over a 5-day period. While it remains to be established whether fecal concentrations in humans principally represent unabsorbed drug or that which has been excreted via biliary elimination, limited data, principally from animals, suggest that the drug and/or its metabolites may undergo substantial biliary excretion. Approximately 50% of urinary excretion (15% of a dose) occurs as the conjugate of 3-hydroxy-2-oxoquazepam, with substantially lower amounts occurring as the conjugate of 3-hydroxy- N -desalkyl-2-oxoquazepam (6% of a dose), the conjugate of N -desalkyl-2-oxoquazepam (4% of a dose), polar metabolites (3% of a dose), and other metabolites and unchanged drug.
Chemistry and Stability
Chemistry
Quazepam is a benzodiazepine. The drug occurs as a white to off-white crystalline powder that is soluble in alcohol and insoluble in water.
Stability
Quazepam tablets should be stored in light-resistant containers at 2-30°C. When stored as directed, quazepam tablets are stable for 3 years following the date of manufacture.
Additional Information
For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, chronic toxicity, acute toxicity, drug interactions, laboratory test interferences, and dosage and administration of quazepam, see the Benzodiazepines General Statement 28:24.08.
AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions September 28, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Please see the general statement for a list of references.
Only references cited for selected revisions after 1984 are available electronically.
900. US Food and Drug Administration. Drug safety communication: FDA requiring Boxed Warning updated to improve safe use of benzodiazepine drug class Includes potential for abuse, addiction, and other serious risks. Silver Spring, MD; 2020 Sep 23. From FDA website. [Web]