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Quazepam

Pronunciation

(KWAZ e pam)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Doral: 15 mg [contains fd&c yellow #6 aluminum lake]

Doral: 15 mg [scored; contains fd&c yellow #6 aluminum lake]

Generic: 15 mg

Brand Names: U.S.

  • Doral

Pharmacologic Category

  • Benzodiazepine

Pharmacology

Binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system, including the limbic system, reticular formation. Enhancement of the inhibitory effect of GABA on neuronal excitability results by increased neuronal membrane permeability to chloride ions. This shift in chloride ions results in hyperpolarization (a less excitable state) and stabilization. Benzodiazepine receptors and effects appear to be linked to the GABA-A receptors. Benzodiazepines do not bind to GABA-B receptors.

Absorption

Rapid

Distribution

Vc/F: 5 to 8.6 L/kg (Ankier, 1988)

Metabolism

Hepatic via CYP3A4, CYP2C9, and CYP2C19 (Fukasawa, 2004; Kato, 2003); forms metabolites (active) 2-oxoquazepam and N-desalkyl-2-oxoquazepam

Excretion

Urine (31%, only trace amounts as unchanged drug); feces (23%)

Time to Peak

~2 hours

Half-Life Elimination

Serum: Quazepam, 2-oxoquazepam: 39 hours; N-desalkyl-2-oxoquazepam: 73 hours

Protein Binding

>95%

Special Populations: Elderly

Elimination half-life of N-desalkyl-2-oxoquazepam is increased 2-fold compared with younger adults.

Special Populations Note

Alcoholism

The potential for excessive sedation or impaired coordination exists.

Use: Labeled Indications

Insomnia: For the treatment of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning

Contraindications

Hypersensitivity to quazepam or other benzodiazepines; established or suspected sleep apnea; pulmonary insufficiency

Dosing: Adult

Hypnotic: Oral: Initial: 7.5 mg at bedtime; in some patients, the dose may be increased to 15 mg if necessary for efficacy.

Dosing: Geriatric

Dosing should be cautious; begin at lower end of dosing range (ie, 7.5 mg)

Dosing: Renal Impairment

No dosage adjustment provided in manufacturer’s labeling.

Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer’s labeling.

Dietary Considerations

Avoid grapefruit juice.

Storage

Store at 20°C to 25°C (68°F to 77°F).

Drug Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

CloZAPine: Benzodiazepines may enhance the adverse/toxic effect of CloZAPine. Management: Consider decreasing the dose of (or possibly discontinuing) benzodiazepines prior to initiating clozapine. Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Fosphenytoin: Benzodiazepines may increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Monitor therapy

Hydrocodone: CNS Depressants may enhance the CNS depressant effect of Hydrocodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Methadone: Benzodiazepines may enhance the CNS depressant effect of Methadone. Avoid combination

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Metyrosine: CNS Depressants may enhance the sedative effect of Metyrosine. Monitor therapy

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

OLANZapine: May enhance the adverse/toxic effect of Benzodiazepines. Management: Avoid concomitant use of parenteral benzodiazepines and IM olanzapine due to risks of additive adverse events (e.g., cardiorespiratory depression). Olanzapine prescribing information provides no specific recommendations regarding oral administration. Avoid combination

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Phenytoin: Benzodiazepines may increase the serum concentration of Phenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Sodium Oxybate: Benzodiazepines may enhance the CNS depressant effect of Sodium Oxybate. Avoid combination

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

Teduglutide: May increase the serum concentration of Benzodiazepines. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Consider therapy modification

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

>10%: Central nervous system: Daytime drowsiness (12%)

<10%:

Central nervous system: Headache (5%), dizziness (2%), fatigue (2%)

Gastrointestinal: Xerostomia (2%), dyspepsia (1%)

Frequency not defined. Note: Asterisked (*) reactions are those reported with benzodiazepines.

Cardiovascular: Palpitation

Central nervous system: Abnormal thinking, agitation, amnesia, anxiety, apathy, ataxia, confusion, depression, dystonia*, euphoria, hallucinations*, hyper-/hypokinesia, incoordination, irritability*, malaise, nervousness, nightmare, paranoid reaction, sleep disturbances*, slurred speech*, speech disorder, stimulation*

Dermatologic: Pruritus, rash

Endocrine & metabolic: Libido decreased, menstrual irregularities*

Gastrointestinal: Abdominal pain, abnormal taste perception, anorexia, constipation, diarrhea, nausea

Genitourinary: Impotence, incontinence, urinary retention*

Hepatic: Jaundice*

Neuromuscular & skeletal: Dysarthria*, muscle spasticity*, tremor, weakness

Ocular: Abnormal vision, cataract

Miscellaneous: Drug dependence, withdrawal*

Postmarketing and/or case reports: Anaphylaxis, angioedema, complex sleep-related behavior (sleep-driving, cooking or eating food, making phone calls)

Warnings/Precautions

Concerns related to adverse effects:

• Abnormal thinking/behavioral changes: Hypnotics/sedatives have been associated with abnormal thinking and behavior changes including decreased inhibition, aggression, bizarre behavior, agitation, hallucinations, and depersonalization. These changes may occur unpredictably and may indicate previously unrecognized psychiatric disorders; evaluate appropriately.

• Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Hypersensitivity reactions: Postmarketing studies have indicated that the use of hypnotic/sedative agents for sleep has been associated with hypersensitivity reactions including anaphylaxis as well as angioedema. Patients that have developed angioedema should not be rechallenged with quazepam.

• Paradoxical reactions: Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines, particularly in adolescent/pediatric or psychiatric patients.

• Psychomotor impairment: Increased risk of psychomotor impairment if usual dose is exceeded, used with concomitant CNS depressants, or a full night of sleep (>7-8 hours) is not possible.

• Sleep-related activities: An increased risk for hazardous sleep-related activities such as sleep-driving; cooking and eating food, and making phone calls while asleep have also been noted. Discontinue treatment in patients who report sleep-related activities.

Disease-related concerns:

• Depression: Use caution in patients with depression, particularly if suicidal risk may be present; prescribe least amount of medication needed.

• Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use.

• Impaired gag reflex: Use with caution in patients with an impaired gag reflex.

• Respiratory disease: Use with caution in patients with respiratory disease.

Concurrent drug therapy issues:

• CNS depressants/psychoactive medications: Use with caution in patients receiving other CNS depressants or psychoactive medication; effects with other sedative drugs or ethanol may be potentiated. Use with other sedative hypnotics is not recommended.

Special populations:

• Debilitated patients: Use with caution in debilitated patients.

• Fall risk: Use with extreme caution in patients who are at risk of falls; benzodiazepines have been associated with falls and traumatic injury.

Other warnings/precautions:

• Appropriate use: Does not have analgesic, antidepressant, or antipsychotic properties. Use lowest effective dose.

• Hypnotic: Appropriate use: Should be used only after evaluation of potential causes of sleep disturbance. Failure of sleep disturbance to resolve after 7-10 days may indicate psychiatric or medical illness. A worsening of insomnia or the emergence of new abnormalities of thought or behavior may represent unrecognized psychiatric or medical illness and requires immediate and careful evaluation.

• Tolerance: Quazepam is a long half-life benzodiazepine. Duration of action after a single dose is determined by redistribution rather than metabolism. Tolerance develops to the hypnotic effects (Vinkers, 2012). Chronic use of this agent may increase the perioperative benzodiazepine dose needed to achieve desired effect.

• Withdrawal: Rebound or withdrawal symptoms, including seizures, may occur following abrupt discontinuation or large decreases in dose. Milder withdrawal symptoms may occur following abrupt discontinuation of short-term therapy. Use caution when reducing dose or withdrawing therapy; decrease slowly and monitor for withdrawal symptoms. Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy.

Monitoring Parameters

Respiratory status; mental status

Pregnancy Risk Factor

C

Pregnancy Considerations

Although information specific to the use of quazepam has not been located, all benzodiazepines are assumed to cross the placenta. Teratogenic effects have been observed with some benzodiazepines; hypoglycemia and respiratory problems in the neonate may occur following exposure late in pregnancy. Maternal use of quazepam later in pregnancy may also be associated with difficulty feeding, hypothermia, hypotonia, and respiratory depression in neonates. Neonatal withdrawal symptoms may occur within days to weeks after birth and “floppy infant syndrome” (which also includes withdrawal symptoms) has been reported with some benzodiazepines (Bergman, 1992; Iqbal, 2002; Wikner, 2007).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache or fatigue. Have patient report immediately to prescriber signs of depression (ie, suicidal ideation, anxiety, emotional instability, illogical thinking), hallucinations, memory impairment, change in balance, severe dizziness, illogical thinking, or considerable asthenia (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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