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Doral

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Doral

Doral

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

CNS-depressant effects and Daytime impairment

Doral is a central nervous system (CNS) depressant and can impair daytime function in some patients even when used as prescribed. Prescribers should monitor for excess depressant effects, but impairment can occur in the absence of subjective symptoms, and may not be reliably detected by ordinary clinical exam (i.e. less than formal psychomotor testing). While pharmacodynamic tolerance or adaptation to some adverse depressant effects of Doral may develop, patients using Doral should be cautioned against driving or engaging in other hazardous activities or activities requiring complete mental alertness.

Additive effects occur with concomitant use of other CNS depressants (e.g., other benzodiazepines, opioids, tricyclic antidepressants, alcohol), including daytime use. Downward dose adjustment of Doral and concomitant CNS depressants should be considered. The potential for adverse drug interactions continues for several days following discontinuation of Doral, until serum levels of both active parent drug and psychoactive metabolites decline.

Use of Doral with other sedative-hypnotics is not recommended. Alcohol generally should not be used during treatment with Doral. The risk of next-day psychomotor impairment is increased if Doral is taken with less than a full night of sleep remaining (7- to 8 hours); if higher than the recommended dose is taken; if co-administered with other CNS depressants[see DOSAGE AND ADMINISTRATION].

Benzodiazepine Withdrawal Syndrome

A withdrawal syndrome similar to that from alcohol (e.g., convulsions, tremor, abdominal and muscle cramps, vomiting, and sweating) can occur following abrupt discontinuation of Doral. The more severe withdrawal effects are usually limited to patients taking higher than recommended doses over an extended time. Abrupt discontinuation should be avoided in such patients, and the dose gradually tapered. Prescribers should monitor patients for tolerance, abuse, and dependence.

Milder withdrawal symptoms (e.g., dysphoria and insomnia) can occur following abrupt discontinuation of benzodiazepines taken at therapeutic levels for short periods [See Drug Abuse and Dependence].

Need to Evaluate for Co-morbid Diagnoses

Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative-hypnotic drugs.

Severe Anaphylactic and Anaphylactoid Reactions

Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including DORAL. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis.

Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with DORAL should not be rechallenged with the drug.

Abnormal Thinking and Behavior Changes

Abnormal thinking and behavior changes have been reported in patients treated with sedative-hypnotics including Doral. Some of these changes include decreased inhibition (e.g., aggressiveness and extroversion that seemed out of character), bizarre behavior, and depersonalization. Visual and auditory hallucinations have also been reported. Amnesia, and other neuro-psychiatric symptoms may occur.

Paradoxical reactions such as stimulation, agitation, increased muscle spasticity, and sleep disturbances may occur unpredictably.

Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake, with amnesia for the event) have been reported with use of sedative-hypnotics. These behaviors can occur with initial treatment or in patients previously tolerant of Doral or other sedative-hypnotics. Although these behaviors can occur with use at therapeutic doses, risk is increased by higher doses or concomitant use of alcohol or other CNS depressants. Due to risk to the patient and community, Doral should be discontinued if “sleep-driving” occurs.

Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events.

Worsening of Depression

Benzodiazepines may worsen depression. Consequently, appropriate precautions (e.g., limiting the total prescription size and increased monitoring for suicidal ideation) should be considered.

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide).

Inform patients about the benefits and risks of DORAL, stressing the importance of use as directed. Assist patients in understanding the Medication Guide and instruct them to read it with each prescription refill.

CNS depressant Effects and Next-Day Impairment

Tell patients that Doral can cause next-day impairment, even in the absence of symptoms. Caution patients against driving or engaging in other hazardous activities or activities requiring complete mental alertness when using Doral. Tell patients that daytime impairment may persist for several days following discontinuation of Doral.

Withdrawal

Instruct patients to contact you before stopping or decreasing the dose of Doral, because withdrawal symptoms can occur.

Abnormal thinking and behavior change

Instruct patients that sedative hypnotics can cause abnormal thinking and behavior change, including “sleep-driving” and other complex behaviors while not being fully awake (preparing and eating food, making phone calls, or having sex). Tell patients to call you immediately if they develop any of these symptoms.

Severe Allergic Reactions

Inform patients that severe allergic reactions can occur from Doral. Describe the signs/symptoms of these reactions and advise patients to seek medical attention immediately if these occur.

Suicide

Tell patients that Doral can worsen depression, and to immediately report any suicidal thoughts.

Alcohol and other drugs

Ask patients about alcohol consumption, medicines they are taking now, and drugs they may be taking without a prescription. Advise patients that alcohol generally should not be used during treatment with Doral.

Pregnancy

Instruct patients to inform you if they are nursing or pregnant, or may become pregnant while taking Doral.

Tolerance, Abuse, and Dependence

Tell patients not to increase the dose of Doral on their own, and to inform you if they believe the drug “does not work”.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

Use In Specific Populations

Pregnancy

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 development 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. DORAL 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.

Nursing Mothers

Quazepam and its metabolites are excreted in human milk. Caution should be exercised when administering DORAL to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Doral may cause confusion and over-sedation in the elderly. Elderly patients generally should be started on a low dose of Doral 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.

Last reviewed on RxList: 5/28/2013
This monograph has been modified to include the generic and brand name in many instances.

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Doral - User Reviews

Doral User Reviews

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