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. Because some of the important adverse effects of sedative-hypnotics appear to be dose related (see PRECAUTIONS and DOSAGE AND ADMINISTRATION), it is important to use the smallest possible effective dose, especially in the elderly.

Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported. These events can occur in sedative-hypnotic-naive as well as in sedative-hypnotic-experienced persons. Although behaviors such as sleep-driving may occur with sedative-hypnotics alone at therapeutic doses, the use of alcohol and other CNS depressants with sedative-hypnotics appears to increase the risk of such behaviors, as does the use of sedative-hypnotics at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of sedative-hypnotics should be strongly considered for patients who report a "sleep-driving" episode.

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.

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.

Patients receiving benzodiazepines should be cautioned about possible combined effects with alcohol and other CNS depressants. Also, caution patients that an additive effect may occur if alcoholic beverages are consumed during the day following the use of benzodiazepines for nighttime sedation. The potential for this interaction continues for several days following their discontinuance until serum levels of psychoactive metabolites have declined.

Patients should also be cautioned about engaging in hazardous occupations requiring complete mental alertness, such as operating machinery or driving a motor vehicle, after ingesting benzodiazepines, including potential impairment of the performance of such activities which may occur the day following ingestion.

Withdrawal symptoms of the type associated with sedatives/hypnotics (e.g., barbiturates, bromides, etc.) and alcohol have been reported after the discontinuation of benzodiazepines. While these symptoms have been more frequently reported after the discontinuation of excessive benzodiazepine doses, there have also been controlled studies demonstrating the occurrence of such symptoms after discontinuation of therapeutic doses of benzodiazepines, generally following prolonged use (but in some instances after periods as brief as 6 weeks). It is generally believed that the gradual reduction of dosage will diminish the occurrence of such symptoms (see Drug Abuse And Dependence).

General: Impaired motor and/or cognitive performance attributable to the accumulation of benzodiazepines and their active metabolites following several days of repeated use at their recommended doses is a concern in certain vulnerable patients (e.g., those especially sensitive to the effects of benzodiazepines or those with a reduced capacity to metabolize and eliminate them). Consequently, elderly or debilitated patients and those with impaired renal or hepatic function should be cautioned about the risk and advised to monitor themselves for signs of excessive sedation or impaired coordination.

The possibility of respiratory depression in patients with chronic pulmonary insufficiency should be considered.

When benzodiazepines are administered to depressed patients, there is a risk that the signs and symptoms of depression may be intensified. Consequently, appropriate precautions (e.g., limiting the total prescription size and increased monitoring for suicidal ideation) should be considered.

Information for Patients

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Doral and should counsel them in its appropriate use. A patient Medication Guide is available for Doral. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Doral.

"Sleep-Driving" and other complex behaviors

There have been reports of people getting out of bed after taking a sedative-hypnotic and driving their cars while not fully awake, often with no memory of the event. If a patient experiences such an episode, it should be reported to his or her doctor immediately, since "sleep-driving" can be dangerous. This behavior is more likely to occur when sedative-hypnotics are taken with alcohol or other central nervous system depressants (see WARNINGS). 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.

It is also suggested that physicians discuss the following information with patients. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

1. Inform your physician about any alcohol consumption and medicine you are taking now, including drugs you may buy without a prescription. Alcohol should generally not be used during treatment with hypnotics.
2. Inform your physician if you are planning to become pregnant, if you are pregnant, or if you become pregnant while you are taking this medicine.
3. Inform your physician if you are nursing.
4. Until you experience how this medicine affects you, do not drive a car or operate potentially dangerous machinery, etc.
5. Benzodiazepines may cause daytime sedation, which may persist for several days following drug discontinuation.
6. Patients should be told not to increase the dose on their own and should inform their physician if they believe the drug "does not work anymore".
7. If benzodiazepines are taken on a prolonged and regular basis (even for periods as brief as 6 weeks), patients should be advised not to stop taking them abruptly or to decrease the dose without consulting their physician, because withdrawal symptoms may occur.

Laboratory Tests: Laboratory tests are not ordinarily required in otherwise healthy patients when quazepam is used as recommended.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Quazepam showed no evidence of carcinogenicity or other significant pathology in oral oncogenicity studies in mice and hamsters.

Quazepam was tested for mutagenicity using the L5178Y TK +/-Mouse Lymphoma Mutagenesis Assay and the Ames Test. The L5178Y TK +/-Assay was equivocal and the Ames Test did not show mutagenic activity.

Reproduction studies in mice conducted with quazepam at doses equal to 60 and 180 times the human dose of 15 mg, and with diazepam at 67 times the human dose, produced slight reductions in the pregnancy rate. Similar reduction in pregnancy rates 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.

Pregnancy, Teratogenic Effects: Pregnancy Category X (See CONTRAINDICATIONS, Usage in Pregnancy) Reproduction studies of quazepam in mice at doses up to 400 times the human dose revealed no major drug-related malformations. Minor developmental variations that occurred were delayed ossification of the sternum, vertebrae, distal phalanges and supraoccipital bones, at doses of 66 and 400 times the human dose. Studies with diazepam at 200 times the human dose showed a similar or greater incidence than quazepam. A reproduction study of quazepam in New Zealand rabbits at doses up to 134 times the human dose demonstrated no effect on fetal morphology or development of offspring.

Nonteratogenic Effects: The child born of a mother who is taking benzodiazepines may be at some risk of withdrawal symptoms from the drug during the postnatal period. Neonatal flaccidity has been reported in children born of mothers who had been receiving benzodiazepines.

Labor and Delivery: DORAL® Tablets have no established use in labor or delivery.

Nursing Mothers: Quazepam and its metabolites are excreted in the milk of lactating women. Therefore, administration of DORAL® Tablets to nursing women is not recommended.

Pediatric Use: Safety and effectiveness in children below the age of 18 years have not been established.

Geriatric Use: In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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