CNS depressant effects: Impaired alertness and motor coordination, including risk of daytime impairment. Caution patients against driving and other activities requiring complete mental alertness (5.1) Benzodiazepine withdrawal syndrome: avoid abrupt discontinuation in at-risk patients (5.2) 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. (5.3) Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur. (5.4) Sleep driving and other complex behaviors while not fully awake. Risk increases with dose and concomitant CNS depressants and alcohol. Immediately evaluate any new onset behavioral changes (5.5) Worsening of depression or suicidal thinking may occur: Prescribe the least number of tablets feasible to avoid intentional overdose (5.6) 5.1 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 (2)]. 5.2 Ben zodiazepine 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 (9)]. 5.3 Need to E valuate 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. 5.4 Severe Anaphylac tic 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. 5.5 Abnorma l 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. 5.6 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.