warnings and cautions
5 WARNINGS AND PRECAUTIONS • CNS depressant effects: Impaired alertness and motor coordination, including risk of morning impairment. Risk increases with dose. Caution patients taking 3 mg dose against driving and against activities requiring complete mental alertness during the morning after use. ( 5.1 ) • Evaluate for Co-Morbid Diagnoses: Reevaluate if insomnia persists after 7 to 10 days of use ( 5.2 ) • Severe Anaphalactic/Anaphylactoid Reactions (angioedema and anaphylaxis have been reported): Do not rechallenge if such reactions occur ( 5.3 ) • Abnormal Thinking, Behavioral Changes (e.g., hallucinations), Complex Behaviors (e.g., “sleep-driving”): Immediately evaluate if occurs ( 5.4 ) • Worsening of Depression or Suicidal Thinking may occur: Prescribe the least number of tablets feasible to avoid intentional overdose ( 5.4 , 5.7 ) • Withdrawal Effects: symptoms may occur with rapid dose reduction or discontinuation ( 5.5 , 9.3 ) • Elderly Patients: Use lower dose due to impaired motor, cognitive performance and increased sensitivity ( 2.2 , 5.7 ) • Patients with hepatic impairment, impaired respiratory function, impaired drug metabolism or hemodynamic responses: Use with caution ( 5.7 ) 5.1 CNS Depressant Effects and Next-Day Impairment Eszopiclone is a central nervous system (CNS) depressant and can impair daytime function in some patients at the higher doses (2 mg or 3 mg), even when used as prescribed. Prescribers should monitor for excess depressant effects, but impairment can occur in the absence of symptoms (or even with subjective improvement), and impairment 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 eszopiclone may develop, patients using 3 mg eszopiclone should be cautioned against driving or engaging in other hazardous activities or activities requiring complete mental alertness the day after use. Additive effects occur with concomitant use of other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol), including daytime use. Downward dose adjustment of eszopiclone and concomitant CNS depressants should be considered [see Dosage and Administration ( 2.4 )]. The use of eszopiclone with other sedative-hypnotics at bedtime or the middle of the night is not recommended. The risk of next-day psychomotor impairment is increased if eszopiclone 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; or co-administered with other drugs that increase the blood levels of eszopiclone [see Dosage and Administration ( 2.3 ) and Clinical Studies ( 14.3 )]. 5.2 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, including eszopiclone. Because some of the important adverse effects of eszopiclone appear to be dose-related, it is important to use the lowest possible effective dose, especially in the elderly [see Dosage and Administration ( 2.1 )] . 5.3 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 eszopiclone. 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 eszopiclone should not be rechallenged with the drug. 5.4 Abnormal Thinking and Behavioral Changes A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of sedative/hypnotics. Some of these changes may be characterized by decreased inhibition (e.g., aggressiveness and extroversion that seem out of character), similar to effects produced by alcohol and other CNS depressants. Other reported behavioral changes have included bizarre behavior, agitation, hallucinations, and depersonalization. Amnesia and other neuropsychiatric symptoms may occur unpredictably. In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), has been reported in association with the use of sedative/hypnotics. 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-naïve as well as in sedative-hypnotic-experienced persons. Although behaviors such as sleep-driving may occur with eszopiclone alone at therapeutic doses, the use of alcohol and other CNS depressants with eszopiclone appears to increase the risk of such behaviors, as does the use of eszopiclone at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of eszopiclone 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. It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above are drug-induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation. 5.5 Withdrawal Effects Following rapid dose decrease or abrupt discontinuation of the use of sedative/hypnotics, there have been reports of signs and symptoms similar to those associated with withdrawal from other CNS-depressant drugs [see Drug Abuse and Dependence ( 9 )] . 5.6 Timing of Drug Administration Eszopiclone should be taken immediately before bedtime. Taking a sedative/hypnotic while still up and about may result in short-term memory impairment, hallucinations, impaired coordination, dizziness, and lightheadedness. 5.7 Special Populations Use in Elderly and/or Debilitated Patients Impaired motor and/or cognitive performance after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a concern in the treatment of elderly and/or debilitated patients. The dose should not exceed 2 mg in elderly or debilitated patients [see Dosage and Administration ( 2.2 )] . Use in Patients with Concomitant Illness Clinical experience with eszopiclone in patients with concomitant illness is limited. Eszopiclone should be used with caution in patients with diseases or conditions that could affect metabolism or hemodynamic responses. A study in healthy volunteers did not reveal respiratory-depressant effects at doses 2.5-fold higher (7 mg) than the recommended dose of eszopiclone. Caution is advised, however, if eszopiclone is prescribed to patients with compromised respiratory function. The dose of eszopiclone should not exceed 2 mg in patients with severe hepatic impairment, because systemic exposure is doubled in such subjects. No dose adjustment appears necessary for subjects with mild or moderate hepatic impairment. No dose adjustment appears necessary in subjects with any degree of renal impairment, since less than 10% of eszopiclone is excreted unchanged in the urine. The dose of eszopiclone should be reduced in patients who are administered potent inhibitors of CYP3A4, such as ketoconazole, while taking eszopiclone. Downward dose adjustment is also recommended when eszopiclone is administered with agents having known CNS-depressant effects. Use in Patients with Depression Sedative/hypnotic drugs should be administered with caution to patients exhibiting signs and symptoms of depression. Suicidal tendencies may be present in such patients, and protective measures may be required. Intentional overdose is more common in this group of patients; therefore, the least amount of drug that is feasible should be prescribed for the patient at any one time.