WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Need to evaluate for co-morbid diagnoses: Revaluate if insomnia persists after 7 to 10 days of use ( 5.1 ) Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported.

Do not rechallenge if such reactions occur ( 5.2 ) Abnormal thinking, behavioral changes, complex behaviors: May include “sleep-driving” and hallucinations.

Immediately evaluate any new onset behavioral changes ( 5.3 ) Depression: Worsening of depression or, suicidal thinking may occur.

Prescribe the least amount feasible to avoid intentional overdose ( 5.3 , 5.6 ) Withdrawal effects: Symptoms may occur with rapid dose reduction or discontinuation ( 5.4 , 9.2 ) CNS depressant effects: Use can impair alertness and motor coordination.

If used in combination with other CNS depressants, dose reductions may be needed due to additive effects.

Do not use with alcohol ( 2.3 , 5.5 ) Elderly/debilitated patients: Use lower dose due to impaired motor, cognitive performance and increased sensitivity ( 2.2 , 5.6 ) Patients with hepatic impairment, mild to moderate COPD, impaired drug metabolism or hemodynamic responses, mild to moderate sleep apnea: Use with caution and monitor closely ( 5.6 ) 5.1 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 zolpidem.

5.2 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 zolpidem.

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 throat, glottis or larynx, airway obstruction may occur and be fatal.

Patients who develop angioedema after treatment with zolpidem should not be rechallenged with the drug.

5.3 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 seemed out of character), similar to effects produced by alcohol and other CNS depressants.

Visual and auditory hallucinations have been reported as well as behavioral changes such as bizarre behavior, agitation and depersonalization.

In controlled trials, <1% of adults with insomnia who received zolpidem reported hallucinations.

In a clinical trial, 7.4% of pediatric patients with insomnia associated with attention-deficit/hyperactivity disorder (ADHD), who received zolpidem reported hallucinations [see Use in Specific Populations (8.4) ] .

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 with sedative-hypnotics, including zolpidem.

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 Ambien CR alone at therapeutic doses, the use of alcohol and other CNS depressants with Ambien CR appears to increase the risk of such behaviors, as does the use of Ambien CR at doses exceeding the maximum recommended dose.

Due to the risk to the patient and the community, discontinuation of Ambien CR 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.

Amnesia, anxiety and other neuro-psychiatric symptoms may occur unpredictably.

In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), have been reported in association with the use of sedative/hypnotics.

It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is 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.

5.4 Withdrawal effects Following the rapid dose decrease or abrupt discontinuation 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) ] .

5.5 CNS depressant effects Ambien CR, like other sedative/hypnotic drugs, has CNS-depressant effects.

Due to the rapid onset of action, Ambien CR should only be taken immediately prior to going to bed.

Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness or motor coordination such as operating machinery or driving a motor vehicle after ingesting the drug, including potential impairment of the performance of such activities that may occur the day following ingestion of Ambien CR.

Ambien CR showed additive effects when combined with alcohol and should not be taken with alcohol.

Patients should also be cautioned about possible combined effects with other CNS-depressant drugs.

Dosage adjustments may be necessary when Ambien CR is administered with such agents because of the potentially additive effects.

5.6 Special populations Use in the 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.

Therefore, the recommended Ambien CR dosage is 6.25 mg in such patients to decrease the possibility of side effects [see Dosage and Administration (2.2) ] .

These patients should be closely monitored.

Use in patients with concomitant illness: Clinical experience with Ambien CR (zolpidem tartrate) in patients with concomitant systemic illness is limited.

Caution is advisable in using Ambien CR in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

Although studies did not reveal respiratory depressant effects at hypnotic doses of zolpidem in normals or in patients with mild to moderate chronic obstructive pulmonary disease (COPD), a reduction in the Total Arousal Index together with a reduction in lowest oxygen saturation and increase in the times of oxygen desaturation below 80% and 90% was observed in patients with mild-to-moderate sleep apnea when treated with an immediate-release formulation of zolpidem tartrate (10 mg) when compared to placebo.

Since sedative/hypnotics have the capacity to depress respiratory drive, precautions should be taken if Ambien CR is prescribed to patients with compromised respiratory function.

Post-marketing reports of respiratory insufficiency, most of which involved patients with pre-existing respiratory impairment, have been received.

Ambien CR should be used with caution in patients with sleep apnea syndrome or myasthenia gravis.

Data in end-stage renal failure patients repeatedly treated with an immediate-release formulation of zolpidem tartrate (10 mg) did not demonstrate drug accumulation or alterations in pharmacokinetic parameters.

No dosage adjustment in renally impaired patients is required; however, these patients should be closely monitored [see Clinical Pharmacology (12.3) ] .

A study in subjects with hepatic impairment did reveal prolonged elimination in this group; therefore, treatment should be initiated with Ambien CR 6.25 mg in patients with hepatic compromise, and they should be closely monitored [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) ] .

Use in patients with depression: As with other sedative/hypnotic drugs, Ambien CR should be administered with caution to patients exhibiting signs or symptoms of depression.

Suicidal tendencies may be present in such patients and protective measures may be required.

Intentional overdosage 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.

Use in pediatric patients: Safety and effectiveness of zolpidem has not been established in pediatric patients.

In an 8-week study in pediatric patients (aged 6–17 years) with insomnia associated with ADHD given an immediate-release oral solution of zolpidem tartrate, zolpidem did not decrease sleep latency compared to placebo.

Hallucinations were reported in 7.4% of the pediatric patients who received zolpidem; none of the pediatric patients who received placebo reported hallucinations [see Use in Specific Populations (8.4) ] .