Ambien CR is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. (1)
DOSAGE AND ADMINISTRATION
Adult dose: 12.5 mg once daily immediately before bedtime (2.1)
Elderly/debilitated/hepatically impaired patients: 6.25 mg once daily immediately before bedtime (2.2)
Tablets to be swallowed whole, not to be crushed, divided or chewed. Should not be taken with or immediately after a meal (2.4)
DOSAGE FORMS AND STRENGTHS
6.25 mg and 12.5 mg extended-release tablets. Tablets not scored (3)
CONTRAINDICATIONS
Known hypersensitivity to zolpidem tartrate or to any of the inactive ingredients in the formulation (4)
WARNINGS AND PRECAUTIONS
Need to eva luate for co-morbid diagnoses: Reva luate 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 eva luate 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)
ADVERSE REACTIONS
Most commonly observed adverse reactions (> 10% in either elderly or adult patients) are: headache, next-day somnolence and dizziness (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis U.S. LLC at 1-800-633-1610 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.
DRUG INTERACTIONS
CNS depressants: Enhanced CNS-depressant effects with combination use. Use with alcohol causes additive psychomotor impairment (7.1)
Imipramine: Decreased alertness observed with combination use. (7.1)
Chlorpromazine: Impaired alertness and psychomotor performance observed with combination use (7.1)
Rifampin: Combination use decreases exposure to and effects of zolpidem (7.2)
Ketoconazole: Combination use increases exposure to and effect of zolpidem (7.2)
USE IN SPECIFIC POPULATIONS
Pregnancy: Based on animal data, zolpidem may cause fetal harm. (8.1)
Nursing mothers: Zolpidem is excreted in human milk. (8.3)
Pediatric use: Safety and effectiveness not established. Hallucinations (incidence rate 7.4%) and other psychiatric and/or nervous system adverse reactions were observed frequently in a study of pediatric patients with Attention-Deficit/Hyperactivity Disorder (5.6, 8.4)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide
Revised: 06/2009
Back to Highlights and Tabs
FULL PRESCRIBING INFORMATION: CONTENTS*
* Sections or subsections omitted from the full prescribing information are not listed
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1Dosage in adults
2.2 Special populations
2.3 Use with CNS depressants
2.4 Administration
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Need to eva luate for co-morbid diagnoses
5.2 Severe anaphylactic and anaphylactoid reactions
5.3 Abnormal thinking and behavioral changes
5.4 Withdrawal effects
5.5 CNS depressant effects
5.6 Special populations
6 ADVERSE REACTIONS
6.1 Clinical trials experience
7 DRUG INTERACTIONS
7.1 CNS-active drugs
7.2 Drugs that affect drug metabolism via cytochrome P450
7.3 Other drugs with no interaction with zolpidem
7.4 Drug-laboratory test interactions
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Labor and delivery
8.3 Nursing mothers
8.4 Pediatric use
8.5 Geriatric use
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled substance
9.2 Abuse
9.3 Dependence
10 OVERDOSAGE
10.1 Signs and symptoms
10.2 Recommended treatment
11DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of action
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, mutagenesis, impairment of fertility
14 CLINICAL STUDIES
14.1 Controlled clinical trials
14.2 Studies pertinent to safety concerns for sedative/hypnotic drugs
17 PATIENT COUNSELING INFORMATION
17.1 Severe anaphylactic and anaphylactoid reactions
17.2Sleep-driving and other complex behaviors
17.3 Administration instructions
17.4 Medication Guide
Ambien CR 6.25 (CIV) Tablet
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Ambien CR (zolpidem tartrate extended-release tablets) is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance (as measured by wake time after sleep onset).
The clinical trials performed in support of efficacy were up to 3 weeks (using polysomnography measurement up to 2 weeks in both adult and elderly patients) and 24 weeks (using patient-reported assessment in adult patients only) in duration [see Clinical Studies (14)].
2 DOSAGE AND ADMINISTRATION
The dose of Ambien CR should be individualized.
2.1Dosage in adults
The recommended dose of Ambien CR for adults is 12.5 mg once daily immediately before bedtime. The total Ambien CR dose should not exceed 12.5 mg per day.
2.2 Special populations
Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate. Patients with hepatic insufficiency do not clear the drug as rapidly as normals. The recommended dose of Ambien CR in both of these patient populations is 6.25 mg once daily immediately before bedtime [see Warnings and Precautions (5.6)].
2.3 Use with CNS depressants
Dosage adjustments may be necessary when Ambien CR is combined with other CNS depressant drugs because of the potentially additive effects [see Warnings and Precautions (5.5)].
2.4 Administration
Ambien CR extended-release tablets should be swallowed whole, and not be divided, crushed, or chewed. The effect of Ambien CR may be slowed by ingestion with or immediately after a meal.
3 DOSAGE FORMS AND STRENGTHS
Ambien CR is available as extended-release tablets containing 6.25 mg or 12.5 mg of zolpidem tartrate for oral administration. Tablets are not scored.
Ambien CR 6.25 mg tablets are pink, round, bi-convex, and debossed with A~ on one side.
Ambien CR 12.5 mg tablets are blue, round, bi-convex, and debossed with A~ on one side.
4 CONTRAINDICATIONS
Ambien CR is contraindicated in patients with known hypersensitivity to zolpidem tartrate or to any of the inactive ingredients in the formulation. Observed reactions include anaphylaxis and angioedema [see Warnings and Precautions (5.2)].
5 WARNINGS AND PRECAUTIONS
5.1 Need to eva luate 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 eva luation 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 eva luated. 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 eva luation.
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)].
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
Serious anaphylactic and anaphylactoid reactions [see Warnings and Precautions (5.2)]
Abnormal thinking, behavior changes, and complex behaviors [see Warnings and Precautions (5.3)]
Withdrawal effects [see Warnings and Precautions (5.4)]
CNS-depressant effects [see Warnings and Precautions (5.5)]
6.1 Clinical trials experience
Associated with discontinuation of treatment: In 3-week clinical trials in adults and elderly patients (> 65 years), 3.5% (7/201) patients receiving Ambien CR 6.25 or 12.5 mg discontinued treatment due to an adverse reaction as compared to 0.9% (2/216) of patients on placebo. The reaction most commonly associated with discontinuation in patients treated with Ambien CR was somnolence (1%).
In a 6-month study in adult patients (18–64 years of age), 8.5% (57/669) of patients receiving Ambien CR 12.5 mg as compared to 4.6% on placebo (16/349) discontinued treatment due to an adverse reaction. Reactions most commonly associated with discontinuation of Ambien CR included anxiety (anxiety, restlessness or agitation) reported in 1.5% (10/669) of patients as compared to 0.3% (1/349) of patients on placebo, and depression (depression, major depression or depressed mood) reported in 1.5% (10/669) of patients as compared to 0.3% (1/349) of patients on placebo.
Data from a clinical study in which selective serotonin reuptake inhibitor- (SSRI-) treated patients were given zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n=95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction; one patient treated with placebo (n =97) was discontinued after an attempted suicide.
Most commonly observed adverse reactions in controlled trials: During treatment with Ambien CR in adults and elderly at daily doses of 12.5 mg and 6.25 mg, respectively, each for three weeks, the most commonly observed adverse reactions associated with the use of Ambien CR were headache, next-day somnolence, and dizziness.
In the 6-month trial eva luating Ambien CR 12.5 mg, the adverse reaction profile was consistent with that reported in short-term trials, except for a higher incidence of anxiety (6.3% for Ambien CR versus 2.6% for placebo).
Adverse reactions observed at an incidence of ≥1% in controlled trials: The following tables enumerate treatment-emergent adverse reaction frequencies that were observed at an incidence equal to 1% or greater among patients with insomnia who received Ambien CR in placebo-controlled trials. Events reported by investigators were classified utilizing the MedDRA dictionary for the purpose of establishing event frequencies. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice, in which patient characteristics and other factors differ from those that prevailed in these clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigators involving related drug products and uses, since each group of drug trials is conducted under a different set of conditions. However, the cited figures provide the physician with a basis for estimating the relative contribution of drug and nondrug factors to the incidence of side effects in the population studied.
The following tables were derived from results of two placebo-controlled efficacy trials involving Ambien CR. These trials involved patients with primary insomnia who were treated for 3 weeks with Ambien CR at doses of 12.5 mg (Table 1) or 6.25 mg (Table 2), respectively. The tables include only adverse reactions occurring at an incidence of at least 1% for Ambien CR patients and with an incidence greater than that seen in the placebo patients.
Table 1. Incidences of Treatment-Emergent Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial in Adults (percentage of patients reporting)
Body System/Adverse Reaction *
Ambien CR
12.5 mg
Placebo
(N = 102)
(N = 110)
*
Reactions reported by at least 1% of patients treated with Ambien CR and at greater frequency than in the placebo group.
†
Hallucinations included hallucinations NOS as well as visual and hypnogogic hallucinations.
