INDICATIONS & USAGE SECTION.


1INDICATIONS 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 weeks (using polysomnography measurement up to weeks in both adult and elderly patients) and 24 weeks (using patient-reported assessment in adult patients only) in duration [see Clinical Studies (14)].. AMBIEN CR, gamma-aminobutyric acid (GABA) receptor positive modulator, is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. (1).

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).Inform patients and their families about the benefits and risks of treatment with AMBIEN CR. Inform patients of the availability of Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with AMBIEN CR and with each prescription refill. Review the AMBIEN CR Medication Guide with every patient prior to initiation of treatment. Instruct patients or caregivers that AMBIEN CR should be taken only as prescribed.. Complex Sleep BehaviorsInstruct patients and their families that AMBIEN CR may cause complex sleep behaviors, including sleep-walking, sleep-driving, preparing and eating food, making phone calls, or having sex while not being fully awake. Serious injuries and death have occurred during complex sleep behavior episodes. Tell patients to discontinue AMBIEN CR and notify their healthcare provider immediately if they develop any of these symptoms [see Boxed Warning, Warnings and Precautions (5.1)]. CNS-Depressant Effects and Next-Day Impairment Tell patients that AMBIEN CR can cause next-day impairment even when used as prescribed, and that this risk is increased if dosing instructions are not carefully followed. Caution patients against driving and other activities requiring complete mental alertness the day after use. Inform patients that impairment can be present despite feeling fully awake. Advise patients that increased drowsiness and decreased consciousness may increase the risk of falls in some patients [see Warnings and Precautions (5.2)].. Severe Anaphylactic and Anaphylactoid ReactionsInform patients that severe anaphylactic and anaphylactoid reactions have occurred with zolpidem. Describe the signs/symptoms of these reactions and advise patients to seek medical attention immediately if any of them occur [see Warnings and Precautions (5.4)].. Suicide Tell patients to immediately report any suicidal thoughts.. Alcohol and other DrugsAsk patients about alcohol consumption, medicines they are taking, and drugs they may be taking without prescription. Advise patients not to use AMBIEN CR if they drank alcohol that evening or before bed.. Tolerance, Abuse, and DependenceTell patients not to increase the dose of AMBIEN CR on their own, and to inform you if they believe the drug does not work.. Administration InstructionsPatients should be counseled to take AMBIEN CR right before they get into bed and only when they are able to stay in bed full night (7-8 hours) before being active again. AMBIEN CR tablets should not be taken with or immediately after meal. Advise patients NOT to take AMBIEN CR if they drank alcohol that evening.. PregnancyAdvise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with AMBIEN CR. Advise patients that use of AMBIEN CR late in the third trimester may cause respiratory depression and sedation in neonates. Advise mothers who used AMBIEN CR during the late third trimester of pregnancy to monitor neonates for signs of sleepiness (more than usual), breathing difficulties, or limpness [see Use in Specific Populations (8.1)]. LactationAdvise breastfeeding mothers using AMBIEN CR to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct breastfeeding mothers to seek immediate medical care if they notice these signs. lactating woman may consider pumping and discarding breastmilk during treatment and for 23 hours after AMBIEN CR administration to minimize drug exposure to breastfed infant [see Use in Specific Populations (8.2)].

ABUSE SECTION.


9.2 Abuse. Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. Tolerance is state of adaptation in which exposure to drug induces changes that result in diminution of one or more of the drug effects over time. Tolerance may occur to both desired and undesired effects of drugs and may develop at different rates for different effects.Addiction is primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is treatable disease, using multidisciplinary approach, but relapse is common.Studies of abuse potential in former drug abusers found that the effects of single doses of zolpidem tartrate 40 mg were similar, but not identical, to diazepam 20 mg, while zolpidem tartrate 10 mg effects were difficult to distinguish from placebo.Because persons with history of addiction to, or abuse of, drugs or alcohol are at increased risk for misuse, abuse and addiction of zolpidem, they should be monitored carefully when receiving zolpidem or any other hypnotic.

ADVERSE REACTIONS SECTION.


6ADVERSE REACTIONS. The following serious adverse reactions are discussed in greater detail in other sections of the labeling:Complex Sleep Behaviors [see Warnings and Precautions (5.1)] CNS-Depressant Effects and Next-Day Impairment [see Warnings and Precautions (5.2)] Severe Anaphylactic and Anaphylactoid Reactions [see Warnings and Precautions (5.4)] Abnormal Thinking and Behavior Changes [see Warnings and Precautions (5.5)] Withdrawal Effects [see Warnings and Precautions (5.9)] Complex Sleep Behaviors [see Warnings and Precautions (5.1)] CNS-Depressant Effects and Next-Day Impairment [see Warnings and Precautions (5.2)] Severe Anaphylactic and Anaphylactoid Reactions [see Warnings and Precautions (5.4)] Abnormal Thinking and Behavior Changes [see Warnings and Precautions (5.5)] Withdrawal Effects [see Warnings and Precautions (5.9)] 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 www.fda.gov/medwatch.. 6.1 Clinical Trials Experience Associated with Discontinuation of TreatmentIn 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 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 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 TrialsDuring 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 evaluating AMBIEN CR 12.5 mg, the adverse reaction profile was consistent with that reported in short-term trials, except for higher incidence of anxiety (6.3% for AMBIEN CR versus 2.6% for placebo).. Adverse Reactions Observed at an Incidence of >=1% in Controlled TrialsThe following tables enumerate treatment-emergent adverse reactions 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 different set of conditions. However, the cited figures provide the physician with 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 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 3-Week Placebo-Controlled Clinical Trial in Adults (percentage of patients reporting)Body SystemAdverse ReactionReactions reported by at least 1% of patients treated with AMBIEN CR and at greater frequency than in the placebo group. AMBIEN CR12.5 mgPlacebo (N=102)(N=110)Infections and infestationsInfluenza30Gastroenteritis10Labyrinthitis10Metabolism and nutrition disordersAppetite disorder10Psychiatric disordersHallucinationsHallucinations included hallucinations NOS as well as visual and hypnagogic hallucinations. 40Disorientation32Anxiety20Depression20Psychomotor retardation20Binge eating10Depersonalization10Disinhibition10Euphoric mood10Mood swings10Stress symptoms10Nervous system disordersHeadache1916Somnolence152Dizziness125Memory disordersMemory disorders include: memory impairment, amnesia, anterograde amnesia. 30Balance disorder20Disturbance in attention20Hypoesthesia21Ataxia10Paresthesia10Eye disordersVisual disturbance30Eye redness20Vision blurred21Altered visual depth perception10Asthenopia10Ear and labyrinth disordersVertigo20Tinnitus10Respiratory, thoracic and mediastinal disordersThroat irritation10Gastrointestinal disordersNausea74Constipation20Abdominal discomfort10Abdominal tenderness10Frequent bowel movements10Gastroesophageal reflux disease10Vomiting10Skin and subcutaneous tissue disordersRash10Skin wrinkling10Urticaria10Musculoskeletal and connective tissue disordersBack pain43Myalgia40Neck pain10Reproductive system and breast disordersMenorrhagia10General disorders and administration site conditionsFatigue32Asthenia10Chest discomfort10InvestigationsBlood pressure increased10Body temperature increased10Injury, poisoning and procedural complicationsContusion10Social circumstancesExposure to poisonous plant10Table 2: Incidences of Treatment-Emergent Adverse Reactions in 3-Week Placebo-Controlled Clinical Trial in Elderly (percentage of patients reporting)Body SystemAdverse Reaction Reactions reported by at least 1% of patients treated with AMBIEN CR and at greater frequency than in the placebo group. AMBIEN CR6.25 mgPlacebo(N=99)(N=106)Infections and infestationsNasopharyngitis64Lower respiratory tract infection10Otitis externa10Upper respiratory tract infection10Psychiatric disordersAnxiety32Psychomotor retardation20Apathy10Depressed mood10Nervous system disordersHeadache1411Dizziness83Somnolence65Burning sensation10Dizziness postural10Memory disordersMemory disorders include: memory impairment, amnesia, anterograde amnesia. 10Muscle contractions involuntary10Paresthesia10Tremor10Cardiac disordersPalpitations20Respiratory, thoracic and mediastinal disordersDry throat10Gastrointestinal disordersFlatulence10Vomiting10Skin and subcutaneous tissue disordersRash10Urticaria10Musculoskeletal and connective tissue disordersArthralgia20Muscle cramp21Neck pain20Renal and urinary disordersDysuria10Reproductive system and breast disordersVulvovaginal dryness10General disorders and administration site conditionsInfluenza like illness10Pyrexia10Injury, poisoning and procedural complicationsNeck injury10. Dose Relationship for Adverse ReactionsThere is evidence from dose comparison trials suggesting dose relationship for many of the adverse reactions associated with zolpidem use, particularly for certain CNS and gastrointestinal adverse events.. Other Adverse Reactions Observed during the Premarketing Evaluation of AMBIEN CROther treatment-emergent adverse reactions associated with participation in AMBIEN CR studies (those reported at frequencies of <1%) were not different in nature or frequency to those seen in studies with immediate-release zolpidem tartrate, which are listed below.. Adverse Events Observed during the Premarketing Evaluation of Immediate-Release Zolpidem TartrateImmediate-release zolpidem tartrate was administered to 3,660 subjects in clinical trials throughout the U.S., Canada, and Europe. Treatment-emergent adverse events associated with clinical trial participation were recorded by clinical investigators using terminology of their own choosing. To provide meaningful estimate of the proportion of individuals experiencing treatment-emergent adverse events, similar types of untoward events were grouped into smaller number of standardized event categories and classified utilizing modified World Health Organization (WHO) dictionary of preferred terms.The frequencies presented, therefore, represent the proportions of the 3,660 individuals exposed to zolpidem, at all doses, who experienced an event of the type cited on at least one occasion while receiving zolpidem. All reported treatment-emergent adverse events are included, except those already listed in the table above of adverse events in placebo-controlled studies, those coding terms that are so general as to be uninformative, and those events where drug cause was remote. It is important to emphasize that, although the events reported did occur during treatment with Ambien, they were not necessarily caused by it.Adverse events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in greater than 1/100 subjects; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in less than 1/1,000 patients.Autonomic nervous system: Frequent: dry mouth. Infrequent: increased sweating, pallor, postural hypotension, syncope. Rare: abnormal accommodation, altered saliva, flushing, glaucoma, hypotension, impotence, increased saliva, tenesmus.Body as whole: Frequent: asthenia. Infrequent: chest pain, edema, falling, fever, malaise, trauma. Rare: allergic reaction, allergy aggravated, anaphylactic shock, face edema, hot flashes, increased ESR, pain, restless legs, rigors, tolerance increased, weight decrease.Cardiovascular system: Infrequent: cerebrovascular disorder, hypertension, tachycardia. Rare: angina pectoris, arrhythmia, arteritis, circulatory failure, extrasystoles, hypertension aggravated, myocardial infarction, phlebitis, pulmonary embolism, pulmonary edema, varicose veins, ventricular tachycardia.Central and peripheral nervous system: Frequent: ataxia, confusion, drowsiness, drugged feeling, euphoria, insomnia, lethargy, lightheadedness, vertigo. Infrequent: agitation, decreased cognition, detached, difficulty concentrating, dysarthria, emotional lability, hallucination, hypoesthesia, illusion, leg cramps, migraine, nervousness, paresthesia, sleeping (after daytime dosing), speech disorder, stupor, tremor. Rare: abnormal gait, abnormal thinking, aggressive reaction, apathy, appetite increased, decreased libido, delusion, dementia, depersonalization, dysphasia, feeling strange, hypokinesia, hypotonia, hysteria, intoxicated feeling, manic reaction, neuralgia, neuritis, neuropathy, neurosis, panic attacks, paresis, personality disorder, somnambulism, suicide attempts, tetany, yawning.Gastrointestinal system: Frequent: diarrhea, dyspepsia, hiccup. Infrequent: anorexia, constipation, dysphagia, flatulence, gastroenteritis. Rare: enteritis, eructation, esophagospasm, gastritis, hemorrhoids, intestinal obstruction, rectal hemorrhage, tooth caries.Hematologic and lymphatic system: Rare: anemia, hyperhemoglobinemia, leukopenia, lymphadenopathy, macrocytic anemia, purpura, thrombosis.Immunologic system: Infrequent: infection. Rare: abscess herpes simplex herpes zoster, otitis externa, otitis media.Liver and biliary system: Infrequent: abnormal hepatic function, increased SGPT. Rare: bilirubinemia, increased SGOT.Metabolic and nutritional: Infrequent: hyperglycemia, thirst. Rare: gout, hypercholesteremia, hyperlipidemia, increased alkaline phosphatase, increased BUN, periorbital edema.Musculoskeletal system: Infrequent: arthritis. Rare: arthrosis, muscle weakness, sciatica, tendinitis.Reproductive system: Infrequent: menstrual disorder, vaginitis. Rare: breast fibroadenosis, breast neoplasm, breast pain.Respiratory system: Frequent: sinusitis. Infrequent: bronchitis, coughing, dyspnea. Rare: bronchospasm, respiratory depression, epistaxis, hypoxia, laryngitis, pneumonia.Skin and appendages: Infrequent: pruritus. Rare: acne, bullous eruption, dermatitis, furunculosis, injection-site inflammation, photosensitivity reaction, urticaria.Special senses: Frequent: diplopia, vision abnormal. Infrequent: eye irritation, eye pain, scleritis, taste perversion, tinnitus. Rare: conjunctivitis, corneal ulceration, lacrimation abnormal, parosmia, photopsia.Urogenital system: Frequent: urinary tract infection. Infrequent: cystitis, urinary incontinence. Rare: acute renal failure, dysuria, micturition frequency, nocturia, polyuria, pyelonephritis, renal pain, urinary retention.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of AMBIEN CR. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Liver and biliary system: acute hepatocellular, cholestatic or mixed liver injury with or without jaundice (i.e., bilirubin >2 ULN, alkaline phosphatase >=2 ULN, transaminase >=5 ULN).

BOXED WARNING SECTION.


WARNING: COMPLEX SLEEP BEHAVIORS. Complex sleep behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur following use of AMBIEN CR. Some of these events may result in serious injuries, including death. Discontinue AMBIEN CR immediately if patient experiences complex sleep behavior [see Contraindications (4) and Warnings and Precautions (5.1)]. WARNING: COMPLEX SLEEP BEHAVIORSSee full prescribing information for complete boxed warning.Complex sleep behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur following use of AMBIEN CR. Some of these events may result in serious injuries, including death. Discontinue AMBIEN CR immediately if patient experiences complex sleep behavior. (4, 5.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisZolpidem was administered to mice and rats for years at oral doses of 4, 18, and 80 mg base/kg/day. In mice, these doses are approximately 2, 9, and 40 times the MRHD of 12.5 mg/day (10 mg zolpidem base) based on mg/m2 body surface area and in rats, these doses are approximately 4, 18, and 80 times the MRHD based on mg/m2 body surface area. No evidence of carcinogenic potential was observed in mice. In rats, renal tumors (lipoma, liposarcoma) were seen at the mid and high doses.. MutagenesisZolpidem was negative in in vitro (bacterial reverse mutation, mouse lymphoma, and chromosomal aberration) and in vivo (mouse micronucleus) genetic toxicology assays.. Impairment of FertilityZolpidem was administered to rats at 4, 20, and 100 mg base/kg/day, which are approximately 4, 20, and 100 times the MRHD of 12.5 mg/day (10 mg zolpidem base) based on mg/m2 body surface area, prior to and during mating, and continuing in females through postpartum day 25. Zolpidem caused irregular estrus cycles and prolonged precoital intervals at the highest dose tested, which is approximately 100 times the MRHD based on mg/m2 body surface area. The NOAEL for these effects is 20 times the MRHD based on mg/m2 body surface area. There was no impairment of fertility at any dose tested.

CLINICAL PHARMACOLOGY SECTION.


12CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Zolpidem is GABA receptor positive modulator presumed to exert its therapeutic effects in the short-term treatment of insomnia through binding to the benzodiazepine site of subunit containing GABA receptors, increasing the frequency of chloride channel opening resulting in the inhibition of neuronal excitation.. 12.2Pharmacodynamics. Zolpidem binds to GABA receptors with greater affinity for subunit relative to and subunit containing receptors. Zolpidem has no appreciable binding affinity for subunit containing GABA receptors. This binding profile may explain the relative absence of myorelaxant effects in animal studies. Zolpidem has no appreciable binding affinity for dopaminergic D2, serotonergic 5HT2, adrenergic, histaminergic or muscarinic receptors.. 12.3 Pharmacokinetics. AMBIEN CR exhibits biphasic absorption characteristics, which results in rapid initial absorption from the gastrointestinal tract similar to zolpidem tartrate immediate-release, then provides extended plasma concentrations beyond three hours after administration. study in 24 healthy male subjects was conducted to compare mean zolpidem plasma concentration-time profiles obtained after single oral administration of AMBIEN CR 12.5 mg and of an immediate-release formulation of zolpidem tartrate (10 mg). The terminal elimination half-life observed with AMBIEN CR (12.5 mg) was similar to that obtained with immediate-release zolpidem tartrate (10 mg). The mean plasma concentration-time profiles are shown in Figure 1.Figure 1: Mean Plasma Concentration-Time Profiles for AMBIEN CR (12.5 mg) and Immediate-Release Zolpidem Tartrate (10 mg)In adult and elderly patients treated with AMBIEN CR, there was no evidence of accumulation after repeated once-daily dosing for up to two weeks.. Figure 1. AbsorptionFollowing administration of AMBIEN CR, administered as single 12.5 mg dose in healthy male adult subjects, the mean peak concentration (Cmax) of zolpidem was 134 ng/mL (range: 68.9 to 197 ng/ml) occurring at median time (Tmax) of 1.5 hours. The mean AUC of zolpidem was 740 nghr/mL (range: 295 to 1359 nghr/mL).A food-effect study in 45 healthy subjects compared the pharmacokinetics of AMBIEN CR 12.5 mg when administered while fasting or within 30 minutes after meal. Results demonstrated that with food, mean AUC and Cmax were decreased by 23% and 30%, respectively, while median Tmax was increased from hours to hours. The half-life was not changed. These results suggest that, for faster sleep onset, AMBIEN CR should not be administered with or immediately after meal.. DistributionTotal protein binding was found to be 92.5 +- 0.1% and remained constant, independent of concentration between 40 and 790 ng/mL.. MetabolismZolpidem is converted to inactive metabolites that are eliminated primarily by renal excretion.. EliminationWhen AMBIEN CR was administered as single 12.5 mg dose in healthy male adult subjects, the mean zolpidem elimination half-life was 2.8 hours (range: 1.62 to 4.05 hr).. Special Populations. ElderlyIn 24 elderly (>=65 years) healthy subjects administered single 6.25 mg dose of AMBIEN CR, the mean peak concentration (Cmax) of zolpidem was 70.6 (range: 35.0 to 161) ng/mL occurring at median time (Tmax) of 2.0 hours. The mean AUC of zolpidem was 413 nghr/mL (range: 124 to 1190 nghr/mL) and the mean elimination half-life was 2.9 hours (range: 1.59 to 5.50 hours).. Hepatic impairmentAMBIEN CR was not studied in patients with hepatic impairment. The pharmacokinetics of an immediate-release formulation of zolpidem tartrate in eight patients with chronic hepatic insufficiency was compared to results in healthy subjects. Following single 20 mg oral zolpidem tartrate dose, mean Cmax and AUC were found to be two times (250 vs 499 ng/mL) and five times (788 vs 4,203 nghr/mL) higher, respectively, in hepatically compromised patients. Tmax did not change. The mean half-life in cirrhotic patients of 9.9 hr (range: 4.1 to 25.8 hr) was greater than that observed in normal subjects of 2.2 hr (range: 1.6 to 2.4 hr) [see Dosage and Administration (2.2), Warnings and Precautions (5.8), Use in Specific Populations (8.7)].. Renal impairmentAMBIEN CR was not studied in patients with renal impairment. The pharmacokinetics of an immediate-release formulation of zolpidem tartrate were studied in 11 patients with end-stage renal failure (mean ClCr 6.5 +- 1.5 mL/min) undergoing hemodialysis three times week, who were dosed with zolpidem tartrate 10 mg orally each day for 14 or 21 days. No statistically significant differences were observed for Cmax, Tmax, half-life, and AUC between the first and last day of drug administration when baseline concentration adjustments were made. Zolpidem was not hemodialyzable. No accumulation of unchanged drug appeared after 14 or 21 days. Zolpidem pharmacokinetics was not significantly different in renally impaired patients. No dosage adjustment is necessary in patients with compromised renal function.. Drug Interactions. CNS depressantsCoadministration of zolpidem with other CNS depressants increases the risk of CNS depression [see Warnings and Precautions (5.2)]. Zolpidem tartrate was evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs. Imipramine in combination with zolpidem produced no pharmacokinetic interaction other than 20% decrease in peak levels of imipramine, but there was an additive effect of decreased alertness. Similarly, chlorpromazine in combination with zolpidem produced no pharmacokinetic interaction, but there was an additive effect of decreased alertness and psychomotor performance.A study involving haloperidol and zolpidem revealed no effect of haloperidol on the pharmacokinetics or pharmacodynamics of zolpidem. The lack of drug interaction following single-dose administration does not predict the absence of an effect following chronic administration.An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see Warnings and Precautions (5.2)]. Following five consecutive nightly doses at bedtime of oral zolpidem tartrate 10 mg in the presence of sertraline 50 mg (17 consecutive daily doses, at 7:00 am, in healthy female volunteers), zolpidem Cmax was significantly higher (43%) and Tmax was significantly decreased (-53%). Pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem.A single-dose interaction study with zolpidem tartrate 10 mg and fluoxetine 20 mg at steady-state levels in male volunteers did not demonstrate any clinically significant pharmacokinetic or pharmacodynamic interactions. When multiple doses of zolpidem and fluoxetine were given at steady state and the concentrations evaluated in healthy females, an increase in the zolpidem half-life (17%) was observed. There was no evidence of an additive effect in psychomotor performance.. Drugs that affect drug metabolism via cytochrome P450Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of inhibitors of other P450 enzymes on the pharmacokinetics of zolpidem is unknown.A single-dose interaction study with zolpidem tartrate 10 mg and itraconazole 200 mg at steady-state levels in male volunteers resulted in 34% increase in AUC0- of zolpidem tartrate. There were no pharmacodynamic effects of zolpidem detected on subjective drowsiness, postural sway, or psychomotor performance.A single-dose interaction study with zolpidem tartrate 10 mg and rifampin 600 mg at steady-state levels in female subjects showed significant reductions of the AUC (-73%), Cmax (-58%), and T1/2 (-36%) of zolpidem together with significant reductions in the pharmacodynamic effects of zolpidem tartrate. Rifampin, CYP3A4 inducer, significantly reduced the exposure to and the pharmacodynamic effects of zolpidem [see Drug Interactions (7.2)].Similarly, St. Johns wort, CYP3A4 inducer, may also decrease the blood levels of zolpidem.A single-dose interaction study with zolpidem tartrate mg and ketoconazole, potent CYP3A4 inhibitor, given as 200 mg twice daily for days increased Cmax of zolpidem (30%) and the total AUC of zolpidem (70%) compared to zolpidem alone and prolonged the elimination half-life (30%) along with an increase in the pharmacodynamic effects of zolpidem [see Drug Interactions (7.2)].Additionally, fluvoxamine (a strong inhibitor of CYP1A2 and weak inhibitor of CYP3A4 and CYP2C9) and ciprofloxacin (a strong inhibitor of CYP1A2 and moderate inhibitor of CYP3A4) are also likely to inhibit zolpidems metabolic pathways, potentially leading to an increase in zolpidem exposure.. Other drugs with no interactions with zolpidemA study involving cimetidine/zolpidem tartrate and ranitidine/zolpidem tartrate combinations revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of zolpidem.Zolpidem tartrate had no effect on digoxin pharmacokinetics and did not affect prothrombin time when given with warfarin in healthy subjects.

CLINICAL STUDIES SECTION.


14CLINICAL STUDIES. 14.1 Controlled Clinical Trials. AMBIEN CR was evaluated in three placebo-controlled studies for the treatment of patients with chronic primary insomnia (as defined in the APA Diagnostic and Statistical Manual of Mental Disorders, DSM IV(TM)).Adult outpatients (18-64 years) with primary insomnia (N=212) were evaluated in double-blind, randomized, parallel-group, 3-week trial comparing AMBIEN CR 12.5 mg and placebo. AMBIEN CR 12.5 mg decreased wake time after sleep onset (WASO) for the first hours during the first nights and for the first hours after weeks of treatment. AMBIEN CR 12.5 mg was superior to placebo on objective measures (polysomnography recordings) of sleep induction (by decreasing latency to persistent sleep [LPS]) during the first nights of treatment and after weeks of treatment. AMBIEN CR 12.5 mg was also superior to placebo on the patient reported global impression regarding the aid to sleep after the first nights and after weeks of treatment.Elderly outpatients (>=65 years) with primary insomnia (N=205) were evaluated in double-blind, randomized, parallel-group, 3-week trial comparing AMBIEN CR 6.25 mg and placebo. AMBIEN CR 6.25 mg decreased wake time after sleep onset (WASO) for the first hours during the first nights and the first hours after weeks of treatment. AMBIEN CR 6.25 mg was superior to placebo on objective measures (polysomnography recordings) of sleep induction (by decreasing LPS) during the first nights of treatment and after weeks on treatment. AMBIEN CR 6.25 mg was superior to placebo on the patient reported global impression regarding the aid to sleep after the first nights and after weeks of treatment.In both studies, in patients treated with AMBIEN CR, polysomnography showed increased wakefulness at the end of the night compared to placebo-treated patients.In 24-week double-blind, placebo controlled, randomized study in adult outpatients (18-64 years) with primary insomnia (N=1025), AMBIEN CR 12.5 mg administered as needed (3 to nights per week) was superior to placebo over 24 weeks, on patient global impression regarding aid to sleep, and on patient-reported specific sleep parameters for sleep induction and sleep maintenance with no significant increased frequency of drug intake observed over time.. 14.2 Studies Pertinent to Safety Concerns for Sedative/Hypnotic Drugs. Next-Day Residual EffectsIn five clinical studies (three controlled studies in adults [18-64 years of age] administered AMBIEN CR 12.5 mg and two controlled studies in the elderly [>=65 years of age] administered AMBIEN CR 6.25 mg or 12.5 mg), the effect of AMBIEN CR on vigilance, memory, or motor function were assessed using neurocognitive tests. In these studies, no significant decrease in performance was observed eight hours after nighttime dose. In addition, no evidence of next-day residual effects was detected with AMBIEN CR 12.5 mg and 6.25 mg using self-ratings of sedation. During the 3-week studies, next-day somnolence was reported by 15% of the adult patients who received 12.5 mg AMBIEN CR versus 2% of the placebo group; next-day somnolence was reported by 6% of the elderly patients who received 6.25 mg AMBIEN CR versus 5% of the placebo group [see Adverse Reactions (6)]. In 6-month study, the overall incidence of next-day somnolence was 5.7% in the AMBIEN CR group as compared to 2% in the placebo group.. Rebound EffectsRebound insomnia, defined as dose-dependent worsening in sleep parameters (latency, sleep efficiency, and number of awakenings) compared with baseline following discontinuation of treatment, is observed with short- and intermediate-acting hypnotics. In the two 3-week placebo-controlled studies in patients with primary insomnia, rebound effect was only observed on the first night after abrupt discontinuation of AMBIEN CR. On the second night, there was no worsening compared to baseline in the AMBIEN CR group.In 6-month placebo-controlled study in which AMBIEN CR was taken as needed (3 to nights per week), within the first month rebound effect was observed for Total Sleep Time (not for WASO) during the first night off medication. After this first month period, no further rebound insomnia was observed. After final treatment discontinuation no rebound was observed.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. AMBIEN CR is contraindicated in patientswho have experienced complex sleep behaviors after taking AMBIEN CR [see Warnings and Precautions (5.1)]. with known hypersensitivity to zolpidem. Observed reactions include anaphylaxis and angioedema [see Warnings and Precautions (5.4)]. who have experienced complex sleep behaviors after taking AMBIEN CR [see Warnings and Precautions (5.1)]. with known hypersensitivity to zolpidem. Observed reactions include anaphylaxis and angioedema [see Warnings and Precautions (5.4)]. Patients who have experienced complex sleep behaviors after taking AMBIEN CR (4)Known hypersensitivity to zolpidem (4). Patients who have experienced complex sleep behaviors after taking AMBIEN CR (4). Known hypersensitivity to zolpidem (4).

CONTROLLED SUBSTANCE SECTION.


9.1 Controlled Substance. Zolpidem tartrate is classified as Schedule IV controlled substance by federal regulation.

DEPENDENCE SECTION.


9.3 Dependence. Physical dependence is state of adaptation that is manifested by specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.Sedative/hypnotics have produced withdrawal signs and symptoms following abrupt discontinuation. These reported symptoms range from mild dysphoria and insomnia to withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. The following adverse events, which are considered to meet the DSM-III-R criteria for uncomplicated sedative/hypnotic withdrawal, were reported during U.S. clinical trials following placebo substitution occurring within 48 hours following last zolpidem treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach cramps, panic attack, nervousness, and abdominal discomfort. These reported adverse events occurred at an incidence of 1% or less. However, available data cannot provide reliable estimate of the incidence, if any, of dependence during treatment at recommended doses. Postmarketing reports of abuse, dependence and withdrawal have been received.

DESCRIPTION SECTION.


11DESCRIPTION. AMBIEN CR contains zolpidem tartrate, gamma-aminobutyric acid (GABA) receptor positive modulator of the imidazopyridine class. AMBIEN CR (zolpidem tartrate) extended-release tablets is available in 6.25 mg and 12.5 mg strength tablets for oral administration.Chemically, zolpidem is N,N,6-trimethyl-2-p-tolylimidazo[1,2-a] pyridine-3-acetamide L-(+)-tartrate (2:1). It has the following structure:Zolpidem tartrate is white to off-white crystalline powder that is sparingly soluble in water, alcohol, and propylene glycol. It has molecular weight of 764.88.AMBIEN CR consists of coated two-layer tablet: one layer that releases its drug content immediately and another layer that allows slower release of additional drug content. The 6.25 mg AMBIEN CR tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, potassium bitartrate, red ferric oxide, sodium starch glycolate, and titanium dioxide. The 12.5 mg AMBIEN CR tablet contains the following inactive ingredients: colloidal silicon dioxide, FD&C Blue 2, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, potassium bitartrate, sodium starch glycolate, titanium dioxide, and yellow ferric oxide.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.


2DOSAGE AND ADMINISTRATION. Use the lowest dose effective for the patient and must not exceed total of 12.5 mg daily (2.1) Recommended initial dose is single dose of 6.25 mg for women and single dose of 6.25 or 12.5 mg for men, immediately before bedtime with at least 7-8 hours remaining before the planned time of awakening (2.1) Geriatric patients and patients with mild to moderate hepatic impairment: Recommended dose is 6.25 mg for men and women (2.2) Lower doses of CNS depressants may be necessary when taken concomitantly with AMBIEN CR (2.3)Tablets to be swallowed whole, not to be crushed, divided or chewed (2.4) The effect of AMBIEN CR may be slowed if taken with or immediately after meal (2.4). Use the lowest dose effective for the patient and must not exceed total of 12.5 mg daily (2.1). Recommended initial dose is single dose of 6.25 mg for women and single dose of 6.25 or 12.5 mg for men, immediately before bedtime with at least 7-8 hours remaining before the planned time of awakening (2.1). Geriatric patients and patients with mild to moderate hepatic impairment: Recommended dose is 6.25 mg for men and women (2.2). Lower doses of CNS depressants may be necessary when taken concomitantly with AMBIEN CR (2.3). Tablets to be swallowed whole, not to be crushed, divided or chewed (2.4) The effect of AMBIEN CR may be slowed if taken with or immediately after meal (2.4). 2.1Dosage in Adults. Use the lowest effective dose for the patient. The recommended initial dose is 6.25 mg for women and either 6.25 or 12.5 mg for men, taken only once per night immediately before bedtime with at least 7-8 hours remaining before the planned time of awakening. If the 6.25 mg dose is not effective, the dose can be increased to 12.5 mg. In some patients, the higher morning blood levels following use of the 12.5 mg dose increase the risk of next-day impairment of driving and other activities that require full alertness [see Warnings and Precautions (5.2)]. The total dose of AMBIEN CR should not exceed 12.5 mg once daily immediately before bedtime. AMBIEN CR should be taken as single dose and should not be readministered during the same night.The recommended initial doses for women and men are different because zolpidem clearance is lower in women.. 2.2 Special Populations. Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate. The recommended dose of AMBIEN CR in these patients is 6.25 mg once daily immediately before bedtime [see Warnings and Precautions (5.2), Use in Specific Populations (8.5)]. Patients with mild to moderate hepatic impairment do not clear the drug as rapidly as normal subjects. The recommended dose of AMBIEN CR in these patients is 6.25 mg once daily immediately before bedtime. Avoid AMBIEN CR use in patients with severe hepatic impairment as it may contribute to encephalopathy [see Warnings and Precautions (5.8), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. 2.3 Use with CNS Depressants. Dosage adjustment may be necessary when AMBIEN CR is combined with other CNS-depressant drugs because of the potentially additive effects [see Warnings and Precautions (5.2)].. 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 meal.

DOSAGE FORMS & STRENGTHS SECTION.


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.. Extended-Release Tablets: 6.25 mg and 12.5 mg. Tablets not scored. (3).

DRUG ABUSE AND DEPENDENCE SECTION.


9DRUG ABUSE AND DEPENDENCE. 9.1 Controlled Substance. Zolpidem tartrate is classified as Schedule IV controlled substance by federal regulation.. 9.2 Abuse. Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. Tolerance is state of adaptation in which exposure to drug induces changes that result in diminution of one or more of the drug effects over time. Tolerance may occur to both desired and undesired effects of drugs and may develop at different rates for different effects.Addiction is primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is treatable disease, using multidisciplinary approach, but relapse is common.Studies of abuse potential in former drug abusers found that the effects of single doses of zolpidem tartrate 40 mg were similar, but not identical, to diazepam 20 mg, while zolpidem tartrate 10 mg effects were difficult to distinguish from placebo.Because persons with history of addiction to, or abuse of, drugs or alcohol are at increased risk for misuse, abuse and addiction of zolpidem, they should be monitored carefully when receiving zolpidem or any other hypnotic.. 9.3 Dependence. Physical dependence is state of adaptation that is manifested by specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.Sedative/hypnotics have produced withdrawal signs and symptoms following abrupt discontinuation. These reported symptoms range from mild dysphoria and insomnia to withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. The following adverse events, which are considered to meet the DSM-III-R criteria for uncomplicated sedative/hypnotic withdrawal, were reported during U.S. clinical trials following placebo substitution occurring within 48 hours following last zolpidem treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach cramps, panic attack, nervousness, and abdominal discomfort. These reported adverse events occurred at an incidence of 1% or less. However, available data cannot provide reliable estimate of the incidence, if any, of dependence during treatment at recommended doses. Postmarketing reports of abuse, dependence and withdrawal have been received.

DRUG INTERACTIONS SECTION.


7DRUG INTERACTIONS. CNS depressants, including alcohol: Possible adverse additive CNS-depressant effects (5.2, 7.1)Imipramine: Decreased alertness observed (7.1)Chlorpromazine: Impaired alertness and psychomotor performance observed (7.1)CYP3A4 inducers (rifampin or St. Johns wort): Combination use may decrease effect (7.2)Ketoconazole: Combination use may increase effect (7.2). CNS depressants, including alcohol: Possible adverse additive CNS-depressant effects (5.2, 7.1). Imipramine: Decreased alertness observed (7.1). Chlorpromazine: Impaired alertness and psychomotor performance observed (7.1). CYP3A4 inducers (rifampin or St. Johns wort): Combination use may decrease effect (7.2). Ketoconazole: Combination use may increase effect (7.2). 7.1 CNS-Active Drugs. CNS DepressantsCoadministration of zolpidem with other CNS depressants increases the risk of CNS depression. Concomitant use of zolpidem with these drugs may increase drowsiness and psychomotor impairment, including impaired driving ability [see Warnings and Precautions (5.1, 5.2)]. Zolpidem tartrate was evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs.. Imipramine, ChlorpromazineImipramine in combination with zolpidem produced no pharmacokinetic interaction other than 20% decrease in peak levels of imipramine, but there was an additive effect of decreased alertness. Similarly, chlorpromazine in combination with zolpidem produced no pharmacokinetic interaction, but there was an additive effect of decreased alertness and psychomotor performance [see Clinical Pharmacology (12.3)].. HaloperidolA study involving haloperidol and zolpidem revealed no effect of haloperidol on the pharmacokinetics or pharmacodynamics of zolpidem. The lack of drug interaction following single-dose administration does not predict the absence of an effect following chronic administration [see Clinical Pharmacology (12.3)].. AlcoholAn additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see Warnings and Precautions (5.1, 5.2)]. SertralineConcomitant administration of zolpidem and sertraline increases exposure to zolpidem [see Clinical Pharmacology (12.3)].. FluoxetineAfter multiple doses of zolpidem tartrate and fluoxetine an increase in the zolpidem half-life (17%) was observed. There was no evidence of an additive effect in psychomotor performance [see Clinical Pharmacology (12.3)].. 7.2 Drugs that Affect Drug Metabolism via Cytochrome P450. Some compounds known to induce or inhibit CYP3A may affect exposure to zolpidem. The effect of drugs that induce or inhibit other P450 enzymes on the exposure to zolpidem is not known.. CYP3A4 Inducers. RifampinRifampin, CYP3A4 inducer, significantly reduced the exposure to and the pharmacodynamic effects of zolpidem. Use of Rifampin in combination with zolpidem may decrease the efficacy of zolpidem and is not recommended [see Clinical Pharmacology (12.3)].. St. Johns wortUse of St. Johns wort, CYP3A4 inducer, in combination with zolpidem may decrease blood levels of zolpidem and is not recommended.. CYP3A4 Inhibitors. KetoconazoleKetoconazole, potent CYP3A4 inhibitor, increased the exposure to and pharmacodynamic effects of zolpidem. Consideration should be given to using lower dose of zolpidem when potent CYP3A4 inhibitor and zolpidem are given together [see Clinical Pharmacology (12.3)].

GERIATRIC USE SECTION.


8.5 Geriatric Use. total of 99 elderly (>=65 years of age) received daily doses of 6.25 mg AMBIEN CR in 3-week placebo-controlled study. The adverse reaction profile of AMBIEN CR 6.25 mg in this population was similar to that of AMBIEN CR 12.5 mg in younger adults (<=64 years of age). Dizziness was reported in 8% of AMBIEN CR-treated patients compared with 3% of those treated with placebo.The dose of AMBIEN CR in elderly patients is 6.25 mg to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative/hypnotic drugs [see Warnings and Precautions (5.2)].

HEPATIC IMPAIRMENT SUBSECTION.


8.7 Hepatic Impairment. The recommended dose of AMBIEN CR in patients with mild to moderate hepatic impairment is 6.25 mg once daily immediately before bedtime. Avoid AMBIEN CR use in patients with severe hepatic impairment as it may contribute to encephalopathy [see Dosage and Administration (2.2), Warnings and Precautions (5.8), Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.


16HOW SUPPLIED/STORAGE AND HANDLING. AMBIEN CR 6.25 mg extended-release tablets are composed of two layersLayers are covered by the coating and are indistinguishable. and are coated, pink, round, biconvex, debossed with A~ on one side and supplied as:NDC NumberSize0024-5501-31bottle of 100AMBIEN CR 12.5 mg extended-release tablets are composed of two layers and are coated, blue, round, biconvex, debossed with A~ on one side and supplied as:NDC NumberSize0024-5521-31bottle of 100. Store between 15C-25C (59F-77F). Limited excursions permissible up to 30C (86F).

LACTATION SECTION.


8.2 Lactation. Risk SummaryLimited data from published literature report the presence of zolpidem in human milk. There are reports of excess sedation in infants exposed to zolpidem through breastmilk [see Clinical Considerations]. There is no information on the effects of zolpidem on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for AMBIEN CR and any potential adverse effects on the breastfed infant from AMBIEN CR or from the underlying maternal condition.. Clinical ConsiderationsInfants exposed to AMBIEN CR through breastmilk should be monitored for excess sedation, hypotonia, and respiratory depression. lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment and for 23 hours (approximately elimination half-lives) after AMBIEN CR administration in order to minimize drug exposure to breast fed infant.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. Zolpidem is GABA receptor positive modulator presumed to exert its therapeutic effects in the short-term treatment of insomnia through binding to the benzodiazepine site of subunit containing GABA receptors, increasing the frequency of chloride channel opening resulting in the inhibition of neuronal excitation.

NONCLINICAL TOXICOLOGY SECTION.


13NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisZolpidem was administered to mice and rats for years at oral doses of 4, 18, and 80 mg base/kg/day. In mice, these doses are approximately 2, 9, and 40 times the MRHD of 12.5 mg/day (10 mg zolpidem base) based on mg/m2 body surface area and in rats, these doses are approximately 4, 18, and 80 times the MRHD based on mg/m2 body surface area. No evidence of carcinogenic potential was observed in mice. In rats, renal tumors (lipoma, liposarcoma) were seen at the mid and high doses.. MutagenesisZolpidem was negative in in vitro (bacterial reverse mutation, mouse lymphoma, and chromosomal aberration) and in vivo (mouse micronucleus) genetic toxicology assays.. Impairment of FertilityZolpidem was administered to rats at 4, 20, and 100 mg base/kg/day, which are approximately 4, 20, and 100 times the MRHD of 12.5 mg/day (10 mg zolpidem base) based on mg/m2 body surface area, prior to and during mating, and continuing in females through postpartum day 25. Zolpidem caused irregular estrus cycles and prolonged precoital intervals at the highest dose tested, which is approximately 100 times the MRHD based on mg/m2 body surface area. The NOAEL for these effects is 20 times the MRHD based on mg/m2 body surface area. There was no impairment of fertility at any dose tested.

OVERDOSAGE SECTION.


10OVERDOSAGE. 10.1 Signs and Symptoms. In postmarketing experience of overdose with zolpidem tartrate alone, or in combination with CNS-depressant agents, impairment of consciousness ranging from somnolence to coma, cardiovascular and/or respiratory compromise, and fatal outcomes have been reported.. 10.2 Recommended Treatment. General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Zolpidems sedative hypnotic effect was shown to be reduced by flumazenil and therefore may be useful; however, flumazenil administration may contribute to the appearance of neurological symptoms (convulsions). As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed. Hypotension and CNS depression should be monitored and treated by appropriate medical intervention. Sedating drugs should be withheld following zolpidem overdosage, even if excitation occurs. The value of dialysis in the treatment of overdosage has not been determined, although hemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated that zolpidem is not dialyzable.As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. The physician may wish to consider contacting poison control center for up-to-date information on the management of hypnotic drug product overdosage.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL 6.25 mg Tablet Bottle Label. A-550NDC 0024-5501-31AMBIENCR(R) (ZOLPIDEM TARTRATE EXTENDED-RELEASE) CIV6.25 mg TabletsDispense with Medication GuideRx only100 TabletsSANOFI. PRINCIPAL DISPLAY PANEL 6.25 mg Tablet Bottle Label.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. AMBIEN CR is not recommended for use in children. Safety and effectiveness of zolpidem in pediatric patients below the age of 18 years have not been established.In an 8-week study in pediatric patients (aged 6-17 years) with insomnia associated with attention-deficit/hyperactivity disorder (ADHD) an oral solution of zolpidem tartrate dosed at 0.25 mg/kg at bedtime did not decrease sleep latency compared to placebo. Psychiatric and nervous system disorders comprised the most frequent (>5%) treatment emergent adverse reactions observed with zolpidem versus placebo and included dizziness (23.5% vs 1.5%), headache (12.5% vs 9.2%), and hallucinations were reported in 7% of the pediatric patients who received zolpidem; none of the pediatric patients who received placebo reported hallucinations [see Warnings and Precautions (5.5)]. Ten patients on zolpidem (7.4%) discontinued treatment due to an adverse reaction.FDA has not required pediatric studies of AMBIEN CR in the pediatric population based on these efficacy and safety findings.

PHARMACODYNULLMICS SECTION.


12.2Pharmacodynamics. Zolpidem binds to GABA receptors with greater affinity for subunit relative to and subunit containing receptors. Zolpidem has no appreciable binding affinity for subunit containing GABA receptors. This binding profile may explain the relative absence of myorelaxant effects in animal studies. Zolpidem has no appreciable binding affinity for dopaminergic D2, serotonergic 5HT2, adrenergic, histaminergic or muscarinic receptors.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. AMBIEN CR exhibits biphasic absorption characteristics, which results in rapid initial absorption from the gastrointestinal tract similar to zolpidem tartrate immediate-release, then provides extended plasma concentrations beyond three hours after administration. study in 24 healthy male subjects was conducted to compare mean zolpidem plasma concentration-time profiles obtained after single oral administration of AMBIEN CR 12.5 mg and of an immediate-release formulation of zolpidem tartrate (10 mg). The terminal elimination half-life observed with AMBIEN CR (12.5 mg) was similar to that obtained with immediate-release zolpidem tartrate (10 mg). The mean plasma concentration-time profiles are shown in Figure 1.Figure 1: Mean Plasma Concentration-Time Profiles for AMBIEN CR (12.5 mg) and Immediate-Release Zolpidem Tartrate (10 mg)In adult and elderly patients treated with AMBIEN CR, there was no evidence of accumulation after repeated once-daily dosing for up to two weeks.. Figure 1. AbsorptionFollowing administration of AMBIEN CR, administered as single 12.5 mg dose in healthy male adult subjects, the mean peak concentration (Cmax) of zolpidem was 134 ng/mL (range: 68.9 to 197 ng/ml) occurring at median time (Tmax) of 1.5 hours. The mean AUC of zolpidem was 740 nghr/mL (range: 295 to 1359 nghr/mL).A food-effect study in 45 healthy subjects compared the pharmacokinetics of AMBIEN CR 12.5 mg when administered while fasting or within 30 minutes after meal. Results demonstrated that with food, mean AUC and Cmax were decreased by 23% and 30%, respectively, while median Tmax was increased from hours to hours. The half-life was not changed. These results suggest that, for faster sleep onset, AMBIEN CR should not be administered with or immediately after meal.. DistributionTotal protein binding was found to be 92.5 +- 0.1% and remained constant, independent of concentration between 40 and 790 ng/mL.. MetabolismZolpidem is converted to inactive metabolites that are eliminated primarily by renal excretion.. EliminationWhen AMBIEN CR was administered as single 12.5 mg dose in healthy male adult subjects, the mean zolpidem elimination half-life was 2.8 hours (range: 1.62 to 4.05 hr).. Special Populations. ElderlyIn 24 elderly (>=65 years) healthy subjects administered single 6.25 mg dose of AMBIEN CR, the mean peak concentration (Cmax) of zolpidem was 70.6 (range: 35.0 to 161) ng/mL occurring at median time (Tmax) of 2.0 hours. The mean AUC of zolpidem was 413 nghr/mL (range: 124 to 1190 nghr/mL) and the mean elimination half-life was 2.9 hours (range: 1.59 to 5.50 hours).. Hepatic impairmentAMBIEN CR was not studied in patients with hepatic impairment. The pharmacokinetics of an immediate-release formulation of zolpidem tartrate in eight patients with chronic hepatic insufficiency was compared to results in healthy subjects. Following single 20 mg oral zolpidem tartrate dose, mean Cmax and AUC were found to be two times (250 vs 499 ng/mL) and five times (788 vs 4,203 nghr/mL) higher, respectively, in hepatically compromised patients. Tmax did not change. The mean half-life in cirrhotic patients of 9.9 hr (range: 4.1 to 25.8 hr) was greater than that observed in normal subjects of 2.2 hr (range: 1.6 to 2.4 hr) [see Dosage and Administration (2.2), Warnings and Precautions (5.8), Use in Specific Populations (8.7)].. Renal impairmentAMBIEN CR was not studied in patients with renal impairment. The pharmacokinetics of an immediate-release formulation of zolpidem tartrate were studied in 11 patients with end-stage renal failure (mean ClCr 6.5 +- 1.5 mL/min) undergoing hemodialysis three times week, who were dosed with zolpidem tartrate 10 mg orally each day for 14 or 21 days. No statistically significant differences were observed for Cmax, Tmax, half-life, and AUC between the first and last day of drug administration when baseline concentration adjustments were made. Zolpidem was not hemodialyzable. No accumulation of unchanged drug appeared after 14 or 21 days. Zolpidem pharmacokinetics was not significantly different in renally impaired patients. No dosage adjustment is necessary in patients with compromised renal function.. Drug Interactions. CNS depressantsCoadministration of zolpidem with other CNS depressants increases the risk of CNS depression [see Warnings and Precautions (5.2)]. Zolpidem tartrate was evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs. Imipramine in combination with zolpidem produced no pharmacokinetic interaction other than 20% decrease in peak levels of imipramine, but there was an additive effect of decreased alertness. Similarly, chlorpromazine in combination with zolpidem produced no pharmacokinetic interaction, but there was an additive effect of decreased alertness and psychomotor performance.A study involving haloperidol and zolpidem revealed no effect of haloperidol on the pharmacokinetics or pharmacodynamics of zolpidem. The lack of drug interaction following single-dose administration does not predict the absence of an effect following chronic administration.An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see Warnings and Precautions (5.2)]. Following five consecutive nightly doses at bedtime of oral zolpidem tartrate 10 mg in the presence of sertraline 50 mg (17 consecutive daily doses, at 7:00 am, in healthy female volunteers), zolpidem Cmax was significantly higher (43%) and Tmax was significantly decreased (-53%). Pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem.A single-dose interaction study with zolpidem tartrate 10 mg and fluoxetine 20 mg at steady-state levels in male volunteers did not demonstrate any clinically significant pharmacokinetic or pharmacodynamic interactions. When multiple doses of zolpidem and fluoxetine were given at steady state and the concentrations evaluated in healthy females, an increase in the zolpidem half-life (17%) was observed. There was no evidence of an additive effect in psychomotor performance.. Drugs that affect drug metabolism via cytochrome P450Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of inhibitors of other P450 enzymes on the pharmacokinetics of zolpidem is unknown.A single-dose interaction study with zolpidem tartrate 10 mg and itraconazole 200 mg at steady-state levels in male volunteers resulted in 34% increase in AUC0- of zolpidem tartrate. There were no pharmacodynamic effects of zolpidem detected on subjective drowsiness, postural sway, or psychomotor performance.A single-dose interaction study with zolpidem tartrate 10 mg and rifampin 600 mg at steady-state levels in female subjects showed significant reductions of the AUC (-73%), Cmax (-58%), and T1/2 (-36%) of zolpidem together with significant reductions in the pharmacodynamic effects of zolpidem tartrate. Rifampin, CYP3A4 inducer, significantly reduced the exposure to and the pharmacodynamic effects of zolpidem [see Drug Interactions (7.2)].Similarly, St. Johns wort, CYP3A4 inducer, may also decrease the blood levels of zolpidem.A single-dose interaction study with zolpidem tartrate mg and ketoconazole, potent CYP3A4 inhibitor, given as 200 mg twice daily for days increased Cmax of zolpidem (30%) and the total AUC of zolpidem (70%) compared to zolpidem alone and prolonged the elimination half-life (30%) along with an increase in the pharmacodynamic effects of zolpidem [see Drug Interactions (7.2)].Additionally, fluvoxamine (a strong inhibitor of CYP1A2 and weak inhibitor of CYP3A4 and CYP2C9) and ciprofloxacin (a strong inhibitor of CYP1A2 and moderate inhibitor of CYP3A4) are also likely to inhibit zolpidems metabolic pathways, potentially leading to an increase in zolpidem exposure.. Other drugs with no interactions with zolpidemA study involving cimetidine/zolpidem tartrate and ranitidine/zolpidem tartrate combinations revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of zolpidem.Zolpidem tartrate had no effect on digoxin pharmacokinetics and did not affect prothrombin time when given with warfarin in healthy subjects.

PREGNULLNCY SECTION.


8.1 Pregnancy. Risk SummaryNeonates born to mothers using zolpidem late in the third trimester of pregnancy have been reported to experience symptoms of respiratory depression and sedation [see Clinical Considerations and Data]. Published data on the use of zolpidem during pregnancy have not reported clear association with zolpidem and major birth defects [see Data]. Oral administration of zolpidem to pregnant rats and rabbits did not indicate risk for adverse effects on fetal development at clinically relevant doses [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.. Clinical Considerations. Fetal/neonatal adverse reactionsZolpidem crosses the placenta and may produce respiratory depression and sedation in neonates. Monitor neonates exposed to AMBIEN CR during pregnancy and labor for signs of excess sedation, hypotonia, and respiratory depression and manage accordingly.. Data. Human dataPublished data from observational studies, birth registries, and case reports on the use of zolpidem during pregnancy do not report clear association with zolpidem and major birth defects.There are limited postmarketing reports of severe to moderate cases of respiratory depression that occurred after birth in neonates whose mothers had taken zolpidem during pregnancy. These cases required artificial ventilation or intratracheal intubation. The majority of neonates recovered within hours to few weeks after birth once treated.Zolpidem has been shown to cross the placenta.. Animal dataOral administration of zolpidem to pregnant rats during the period of organogenesis at 4, 20, and 100 mg base/kg/day, which are approximately 4, 20, and 100 times the maximum recommended human dose (MRHD) of 12.5 mg/day (10 mg zolpidem base) based on mg/m2 body surface area, caused delayed fetal development (incomplete fetal skeletal ossification) at maternally toxic (ataxia) doses 20 and 100 times the MRHD based on mg/m2 body surface area.Oral administration of zolpidem to pregnant rabbits during the period of organogenesis at 1, 4, and 16 mg base/kg/day, which are approximately 2, 8, and 30 times the MRHD of 12.5 mg/day (10 mg zolpidem base) based on mg/m2 body surface area caused embryo-fetal death and delayed fetal development (incomplete fetal skeletal ossification) at maternally toxic (decreased body weight gain) dose 30 times the MRHD based on mg/m2 body surface area.Oral administration of zolpidem to pregnant rats from day 15 of gestation through lactation at 4, 20, and 100 mg base/kg/day, which are approximately 4, 20, and 100 times the MRHD of 12.5 mg/day (10 mg zolpidem base) based on mg/m2 body surface area, delayed offspring growth and decreased survival at doses 20 and 100 times, respectively, the MRHD based on mg/m2 body surface area.

SPL MEDGUIDE SECTION.


MEDICATION GUIDE. AMBIEN CR(R) (ambe-n see ahr) (zolpidem tartrate) extended-release tablets C-IV Read the Medication Guide that comes with AMBIEN CR before you start taking it and each time you get refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment.What is the most important information should know about AMBIEN CRDo not take more AMBIEN CR than prescribed.Do not take AMBIEN CR unless you are able to stay in bed full night (7 to hours) before you must be active again.Take AMBIEN CR right before you get in bed, not sooner.AMBIEN CR may cause serious side effects including complex sleep behaviors that have caused serious injury and death. After taking AMBIEN CR, you may get up out of bed while not being fully awake and do an activity that you do not know you are doing (complex sleep behaviors). The next morning, you may not remember that you did anything during the night. These activities may occur with AMBIEN CR whether or not you drink alcohol or take other medicines that make you sleepy. Reported activities include: driving car (sleep-driving)making and eating foodtalking on the phonehaving sexsleep-walkingStop taking AMBIEN CR and call your healthcare provider right away if you find out that you have done any of the above activities after taking AMBIEN CR. You should not drive car or do things that require clear thinking the day after you take AMBIEN CR.Do not take AMBIEN CR if you: have ever experienced complex sleep behavior (such as driving car, making and eating food, talking on the phone, or having sex while not being fully awake) after taking AMBIEN CR.drank alcohol that evening or before bed.take other medicines that can make you sleepy. Taking AMBIEN CR with other drugs can cause side effects. Talk to your healthcare provider about all of your medicines. Your healthcare provider will tell you if you can take AMBIEN CR with your other medicines.cannot get full nights sleep.What is AMBIEN CR AMBIEN CR is sedative-hypnotic (sleep) medicine. AMBIEN CR is used in adults for the treatment of sleep problem called insomnia. Symptoms of insomnia include: trouble falling asleep waking up often during the nightAMBIEN CR is not recommended for use in children under the age of 18 years.AMBIEN CR is federally controlled substance (C-IV) because it can be abused or lead to dependence. Keep AMBIEN CR in safe place to prevent misuse and abuse. Selling or giving away AMBIEN CR may harm others, and is against the law. Tell your healthcare provider if you have ever abused or have been dependent on alcohol, prescription medicines or street drugs.Who should not take AMBIEN CR Do not take AMBIEN CR if you are allergic to zolpidem or any other ingredients in AMBIEN CR. See the end of this Medication Guide for complete list of ingredients in AMBIEN CR. Do not take AMBIEN CR if you have had an allergic reaction to drugs containing zolpidem, such as Ambien, Edluar, Zolpimist, or Intermezzo.Symptoms of serious allergic reaction to zolpidem can include:swelling of your face, lips, and throat that may cause difficulty breathing or swallowing What should tell my healthcare provider before taking AMBIEN CRAMBIEN CR may not be right for you. Before starting AMBIEN CR, tell your healthcare provider about all of your health conditions, including if you:have history of depression, mental illness, or suicidal thoughtshave history of drug or alcohol abuse or addictionhave kidney or liver diseasehave lung disease or breathing problemsare pregnant, planning to become pregnant. Talk to your healthcare provider about the risk to your unborn baby if you take AMBIEN CR.Using AMBIEN CR in the last trimester of pregnancy may cause breathing difficulties or excess sleepiness in your newborn. Monitor for signs of sleepiness (more than usual), trouble breathing, or limpness in the newborn if AMBIEN CR is taken late in pregnancy.are breastfeeding or plan to breastfeed. AMBIEN CR passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while you take AMBIEN CR.Tell your healthcare provider about all of the medicines you take, including prescription and nonprescription medicines, vitamins and herbal supplements.Medicines can interact with each other, sometimes causing serious side effects. Do not take AMBIEN CR with other medicines that can make you sleepy unless your healthcare provider tells you to. Know the medicines you take. Keep list of your medicines with you to show your healthcare provider and pharmacist each time you get new medicine.How should take AMBIEN CRSee What is the most important information should know about AMBIEN CR Take AMBIEN CR exactly as prescribed. Only take AMBIEN CR tablet night if needed.Do not take AMBIEN CR if you drank alcohol that evening or before bed.You should not take AMBIEN CR with or right after meal. AMBIEN CR may help you fall asleep faster if you take it on an empty stomach.Take AMBIEN CR Tablets whole. Do not break, crush, dissolve or chew AMBIEN CR tablets before swallowing. If you cannot swallow AMBIEN CR tablets whole, tell your healthcare provider. You may need different medicine.Call your healthcare provider if your insomnia worsens or is not better within to 10 days. This may mean that there is another condition causing your sleep problems.If you take too much AMBIEN CR or overdose, get emergency treatment.What are the possible side effects of AMBIEN CRAMBIEN CR may cause serious side effects including:getting out of bed while not being fully awake and doing an activity that you do not know you are doing. (See What is the most important information should know about AMBIEN CR)abnormal thoughts and behavior. Symptoms include more outgoing or aggressive behavior than normal, confusion, acting strangely, agitation, hallucinations, worsening of depression, and suicidal thoughts or actions.memory lossanxietysevere allergic reactions. Symptoms include swelling of the tongue or throat, trouble breathing, and nausea and vomiting. Get emergency medical help if you get these symptoms after taking AMBIEN CR.Call your healthcare provider right away if you have any of the above side effects or any other side effects that worry you while using AMBIEN CR.The most common side effects of AMBIEN CR are:headachesleepinessdizzinessdrowsiness the next day after you take AMBIEN CRAfter you stop taking sleep medicine, you may have symptoms for to days such as:trouble sleepingnauseaflushinglightheadednessuncontrolled cryingvomitingstomach crampspanic attacknervousnessstomach area painThese are not all the side effects of AMBIEN CR. Ask your healthcare provider or pharmacist for more information.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store AMBIEN CRStore AMBIEN CR at room temperature, 59F to 77F (15C to 25C).Keep AMBIEN CR and all medicines out of reach of children.General Information about the safe and effective use of AMBIEN CRMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use AMBIEN CR for condition for which it was not prescribed. Do not share AMBIEN CR with other people, even if they have the same symptoms that you have. It may harm them and it is against the law.This Medication Guide summarizes the most important information about AMBIEN CR. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about AMBIEN CR that is written for healthcare professionals.For more information, go to www.ambiencr.com or call 1-800-633-1610.What are the ingredients in AMBIEN CRActive Ingredient: Zolpidem tartrateInactive Ingredients:The 6.25 mg tablets contain: colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, potassium bitartrate, red ferric oxide, sodium starch glycolate, and titanium dioxide.The 12.5 mg tablets contain: colloidal silicon dioxide, FD&C Blue 2, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, potassium bitartrate, sodium starch glycolate, titanium dioxide, and yellow ferric oxide.This Medication Guide has been approved by the U.S. Food and Drug Administration.sanofi-aventis U.S. LLCBridgewater, NJ 08807A SANOFI COMPANYRevised: August 2019(C)2019 sanofi-aventis U.S. LLC. Do not take more AMBIEN CR than prescribed.. Do not take AMBIEN CR unless you are able to stay in bed full night (7 to hours) before you must be active again.. Take AMBIEN CR right before you get in bed, not sooner.. driving car (sleep-driving). making and eating food. talking on the phone. having sex. sleep-walking. have ever experienced complex sleep behavior (such as driving car, making and eating food, talking on the phone, or having sex while not being fully awake) after taking AMBIEN CR.. drank alcohol that evening or before bed.. take other medicines that can make you sleepy. Taking AMBIEN CR with other drugs can cause side effects. Talk to your healthcare provider about all of your medicines. Your healthcare provider will tell you if you can take AMBIEN CR with your other medicines.. cannot get full nights sleep.. trouble falling asleep. waking up often during the night. Do not take AMBIEN CR if you are allergic to zolpidem or any other ingredients in AMBIEN CR. See the end of this Medication Guide for complete list of ingredients in AMBIEN CR.. Do not take AMBIEN CR if you have had an allergic reaction to drugs containing zolpidem, such as Ambien, Edluar, Zolpimist, or Intermezzo.Symptoms of serious allergic reaction to zolpidem can include:swelling of your face, lips, and throat that may cause difficulty breathing or swallowing swelling of your face, lips, and throat that may cause difficulty breathing or swallowing. have history of depression, mental illness, or suicidal thoughts. have history of drug or alcohol abuse or addiction. have kidney or liver disease. have lung disease or breathing problems. are pregnant, planning to become pregnant. Talk to your healthcare provider about the risk to your unborn baby if you take AMBIEN CR.. Using AMBIEN CR in the last trimester of pregnancy may cause breathing difficulties or excess sleepiness in your newborn. Monitor for signs of sleepiness (more than usual), trouble breathing, or limpness in the newborn if AMBIEN CR is taken late in pregnancy.. are breastfeeding or plan to breastfeed. AMBIEN CR passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while you take AMBIEN CR.. See What is the most important information should know about AMBIEN CR Take AMBIEN CR exactly as prescribed. Only take AMBIEN CR tablet night if needed.. Do not take AMBIEN CR if you drank alcohol that evening or before bed.. You should not take AMBIEN CR with or right after meal. AMBIEN CR may help you fall asleep faster if you take it on an empty stomach.. Take AMBIEN CR Tablets whole. Do not break, crush, dissolve or chew AMBIEN CR tablets before swallowing. If you cannot swallow AMBIEN CR tablets whole, tell your healthcare provider. You may need different medicine.. Call your healthcare provider if your insomnia worsens or is not better within to 10 days. This may mean that there is another condition causing your sleep problems.. If you take too much AMBIEN CR or overdose, get emergency treatment.. getting out of bed while not being fully awake and doing an activity that you do not know you are doing. (See What is the most important information should know about AMBIEN CR). abnormal thoughts and behavior. Symptoms include more outgoing or aggressive behavior than normal, confusion, acting strangely, agitation, hallucinations, worsening of depression, and suicidal thoughts or actions.. memory loss. anxiety. severe allergic reactions. Symptoms include swelling of the tongue or throat, trouble breathing, and nausea and vomiting. Get emergency medical help if you get these symptoms after taking AMBIEN CR.. headache. sleepiness. dizziness. drowsiness the next day after you take AMBIEN CR. trouble sleeping. nausea. flushing. lightheadedness. uncontrolled crying. vomiting. stomach cramps. panic attack. nervousness. stomach area pain.

SPL UNCLASSIFIED SECTION.


2.1Dosage in Adults. Use the lowest effective dose for the patient. The recommended initial dose is 6.25 mg for women and either 6.25 or 12.5 mg for men, taken only once per night immediately before bedtime with at least 7-8 hours remaining before the planned time of awakening. If the 6.25 mg dose is not effective, the dose can be increased to 12.5 mg. In some patients, the higher morning blood levels following use of the 12.5 mg dose increase the risk of next-day impairment of driving and other activities that require full alertness [see Warnings and Precautions (5.2)]. The total dose of AMBIEN CR should not exceed 12.5 mg once daily immediately before bedtime. AMBIEN CR should be taken as single dose and should not be readministered during the same night.The recommended initial doses for women and men are different because zolpidem clearance is lower in women.

STORAGE AND HANDLING SECTION.


Store between 15C-25C (59F-77F). Limited excursions permissible up to 30C (86F).

USE IN SPECIFIC POPULATIONS SECTION.


8USE IN SPECIFIC POPULATIONS. Pregnancy: May cause respiratory depression and sedation in neonates with exposure late in the third trimester. (8.1)Lactation: lactating woman may pump and discard breast milk during treatment and for 23 hours after AMBIEN CR administration. (8.2)Pediatric use: Safety and effectiveness not established. Hallucinations (incidence rate 7%) and other psychiatric and/or nervous system adverse reactions were observed frequently in study of pediatric patients with Attention-Deficit/Hyperactivity Disorder. (5.5, 8.4). Pregnancy: May cause respiratory depression and sedation in neonates with exposure late in the third trimester. (8.1). Lactation: lactating woman may pump and discard breast milk during treatment and for 23 hours after AMBIEN CR administration. (8.2). Pediatric use: Safety and effectiveness not established. Hallucinations (incidence rate 7%) and other psychiatric and/or nervous system adverse reactions were observed frequently in study of pediatric patients with Attention-Deficit/Hyperactivity Disorder. (5.5, 8.4). 8.1 Pregnancy. Risk SummaryNeonates born to mothers using zolpidem late in the third trimester of pregnancy have been reported to experience symptoms of respiratory depression and sedation [see Clinical Considerations and Data]. Published data on the use of zolpidem during pregnancy have not reported clear association with zolpidem and major birth defects [see Data]. Oral administration of zolpidem to pregnant rats and rabbits did not indicate risk for adverse effects on fetal development at clinically relevant doses [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.. Clinical Considerations. Fetal/neonatal adverse reactionsZolpidem crosses the placenta and may produce respiratory depression and sedation in neonates. Monitor neonates exposed to AMBIEN CR during pregnancy and labor for signs of excess sedation, hypotonia, and respiratory depression and manage accordingly.. Data. Human dataPublished data from observational studies, birth registries, and case reports on the use of zolpidem during pregnancy do not report clear association with zolpidem and major birth defects.There are limited postmarketing reports of severe to moderate cases of respiratory depression that occurred after birth in neonates whose mothers had taken zolpidem during pregnancy. These cases required artificial ventilation or intratracheal intubation. The majority of neonates recovered within hours to few weeks after birth once treated.Zolpidem has been shown to cross the placenta.. Animal dataOral administration of zolpidem to pregnant rats during the period of organogenesis at 4, 20, and 100 mg base/kg/day, which are approximately 4, 20, and 100 times the maximum recommended human dose (MRHD) of 12.5 mg/day (10 mg zolpidem base) based on mg/m2 body surface area, caused delayed fetal development (incomplete fetal skeletal ossification) at maternally toxic (ataxia) doses 20 and 100 times the MRHD based on mg/m2 body surface area.Oral administration of zolpidem to pregnant rabbits during the period of organogenesis at 1, 4, and 16 mg base/kg/day, which are approximately 2, 8, and 30 times the MRHD of 12.5 mg/day (10 mg zolpidem base) based on mg/m2 body surface area caused embryo-fetal death and delayed fetal development (incomplete fetal skeletal ossification) at maternally toxic (decreased body weight gain) dose 30 times the MRHD based on mg/m2 body surface area.Oral administration of zolpidem to pregnant rats from day 15 of gestation through lactation at 4, 20, and 100 mg base/kg/day, which are approximately 4, 20, and 100 times the MRHD of 12.5 mg/day (10 mg zolpidem base) based on mg/m2 body surface area, delayed offspring growth and decreased survival at doses 20 and 100 times, respectively, the MRHD based on mg/m2 body surface area.. 8.2 Lactation. Risk SummaryLimited data from published literature report the presence of zolpidem in human milk. There are reports of excess sedation in infants exposed to zolpidem through breastmilk [see Clinical Considerations]. There is no information on the effects of zolpidem on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for AMBIEN CR and any potential adverse effects on the breastfed infant from AMBIEN CR or from the underlying maternal condition.. Clinical ConsiderationsInfants exposed to AMBIEN CR through breastmilk should be monitored for excess sedation, hypotonia, and respiratory depression. lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment and for 23 hours (approximately elimination half-lives) after AMBIEN CR administration in order to minimize drug exposure to breast fed infant.. 8.4 Pediatric Use. AMBIEN CR is not recommended for use in children. Safety and effectiveness of zolpidem in pediatric patients below the age of 18 years have not been established.In an 8-week study in pediatric patients (aged 6-17 years) with insomnia associated with attention-deficit/hyperactivity disorder (ADHD) an oral solution of zolpidem tartrate dosed at 0.25 mg/kg at bedtime did not decrease sleep latency compared to placebo. Psychiatric and nervous system disorders comprised the most frequent (>5%) treatment emergent adverse reactions observed with zolpidem versus placebo and included dizziness (23.5% vs 1.5%), headache (12.5% vs 9.2%), and hallucinations were reported in 7% of the pediatric patients who received zolpidem; none of the pediatric patients who received placebo reported hallucinations [see Warnings and Precautions (5.5)]. Ten patients on zolpidem (7.4%) discontinued treatment due to an adverse reaction.FDA has not required pediatric studies of AMBIEN CR in the pediatric population based on these efficacy and safety findings.. 8.5 Geriatric Use. total of 99 elderly (>=65 years of age) received daily doses of 6.25 mg AMBIEN CR in 3-week placebo-controlled study. The adverse reaction profile of AMBIEN CR 6.25 mg in this population was similar to that of AMBIEN CR 12.5 mg in younger adults (<=64 years of age). Dizziness was reported in 8% of AMBIEN CR-treated patients compared with 3% of those treated with placebo.The dose of AMBIEN CR in elderly patients is 6.25 mg to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative/hypnotic drugs [see Warnings and Precautions (5.2)].. 8.6 Gender Difference in Pharmacokinetics Women clear zolpidem tartrate from the body at lower rate than men. Cmax and AUC parameters of zolpidem from AMBIEN CR were, respectively, approximately 50% and 75% higher at the same dose in adult female subjects compared to adult male subjects. Between and 12 hours after dosing, zolpidem concentrations were to fold higher in adult female compared to adult male subjects. Given the higher blood levels of zolpidem tartrate in women compared to men at given dose, the recommended initial dose of AMBIEN CR for adult women is 6.25 mg, and the recommended dose for adult men is 6.25 or 12.5 mg.In geriatric patients, clearance of zolpidem is similar in men and women. The recommended dose of AMBIEN CR in geriatric patients is 6.25 mg regardless of gender.. 8.7 Hepatic Impairment. The recommended dose of AMBIEN CR in patients with mild to moderate hepatic impairment is 6.25 mg once daily immediately before bedtime. Avoid AMBIEN CR use in patients with severe hepatic impairment as it may contribute to encephalopathy [see Dosage and Administration (2.2), Warnings and Precautions (5.8), Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.


5WARNINGS AND PRECAUTIONS. CNS-Depressant Effects: Impaired alertness and motor coordination, including risk of morning impairment. Risk increases with dose and use with other CNS depressants and alcohol. Caution patients against driving and other activities requiring complete mental alertness the morning after use. (5.2)Need to Evaluate for Comorbid Diagnoses: Reevaluate if insomnia persists after to 10 days of use. (5.3)Severe Anaphylactic/Anaphylactoid Reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur. (5.4)Abnormal Thinking and Behavioral Changes: Changes including decreased inhibition, bizarre behavior, agitation, and depersonalization have been reported. Immediately evaluate any new onset behavioral changes. (5.5)Depression: Worsening of depression or suicidal thinking may occur. Prescribe the least amount of tablets feasible to avoid intentional overdose. (5.6)Respiratory Depression: Consider this risk before prescribing in patients with compromised respiratory function. (5.7)Hepatic Impairment: Avoid AMBIEN CR use in patients with severe hepatic impairment. (5.8)Withdrawal Effects: Symptoms may occur with rapid dose reduction or discontinuation. (5.9, 9.3). CNS-Depressant Effects: Impaired alertness and motor coordination, including risk of morning impairment. Risk increases with dose and use with other CNS depressants and alcohol. Caution patients against driving and other activities requiring complete mental alertness the morning after use. (5.2). Need to Evaluate for Comorbid Diagnoses: Reevaluate if insomnia persists after to 10 days of use. (5.3). Severe Anaphylactic/Anaphylactoid Reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur. (5.4). Abnormal Thinking and Behavioral Changes: Changes including decreased inhibition, bizarre behavior, agitation, and depersonalization have been reported. Immediately evaluate any new onset behavioral changes. (5.5). Depression: Worsening of depression or suicidal thinking may occur. Prescribe the least amount of tablets feasible to avoid intentional overdose. (5.6). Respiratory Depression: Consider this risk before prescribing in patients with compromised respiratory function. (5.7). Hepatic Impairment: Avoid AMBIEN CR use in patients with severe hepatic impairment. (5.8). Withdrawal Effects: Symptoms may occur with rapid dose reduction or discontinuation. (5.9, 9.3). 5.1 Complex Sleep Behaviors. Complex sleep behaviors, including sleep-walking, sleep-driving, and engaging in other activities while not fully awake, may occur following the first or any subsequent use of AMBIEN CR. Patients can be seriously injured or injure others during complex sleep behaviors. Such injuries may result in fatal outcome. Other complex sleep behaviors (e.g., preparing and eating food, making phone calls, or having sex) have also been reported. Patients usually do not remember these events. Postmarketing reports have shown that complex sleep behaviors may occur with AMBIEN CR alone at recommended doses, with or without the concomitant use of alcohol or other central nervous system (CNS) depressants [see Drug Interactions (7.1)]. Discontinue AMBIEN CR immediately if patient experiences complex sleep behavior [see Contraindications (4)].. 5.2 CNS-Depressant Effects and Next-Day Impairment. AMBIEN CR is 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 AMBIEN CR may develop, patients using AMBIEN CR 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 [see Drug Interactions (7.1)]. Downward dose adjustment of AMBIEN CR and concomitant CNS depressants should be considered [see Dosage and Administration (2.3)]. The use of AMBIEN CR with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended.The risk of next-day psychomotor impairment is increased if AMBIEN CR is taken with less than full night of sleep remaining (7 to hours); if higher than the recommended dose is taken; if coadministered with other CNS depressants or alcohol; or coadministered with other drugs that increase the blood levels of zolpidem. Patients should be warned against driving and other activities requiring complete mental alertness if AMBIEN CR is taken in these circumstances [see Dosage and Administration (2), Clinical Studies (14.2)].Vehicle drivers and machine operators should be warned that, as with other hypnotics, there may be possible risk of adverse reactions including drowsiness, prolonged reaction time, dizziness, sleepiness, blurred/double vision, reduced alertness, and impaired driving the morning after therapy. In order to minimize this risk full night of sleep (7-8 hours) is recommended.Because AMBIEN CR can cause drowsiness and decreased level of consciousness, patients, particularly the elderly, are at higher risk of falls.. 5.3 Need to Evaluate for Comorbid Diagnoses. Because sleep disturbances may be the presenting manifestation of physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after careful evaluation of the patient. The failure of insomnia to remit after to 10 days of treatment may indicate the presence of 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. 5.4 Severe Anaphylactic and Anaphylactoid Reactions. 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. 5.5 Abnormal Thinking and Behavioral Changes. Abnormal thinking and behavior changes have been reported in patients treated with sedative/hypnotics, including AMBIEN CR. Some of these changes included decreased inhibition (e.g., aggressiveness and extroversion that seemed out of character), bizarre behavior, agitation and depersonalization. Visual and auditory hallucinations have been reported. In controlled trials, <1% of adults with insomnia reported hallucinations. In clinical trial, 7% of pediatric patients treated with Ambien 0.25 mg/kg taken at bedtime reported hallucinations versus 0% treated with placebo [see Use in Specific Populations (8.4)]. It can rarely be determined with certainty whether particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or 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.. 5.6 Use in Patients with Depression. In primarily depressed patients treated with sedative-hypnotics, worsening of depression, and suicidal thoughts and actions (including completed suicides), have been reported. 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 lowest number of tablets that is feasible should be prescribed for the patient at any one time. 5.7 Respiratory Depression. Although studies with 10 mg zolpidem tartrate did not reveal respiratory depressant effects at hypnotic doses in healthy subjects or in patients with mild to moderate chronic obstructive pulmonary disease (COPD), reduction in the Total Arousal Index, together with 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 zolpidem 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. Postmarketing reports of respiratory insufficiency in patients receiving 10 mg of zolpidem tartrate, most of whom had pre-existing respiratory impairment, have been reported. The risk of respiratory depression should be considered prior to prescribing AMBIEN CR in patients with respiratory impairment including sleep apnea and myasthenia gravis.. 5.8 Precipitation of Hepatic Encephalopathy. Drugs affecting GABA receptors, such as zolpidem tartrate, have been associated with precipitation of hepatic encephalopathy in patients with hepatic insufficiency. In addition, patients with hepatic insufficiency do not clear zolpidem tartrate as rapidly as patients with normal hepatic function. Avoid AMBIEN CR use in patients with severe hepatic impairment as it may contribute to encephalopathy [see Dosage and Administration (2.2), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].. 5.9 Withdrawal Effects. There have been reports of withdrawal signs and symptoms following the rapid dose decrease or abrupt discontinuation of zolpidem. Monitor patients for tolerance, abuse, and dependence [see Drug Abuse and Dependence (9.2, 9.3)].