Zolpidem tartrateextended-release

Overdose

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.

General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. 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 a poison control center for up-to­date information on the management of hypnotic drug product overdosage.

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.

General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Zolpidem's 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 a poison control center for up-todate information on the management of hypnotic drug product overdosage.

Contraindications

Known hypersensitivity to zolpidem tartrate.

Zolpidem Tartrateextended-Release is contraindicated in patients with known hypersensitivity to zolpidem. Observed reactions include anaphylaxis and angioedema.

Pharmaceutical form

Undesirable effects

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

• Serious anaphylactic and anaphylactoid reactions.
• Abnormal thinking, behavior changes, and complex behaviors.
• Withdrawal effects.
• CNS-depressant effects.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating incidence rates.

Approximately 4% of 1,701 patients who received zolpidem tartrate at all doses (1.25 to 90 mg) in U.S. premarketing clinical trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from U.S. trials were daytime drowsiness (0.5%), dizziness (0.4%), headache (0.5%), nausea (0.6%), and vomiting (0.5%).

Approximately 4% of 1,959 patients who received zolpidem at all doses (1 to 50 mg) in similar foreign trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from these trials were daytime drowsiness (1.1%), dizziness/vertigo (0.8%), amnesia (0.5%), nausea (0.5%), headache (0.4%), and falls (0.4%).

Data from a clinical study in which selective serotonin reuptake inhibitor (SSRI)-treated patients were given zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n=95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction; one patient treated with placebo (n=97) was discontinued after an attempted suicide.

During short-term treatment (up to 10 nights) with zolpidem tartrate at doses up to 10 mg, the most commonly observed adverse reactions associated with the use of zolpidem and seen at statistically significant differences from placebo-treated patients were drowsiness (reported by 2% of zolpidem patients), dizziness (1%), and diarrhea (1%). During longer-term treatment (28 to 35 nights) with zolpidem tartrate at doses up to 10 mg, the most commonly observed adverse reactions associated with the use of zolpidem and seen at statistically significant differences from placebo-treated patients were dizziness (5%) and drugged feelings (3%).

The 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 zolpidem tartrate and at a greater incidence than placebo in U.S. placebo-controlled trials. Events reported by investigators were classified utilizing a modified World Health Organization (WHO) dictionary of preferred terms for the purpose of establishing event frequencies. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice, in which patient characteristics and other factors differ from those that prevailed in these clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigators involving related drug products and uses, since each group of drug trials is conducted under a different set of conditions. However, the cited figures provide the physician with a basis for estimating the relative contribution of drug and nondrug factors to the incidence of side effects in the population studied.

The following table was derived from results of 11 placebo-controlled short-term U.S. efficacy trials involving zolpidem in doses ranging from 1.25 to 20 mg. The table is limited to data from doses up to and including 10 mg, the highest dose recommended for use.

Incidence of Treatment-Emergent Adverse Reactions in Placebo-Controlled Clinical Trials Lasting up to 10 Nights (Percentage of patients reporting)

The following table was derived from results of three placebo-controlled long-term efficacy trials involving zolpidem tartrate. These trials involved patients with chronic insomnia who were treated for 28 to 35 nights with zolpidem tartrate at doses of 5, 10, or 15 mg. The table is limited to data from doses up to and including 10 mg, the highest dose recommended for use. The table includes only adverse reactions occurring at an incidence of at least 1% for zolpidem tartrate patients.

Incidence of Treatment-Emergent Adverse Reactions in Placebo-Controlled Clinical Trials Lasting up to 35 Nights (Percentage of patients reporting)

There is evidence from dose comparison trials suggesting a dose relationship for many of the adverse reactions associated with zolpidem tartrate use, particularly for certain CNS and gastrointestinal adverse reactions.

The effect of chronic daily administrations of Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) on oral tissue has not been evaluated. In pharmacokinetic studies conducted with Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) in healthy subjects, an oral soft tissue exam was performed and no signs of oral irritation were noted following administration of single doses of Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray).

Zolpidem tartrate was administered to 3,660 subjects in clinical trials throughout the United States, Canada, and Europe. Treatment-emergent adverse event associated with clinical trial participation were recorded by clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing treatment-emergent adverse events, similar types of untoward events were grouped into a smaller number of standardized event categories and classified utilizing a modified WHO dictionary of preferred terms.

The frequencies presented, therefore, represent the proportions of the 3,660 individuals exposed to zolpidem tartrate, at all doses, who experienced an event of the type cited on at least one occasion while receiving zolpidem tartrate. 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 a drug cause was remote. It is important to emphasize that, although the events reported did occur during treatment with zolpidem tartrate, 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: Infrequent: increased sweating, pallor, postural hypotension, syncope. Rare: abnormal accommodation, altered saliva, flushing, glaucoma, hypotension, impotence, increased saliva, tenesmus.

Body as a whole: Frequent: asthenia. Infrequent: edema, falling, fatigue, 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, euphoria, headache, insomnia, vertigo. Infrequent: agitation, anxiety, 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: dyspepsia, hiccup, nausea. Infrequent: anorexia, constipation, dysphagia, flatulence, gastroenteritis, vomiting. 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: Frequent: arthralgia, myalgia. Infrequent: arthritis. Rare: arthrosis, muscle weakness, sciatica, tendonitis.

Reproductive system: Infrequent: menstrual disorder, vaginitis. Rare: breast fibroadenosis, breast neoplasm, breast pain.

Respiratory system: Frequent: upper respiratory infection. Infrequent: bronchitis, coughing, dyspnea, rhinitis. Rare: bronchospasm, 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.

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

• CNS-depressant effects and next-day impairment
• Serious anaphylactic and anaphylactoid reactions
• Abnormal thinking and behavior changes, and complex behaviors
• Withdrawal effects

In 3-week clinical trials in adults and elderly patients ( > 65 years), 3.5% (7/201) patients receiving Zolpidem Tartrateextended-Release 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 Zolpidem Tartrateextended-Release was somnolence (1%).

In a 6-month study in adult patients (18-64 years of age), 8.5% (57/669) of patients receiving Zolpidem Tartrateextended-Release 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 Zolpidem Tartrateextended-Release included anxiety (anxiety, restlessness or agitation) reported in 1.5% (10/669) of patients as compared to 0.3% (1/349) of patients on placebo, and depression (depression, major depression or depressed mood) reported in 1.5% (10/669) of patients as compared to 0.3% (1/349) of patients on placebo.

Data from a clinical study in which selective serotonin reuptake inhibitor-(SSRI-) treated patients were given zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n=95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction; one patient treated with placebo (n =97) was discontinued after an attempted suicide.

During treatment with Zolpidem Tartrateextended-Release 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 Zolpidem Tartrateextended-Release were headache, next-day somnolence, and dizziness.

In the 6-month trial evaluating Zolpidem Tartrateextended-Release 12.5 mg, the adverse reaction profile was consistent with that reported in short-term trials, except for a higher incidence of anxiety (6.3% for Zolpidem Tartrateextended-Release versus 2.6% for placebo).

The following tables enumerate treatment-emergent adverse reaction frequencies that were observed at an incidence equal to 1% or greater among patients with insomnia who received Zolpidem Tartrateextended-Release in placebo-controlled trials. Events reported by investigators were classified utilizing the MedDRA dictionary for the purpose of establishing event frequencies. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice, in which patient characteristics and other factors differ from those that prevailed in these clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigators involving related drug products and uses, since each group of drug trials is conducted under a different set of conditions. However, the cited figures provide the physician with a basis for estimating the relative contribution of drug and nondrug factors to the incidence of side effects in the population studied.

The following tables were derived from results of two placebo-controlled efficacy trials involving Zolpidem Tartrateextended-Release. These trials involved patients with primary insomnia who were treated for 3 weeks with Zolpidem Tartrateextended-Release 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 Zolpidem Tartrateextended-Release patients and with an incidence greater than that seen in the placebo patients.

Table 1: Incidences of Treatment-Emergent Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial in Adults (percentage of patients reporting)

Table 2: Incidences of Treatment-Emergent Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial in Elderly (percentage of patients reporting)

There is evidence from dose comparison trials suggesting a dose relationship for many of the adverse reactions associated with zolpidem use, particularly for certain CNS and gastrointestinal adverse events.

Other treatment-emergent adverse reactions associated with participation in Zolpidem Tartrateextended-Release 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.

Immediate-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 a meaningful estimate of the proportion of individuals experiencing treatment-emergent adverse events, similar types of untoward events were grouped into a smaller number of standardized event categories and classified utilizing a 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 a 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 a 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.

The following adverse reactions have been identified during post-approval use of Zolpidem Tartrateextended-Release. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Liver and biliary system: acute hepatocellular, cholestatic or mixed liver injury with or without jaundice (i.e., bilirubin > 2x ULN, alkaline phosphatase ≥ 2x ULN, transaminase ≥ 5x ULN).

Therapeutic indications

Zolpidem Tartrateextended-Release (zolpidem tartrate) Oral Spray is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation. Zolpidem tartrate has been shown to decrease sleep latency for up to 35 days in controlled clinical studies. The clinical trials performed in support of efficacy were 4-5 weeks in duration with the final formal assessments of sleep latency performed at the end of treatment.

Zolpidem Tartrateextended-Release (zolpidem tartrate extended-release tablets) is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance (as measured by wake time after sleep onset).

The clinical trials performed in support of efficacy were up to 3 weeks (using polysomnography measurement up to 2 weeks in both adult and elderly patients) and 24 weeks (using patient-reported assessment in adult patients only) in duration.

Pharmacokinetic properties

Zolpidem Tartrateextended-Release (zolpidem tartrate) Oral Spray is bioequivalent to Ambien® tablets (Sanofi-Aventis). The pharmacokinetic profile of Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) is characterized by rapid absorption from the oral mucosa and gastrointestinal tract, and a short t½ in healthy subjects.

In a single-dose crossover study in 10 healthy young (18-40 years of age) male subjects administered 2.5, 5, and 10 mg Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) , the results demonstrated a linear relationship to dose for mean Cmax and AUC0-∞ over the range of doses administered in the study.

In a single-dose crossover study in 43 healthy young (18-45 years of age) subjects administered 5 and 10 mg Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) , the means for Cmax were 114 (range: 19 to 197) and 210 ng/mL (range: 77 to 401), respectively, occurring at a mean Tmax of approximately 0.9 hours for both. The mean zolpidem t½ was 2.7 (range: 1.7 to 5.0) and 3.0 hours (range: 1.7 to 8.4), for 5 and 10 mg Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) , respectively. In the same study, the means for Cmax were 123 (range: 53 to 221) and 219 ng/mL (range: 101 to 446) for 5 and 10 mg Ambien® tablets, respectively, occurring at a mean Tmax of 0.9 and 1.0 hours, respectively. The mean zolpidem t½ was 2.8 (range: 1.5 to 6.0) and 3.1 hours (range: 1.1 to 8.6) for the 5 and 10 mg Ambien® tablets, respectively.

Zolpidem is converted to inactive metabolites that are eliminated primarily by renal excretion. Total protein binding for zolpidem was found to be 92.5 ± 0.1% and remained constant, independent of concentration between 40 and 790 ng/mL. Zolpidem did not accumulate in young adults following nightly dosing with 20 mg zolpidem tartrate for 2 weeks.

A food-effect crossover study in 14 healthy young (18-45 years of age) male subjects compared the pharmacokinetics of Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) 10 mg when administered while fasting at least 8 hours or 5 minutes after eating a standard high-fat meal. Results demonstrated that with food, mean AUC0-∞ and Cmax were decreased by 27% and 58%, respectively, while mean Tmax was prolonged by 225% (from 0.8 to 2.6 hours). These results suggest that, for faster sleep onset, as with all zolpidem products, Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) should not be administered with or immediately after a meal.

Elderly: In the elderly, the dose for zolpidem tartrate should be 5 mg. This recommendation is based on several studies in which the mean Cmax, t½, and AUC were significantly increased when compared to results in young adults administered zolpidem tartrate. In a pharmacokinetic study of 24 elderly ( ≥ 65 years of age) subjects administered 5 mg Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) , the means for Cmax and AUC were 134 ng/mL and 493 ng*hr/mL respectively, following administration of a single 5 mg oral dose of Zolpidem Tartrateextended-Release. Zolpidem tartrate did not accumulate in elderly subjects following nightly oral dosing of 10 mg for 1 week.

Hepatic Impairment: The pharmacokinetics of zolpidem in eight patients with chronic hepatic insufficiency were compared to results in healthy subjects. Following a 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 ng*hr/mL) higher, respectively, in hepatically compromised patients. Tmax did not change. The mean t½ in cirrhotic patients of 9.9 hours (range: 4.1 to 25.8 hours) was greater than that observed in normal subjects of 2.2 hours (range: 1.6 to 2.4 hours). Dosing should be modified accordingly in patients with hepatic insufficiency.

Renal Impairment: The pharmacokinetics of zolpidem were studied in 11 patients with endstage renal failure (mean ClCr = 6.5 ± 1.5 mL/min) undergoing hemodialysis three times a 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, t½, and AUC between the first and last day of drug administration when baseline concentration adjustments were made. On Day 1, Cmax was 172 ± 29 ng/mL (range: 46 to 344 ng/mL). After repeated dosing for 14 or 21 days, Cmax was 203 ± 32 ng/mL (range: 28 to 316 ng/mL). On Day 1, Tmax was 1.7 ± 0.3 hours (range: 0.5 to 3.0 hours); after repeated dosing Tmax was 0.8 ± 0.2 hour (range: 0.5 to 2.0 hours). This variation is accounted for by noting that last-day serum sampling began 10 hours after the previous dose, rather than after 24 hours. This resulted in residual drug concentration and a shorter period to reach maximal serum concentration. On Day 1, t½ was 2.4 ± 0.4 hours (range: 0.4 to 5.1 hours). After repeated dosing, t½ was 2.5 ± 0.4 hours (range: 0.7 to 4.2 hours). AUC was 796 ± 159 ng*hr/mL after the first dose and 818 ± 170 ng*hr/mL after repeated dosing. Zolpidem was not hemodialyzable. No accumulation of unchanged drug appeared after 14 or 21 days. Zolpidem pharmacokinetics were not significantly different in renally impaired patients.

No dosage adjustment is necessary in patients with compromised renal function. However, as a general precaution, these patients should be closely monitored.

Women clear zolpidem tartrate from the body at a lower rate than men. Cmax and AUC parameters of zolpidem from Zolpidem Tartrateextended-Release were, respectively, approximately 50% and 75% higher at the same dose in adult female subjects compared to adult male subjects. Between 6 and 12 hours after dosing, zolpidem concentrations were 2-to 3 fold higher in adult female compared to adult male subjects. Given the higher blood levels of zolpidem tartrate in women compared to men at a 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 Zolpidem Tartrateextended-Release in geriatric patients is 6.25 mg regardless of gender.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavioral 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.

Rare cases of angioedema involving the tongue, glottis, or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including zolpidem. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the throat, glottis, or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with zolpidem should not be rechallenged with the drug.

A variety of abnormal thinking and behavioral changes have been reported to occur in association with the use of sedative-hypnotics. Some of these changes may be characterized by decreased inhibition (e.g., aggressiveness and extroversion that seemed out of character), similar to effects produced by alcohol and other CNS depressants. Visual and auditory hallucinations have been reported as well as behavioral changes such as bizarre behavior, agitation, and depersonalization. In controlled trials, < 1% of adults with insomnia who received zolpidem reported hallucinations. In a clinical trial, 7.4% of pediatric patients with insomnia associated with attention-deficit/hyperactivity disorder (ADHD), who received zolpidem, reported hallucinations.

Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported with sedative-hypnotics, including zolpidem. These events can occur in sedative-hypnotic-naive as well as in sedative­hypnotic-experienced persons. Although behaviors such as “sleep-driving” may occur with Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) alone at therapeutic doses, the use of alcohol and other CNS depressants with zolpidem tartrate appears to increase the risk of such behaviors, as does the use of zolpidem at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) should be strongly considered for patients who report a “sleep-driving” episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with “sleep-driving”, patients usually do not remember these events. Amnesia, anxiety, and other neuropsychiatric symptoms may occur unpredictably.

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

It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

Following the rapid dose decrease or abrupt discontinuation of sedative-hypnotics, there have been reports of signs and symptoms similar to those associated with withdrawal from other CNS-depressant drugs.

Zolpidem tartrate, like other sedative-hypnotic drugs, has CNS-depressant effects. Due to the rapid onset of action, Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) should only be administered immediately prior to going to bed. Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness or motor coordination such as operating machinery or driving a motor vehicle after ingesting the drug, including potential impairment of the performance of such activities that may occur the day following administration of Zolpidem Tartrateextended-Release. Zolpidem tartrate showed additive effects when combined with alcohol and should not be taken with alcohol. Patients should also be cautioned about possible combined effects with other CNS-depressant drugs. Dosage adjustments may be necessary when Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) is administered with such agents because of the potentially additive effects.

Impaired motor and/or cognitive performance after repeated exposure or unusual sensitivity to sedative-hypnotic drugs is a concern in the treatment of elderly and/or debilitated patients. Therefore, the recommended Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) dosage is 5 mg in such patients to decrease the possibility of side effects. These patients should be closely monitored.

Clinical experience with zolpidem tartrate in patients with concomitant systemic illness is limited. Caution is advisable in using Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

Although studies did not reveal respiratory depressant effects at hypnotic doses of zolpidem in normal subjects or in patients with mild to moderate chronic obstructive pulmonary disease (COPD), a reduction in the Total Arousal Index together with a reduction in lowest oxygen saturation and increase in the times of oxygen desaturation below 80% and 90% was observed in patients with mild-to-moderate sleep apnea when treated with zolpidem tartrate (10 mg) when compared to placebo. Since sedative-hypnotics have the capacity to depress respiratory drive, precautions should be taken if Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) is prescribed to patients with compromised respiratory function. Post-marketing reports of respiratory insufficiency, most of which involved patients with pre-existing respiratory impairment, have been received. Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) should be used with caution in patients with sleep apnea syndrome or myasthenia gravis.

Data in end-stage renal failure patients repeatedly treated with zolpidem tartrate did not demonstrate drug accumulation or alterations in pharmacokinetic parameters. No dosage adjustment in renally impaired patients is required; however, these patients should be closely monitored.

A study in subjects with hepatic impairment did reveal prolonged elimination in this group; therefore, treatment should be initiated with 5 mg in patients with hepatic compromise, and they should be closely monitored.

As with other sedative-hypnotic drugs, Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) should be administered with caution to patients exhibiting signs or symptoms of depression. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional over-dosage is more common in this group of patients; therefore, the least amount of drug that is feasible should be prescribed for the patient at any one time.

Safety and effectiveness of zolpidem have not been established in pediatric patients. In an 8-week study in pediatric patients (6-17 years of age) with insomnia associated with ADHD, zolpidem did not decrease sleep latency compared to placebo. Hallucinations were reported in 7.4% of the pediatric patients who received zolpidem tartrate; none of the pediatric patients who received placebo reported hallucinations.

Prescribers or other healthcare professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with sedative-hypnotics, should counsel them in its appropriate use, and should instruct them to read the accompanying Medication Guide and Patient Instructions for Use.

Inform 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.

There have been reports of people getting out of bed after taking a sedative-hypnotic and driving their cars while not fully awake, often with no memory of the event. If a patient experiences such an episode, it should be reported to his or her doctor immediately, since “sleep-driving” can be dangerous. This behavior is more likely to occur when Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) is taken with alcohol or other central nervous system depressants. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with “sleepdriving”, patients usually do not remember these events.

In addition patients should be advised to report all concomitant medications to the prescriber. Patients should be instructed to report events such as “sleep-driving” and other complex behaviors immediately to the prescriber.

See the DOSAGE AND ADMINISTRATION section. Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) is packaged in a child-resistant container. Patients should be referred to the Patient Instructions for Use (following the Medication Guide) for detailed instructions on how to use Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray). Patients should be counseled to take Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) right before they get into bed and only when they are able to stay in bed a full night (7-8 hours) before being active again. Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) should not be taken with or immediately after a meal. Advise patients NOT to take Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) when drinking alcohol.

Zolpidem was administered to mice and rats for 2 years at dietary dosages of 4, 18, and 80 mg base/kg. In mice, these doses are ≈ 2.5, 10, and 50 times the maximum recommended human dose (MRHD) of 10 mg/day (8 mg zolpidem base) on mg/m² basis. In rats, these doses are ≈ 5, 20, and 100 times the MRHD on a mg/m² basis. No evidence of carcinogenic potential was observed in mice. In rats, renal tumors (lipoma, liposarcoma) were seen at the mid- and high doses.

Zolpidem was negative in in vitro (bacterial reverse mutation, mouse lymphoma, and chromosomal aberration) and in vivo (mouse micronucleus) genetic toxicology assays.

Oral administration of zolpidem (doses of 4, 20, and 100 mg base/kg or ≈5, 24, and 120 times the MRHD on a mg/m² basis) to rats prior to and during mating, and continuing in females through postpartum day 25, resulted in irregular estrus cycles and prolonged precoital intervals. The no-effect dose for these findings is ≈24 times the MRHD on a mg/m² basis. There was no impairment of fertility at any dose tested.

There are no adequate and well-controlled studies of Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) in pregnant women. Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Studies to assess the effects on children whose mothers took zolpidem during pregnancy have not been conducted. There is a published case report documenting the presence of zolpidem in human umbilical cord blood. Children born to mothers taking sedative-hypnotic drugs may be at some risk for withdrawal symptoms from the drug during the postnatal period. In addition, neonatal flaccidity has been reported in infants born of mothers who received sedative-hypnotic drugs during pregnancy.

Administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring development at doses greater than the maximum recommended human dose (MRHD) of 10 mg/day (8 mg/day zolpidem base); however, teratogenicity was not observed.

When zolpidem was administered at oral doses of 4, 20, and 100 mg base/kg ( 5, 24, and 120 times the MRHD on a mg/m² basis) to pregnant rats during the period of organogenesis, dose-related decreases in fetal skull ossification were observed at all but the low dose, which is 5 times the MRHD on a mg/m² basis. In rabbits treated during organogenesis with zolpidem at oral doses of 1, 4, and 16 mg base/kg (≈ 2.5, 10, and 40 times the MRHD on a mg/m² basis), increased embryo-fetal death and incomplete fetal skeletal ossification were seen at the highest dose tested. The no-effect dose for embryo-fetal toxicity in rabbits is ≈ 10 times the MRHD on a mg/m² basis. Administration of zolpidem to rats at oral doses of 4, 20, and 100 mg base/kg (≈ 5, 24, and 120 times the MRHD on a mg/m² basis) during the latter part of pregnancy and throughout lactation produced decreased offspring growth and survival at all but the low dose, which is ≈ 5 times the MRHD on a mg/m² basis.

Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) has no established use in labor and delivery.

Zolpidem is excreted into human milk. Studies in lactating mothers indicate that the t½ of zolpidem is similar to that in non-lactating women (2.6 ± 0.3hours). Between 0.004% and 0.019% of the total administered dose is excreted into milk. The effect of zolpidem on the nursing infant is not known.

Safety and effectiveness of zolpidem have not been established in pediatric patients.

In an 8-week controlled study, 201 pediatric patients (6-17 years of age) with insomnia associated with ADHD (90% of the patients were using psychoanaleptics) were treated with an oral solution of zolpidem (n=136) or placebo (n=65). Zolpidem did not significantly decrease latency to persistent sleep, compared to placebo, as measured by polysomnography after 4 weeks of treatment. Psychiatric and nervous system disorders comprised the most frequent ( > 5%) treatment emergent adverse reactions observed with zolpidem tartrate versus placebo and included dizziness (23.5% vs 1.5%), headache (12.5% vs 9.2%), and hallucinations (7.4% vs 0%). Ten patients on zolpidem (7.4%) discontinued treatment due to an adverse reaction.

A total of 154 patients in U.S. controlled clinical trials and 897 patients in non-U.S. clinical trials who received zolpidem were ≥ 60 years of age. In a pool of U.S. patients receiving zolpidem at doses of ≥ 10 mg or placebo, there were three adverse reactions occurring at an incidence of at least 3% for zolpidem tartrate and for which the zolpidem incidence was at least twice the placebo incidence (i.e., they could be considered drug related).

A total of 30/1,959 (1.5%) non-U.S. patients receiving zolpidem reported falls, including 28/30 (93%) who were ≥ 70 years of age. Of these 28 patients, 23 (82%) were receiving zolpidem doses > 10 mg. A total of 24/1,959 (1.2%) non-U.S. patients receiving zolpidem reported confusion, including 18/24 (75%) who were ≥ 70 years of age. Of these 18 patients, 14 (78%) were receiving zolpidem doses > 10 mg.

The dose of Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) in elderly patients is 5 mg to minimize the adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative-hypnotic drugs.

Included as part of the PRECAUTIONS section.

Zolpidem Tartrateextended-Release is a central nervous system (CNS) depressant and can impair daytime function in some patients even when used as prescribed. Prescribers should monitor for excess depressant effects, but impairment can occur in the absence of subjective symptoms, and may not be reliably detected by ordinary clinical exam (i.e. less than formal psychomotor testing). While pharmacodynamic tolerance or adaptation to some adverse depressant effects of Zolpidem Tartrateextended-Release may develop, patients using Zolpidem Tartrateextended-Release should be cautioned against driving or engaging in other hazardous activities or activities requiring complete mental alertness the day after use.

Additive effects occur with concomitant use of other CNS depressants (e.g. benzodiazepines, opioids, tricyclic antidepressants, alcohol), including daytime use. Downward dose adjustment of Zolpidem Tartrateextended-Release and concomitant CNS depressants should be considered.

The use of Zolpidem Tartrateextended-Release 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 Zolpidem Tartrateextended-Release is taken with less than a full night of sleep remaining (7 to 8 hours); if higher than the recommended dose is taken; if co-administered with other CNS depressants or alcohol; or co-administered with other drugs that increase the blood levels of zolpidem. Patients should be warned against driving and other activities requiring complete mental alertness if Zolpidem Tartrateextended-Release is taken in these circumstances.

Vehicle drivers and machine operators should be warned that, as with other hypnotics, there may be a 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 a full night of sleep (7-8 hours) is recommended.

Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative/hypnotic drugs, including zolpidem.

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.

Abnormal thinking and behavior changes have been reported in patients treated with sedative/hypnotics, including Zolpidem Tartrateextended-Release. 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 a clinical trial, 7% of pediatric patients treated with AMBIEN 0.25 mg/kg taken at bedtime reported hallucinations versus 0% treated with placebo.

Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported in sedative-hypnotic-naive as well as in sedative-hypnotic-experienced persons. Although behaviors such as “sleep-driving” have occurred with Zolpidem Tartrateextended-Release alone at therapeutic doses, the co-administration of alcohol and other CNS depressants increases the risk of such behaviors, as does the use of Zolpidem Tartrateextended-Release at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of Zolpidem Tartrateextended-Release should be strongly considered for patients who report a “sleep-driving” episode.

Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with “sleep-driving”, patients usually do not remember these events. Amnesia, anxiety and other neuro-psychiatric symptoms may also occur.

It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

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.

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), a reduction in the Total Arousal Index, together with a reduction in lowest oxygen saturation and increase in the times of oxygen desaturation below 80% and 90%, was observed in patients with mild-to-moderate sleep apnea when treated with zolpidem compared to placebo. Since sedative-hypnotics have the capacity to depress respiratory drive, precautions should be taken if Zolpidem Tartrateextended-Release is prescribed to patients with compromised respiratory function. Post-marketing 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 Zolpidem Tartrateextended-Release in patients with respiratory impairment including sleep apnea and myasthenia gravis.

GABA agonists 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 Zolpidem Tartrateextended-Release use in patients with severe hepatic impairment as it may contribute to encephalopathy.

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.

Zolpidem can cause drowsiness and a decreased level of consciousness, which may lead to falls and consequently to severe injuries. Severe injuries such as hip fractures and intracranial hemorrhage have been reported.

Advise patients to read the FDA-approved patient labeling (Medication Guide). Inform patients and their families about the benefits and risks of treatment with Zolpidem Tartrateextended-Release. Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with Zolpidem Tartrateextended-Release and with each prescription refill. Review the Zolpidem Tartrateextended-Release Medication Guide with every patient prior to initiation of treatment. Instruct patients or caregivers that AMBIEN CR should be taken only as prescribed.

Tell patients that Zolpidem Tartrateextended-Release 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.

Inform 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.

Instruct patients and their families that sedative hypnotics can cause abnormal thinking and behavior change, including “sleep driving” and other complex behaviors while not being fully awake (preparing and eating food, making phone calls, or having sex). Tell patients to call you immediately if they develop any of these symptoms.

Tell patients to immediately report any suicidal thoughts.

Ask patients about alcohol consumption, medicines they are taking, and drugs they may be taking without a prescription. Advise patients not to use Zolpidem Tartrateextended-Release if they drank alcohol that evening or before bed.

Tell patients not to increase the dose of Zolpidem Tartrateextended-Release on their own, and to inform you if they believe the drug “does not work”.

Patients should be counseled to take Zolpidem Tartrateextended-Release right before they get into bed and only when they are able to stay in bed a full night (7-8 hours) before being active again. Zolpidem Tartrateextended-Release tablets should not be taken with or immediately after a meal. Advise patients NOT to take Zolpidem Tartrateextended-Release if they drank alcohol that evening.

Zolpidem was administered to mice and rats for 2 years at oral doses of 4, 18, and 80 mg base/kg. In mice, these doses are approximately 2, 9, and 40 times the maximum recommended human dose (MRHD) of 12.5 mg/day (10 mg zolpidem base) on mg/m² basis. In rats, these doses are approximately 4, 18, and 80 times the MRHD on a mg/m² basis. No evidence of carcinogenic potential was observed in mice. In rats, renal tumors (lipoma, liposarcoma) were seen at the mid-and high doses.

Zolpidem was negative in in vitro (bacterial reverse mutation, mouse lymphoma, and chromosomal aberration) and in vivo (mouse micronucleus) genetic toxicology assays.

Oral administration of zolpidem (doses of 4, 20, and 100 mg base/kg/day) to rats prior to and during mating, and continuing in females through postpartum day 25, resulted in irregular estrus cycles and prolonged precoital intervals at the highest dose tested. The no-effect dose for these findings is approximately 20 times the MRHD on a mg/m² basis. There was no impairment of fertility at any dose tested.

There are no adequate and well-controlled studies of Zolpidem Tartrateextended-Release in pregnant women. Studies in children to assess the effects of prenatal exposure to zolpidem have not been conducted; however, cases of severe neonatal respiratory depression have been reported when zolpidem was used at the end of pregnancy, especially when taken with other CNS depressants. Children born to mothers taking sedative-hypnotic drugs may be at risk for withdrawal symptoms during the postnatal period. Neonatal flaccidity has also been reported in infants born to mothers who received sedative-hypnotic drugs during pregnancy. Zolpidem Tartrateextended-Release should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring development at doses greater than the Zolpidem Tartrateextended-Release maximum recommended human dose (MRHD) of 12.5 mg/day (approximately 10 mg/day zolpidem base); however, teratogenicity was not observed.

When zolpidem was administered at oral doses of 4, 20, and 100 mg base/kg/day to pregnant rats during the period of organogenesis, dose-related decreases in fetal skull ossification occurred at all but the lowest dose, which is approximately 4 times the MRHD on a mg/m² basis. In rabbits treated during organogenesis with zolpidem at oral doses of 1, 4, and 16 mg base/kg/day, increased embryo-fetal death and incomplete fetal skeletal ossification occurred at the highest dose. The no-effect dose for embryo-fetal toxicity in rabbits is approximately 8 times the MRHD on a mg/m² basis. Administration of zolpidem to rats at oral doses of 4, 20, and 100 mg base/kg/day during the latter part of pregnancy and throughout lactation produced decreased offspring growth and survival at all but the lowest dose, which is approximately 4 times the MRHD on a mg/m² basis.

Zolpidem Tartrateextended-Release has no established use in labor and delivery.

Zolpidem is excreted in human milk. Caution should be exercised when Zolpidem Tartrateextended-Release is administered to a nursing woman.

Zolpidem Tartrateextended-Release 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. Ten patients on zolpidem (7.4%) discontinued treatment due to an adverse reaction.

FDA has not required pediatric studies of Zolpidem Tartrateextended-Release in the pediatric population based on these efficacy and safety findings.

A total of 99 elderly ( ≥ 65 years of age) received daily doses of 6.25 mg Zolpidem Tartrateextended-Release in a 3week placebo-controlled study. The adverse reaction profile of Zolpidem Tartrateextended-Release 6.25 mg in this population was similar to that of Zolpidem Tartrateextended-Release 12.5 mg in younger adults ( ≤ 64 years of age). Dizziness was reported in 8% of Zolpidem Tartrateextended-Release-treated patients compared with 3% of those treated with placebo.

The dose of Zolpidem Tartrateextended-Release 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.

Women clear zolpidem tartrate from the body at a lower rate than men. Cmax and AUC parameters of zolpidem from Zolpidem Tartrateextended-Release were, respectively, approximately 50% and 75% higher at the same dose in adult female subjects compared to adult male subjects. Between 6 and 12 hours after dosing, zolpidem concentrations were 2-to 3 fold higher in adult female compared to adult male subjects. Given the higher blood levels of zolpidem tartrate in women compared to men at a 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 Zolpidem Tartrateextended-Release in geriatric patients is 6.25 mg regardless of gender.

The recommended dose of Zolpidem Tartrateextended-Release in patients with mild to moderate hepatic impairment is 6.25 mg once daily immediately before bedtime. Avoid Zolpidem Tartrateextended-Release use in patients with severe hepatic impairment as it may contribute to encephalopathy.

Dosage (Posology) and method of administration

The dose of Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) should be individualized.

The recommended dose for adults is 10 mg once daily immediately before bedtime. The total Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) dose should not exceed 10 mg per day.

Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate. Patients with hepatic insufficiency do not clear the drug as rapidly as normal subjects. The recommended dose of Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) in both of these patient populations is 5 mg once daily immediately before bedtime.

Dosage adjustment may be necessary when Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) is combined with other CNS-depressant drugs because of the potentially additive effects.

Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) is packaged in a child-resistant container. For detailed instructions on how to use Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) , refer to the Patient Instructions for Use (following the Medication Guide). Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) must be primed before it is used for the first time. To prime, patients should be told to point the black spray opening away from their face and other people and spray 5 times. For administration, the child-resistant container should be held upright with the black spray opening pointed directly into the mouth. The patient should fully press down on the pump to make sure a full dose (5 mg) of Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) is sprayed directly into the mouth over the tongue. If a 10 mg dose is prescribed, a second spray should be administered.

If the patient does not use Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) for at least 14 days, it must be primed again with 1 spray. The patient should be referred to the Patient Instructions for Use included at the end of the Medication Guide.

The effect of Zolpidem Tartrateextended-Release (zolpidem tartrate oral spray) may be slowed by ingestion with or immediately after a meal.

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. The total dose of Zolpidem Tartrateextended-Release should not exceed 12.5 mg once daily immediately before bedtime. Zolpidem Tartrateextended-Release should be taken as a 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.

Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate. The recommended dose of Zolpidem Tartrateextended-Release in these patients is 6.25 mg once daily immediately before bedtime.

Patients with mild to moderate hepatic impairment do not clear the drug as rapidly as normal subjects. The recommended dose of Zolpidem Tartrateextended-Release in these patients is 6.25 mg once daily immediately before bedtime. Avoid Zolpidem Tartrateextended-Release use in patients with severe hepatic impairment as it may contribute to encephalopathy.

Dosage adjustment may be necessary when Zolpidem Tartrateextended-Release is combined with other CNS depressant drugs because of the potentially additive effects.

Zolpidem Tartrateextended-Release extended-release tablets should be swallowed whole, and not be divided, crushed, or chewed. The effect of Zolpidem Tartrateextended-Release may be slowed by ingestion with or immediately after a meal.