Zolpidem Tartrate (zolpidem tartrate 6.25 mg) Dailymed

• 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. Instruct patients on correct use. ( 5.2)
• Need to Evaluate for Comorbid Diagnoses: Reevaluate if insomnia persists after 7 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 Zolpidem Tartrate Extended-Release Tablets 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 Zolpidem Tartrate Extended-Release Tablets. Patients can be seriously injured or injure others during complex sleep behaviors. Such injuries may result in a 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 Zolpidem Tartrate Extended-Release Tablets 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 Zolpidem Tartrate Extended-Release Tablets immediately if a patient experiences a complex sleep behavior [see Contraindications (4)] .

5.2 CNS-Depressant Effects and Next-Day Impairment

Zolpidem Tartrate Extended-Release Tablets are a 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 Tartrate Extended-Release Tablets may develop, patients using Zolpidem Tartrate Extended-Release Tablets 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 Zolpidem Tartrate Extended-Release Tablets and concomitant CNS depressants should be considered [see Dosage and Administration (2.3)] .

The use of Zolpidem Tartrate Extended-Release Tablets 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 Tartrate Extended-Release Tablets are taken with less than a full night of sleep remaining (7 to 8 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 Zolpidem Tartrate Extended-Release Tablets are 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 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 Zolpidem Tartrate Extended-Release Tablets can cause drowsiness and a 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 a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative/hypnotic drugs, including zolpidem.

5.4 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 Zolpidem Tartrate Extended-Release Tablets. 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 zolpidem 0.25 mg/kg taken at bedtime reported hallucinations versus 0% treated with placebo [see Use in Specific Populations (8.4)] . There have been postmarketing reports of delirium with zolpidem use [see Adverse Reactions (6.2)] .

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

5.6 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), 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 Tartrate Extended-Release Tablets are prescribed to patients with compromised respiratory function or concomitant use with opioids or other CNS depressants. 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 Zolpidem Tartrate Extended-Release Tablets in patients with respiratory impairment including sleep apnea and myasthenia gravis or with concomitant opioid use [see Dosage and Administration (2.3), Drug Interactions (7.1)] .

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 Zolpidem Tartrate Extended-Release Tablets 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)] .

6 Adverse 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)]

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 Treatment

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

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

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

Most Commonly Observed Adverse Reactions in Controlled Trials

During treatment with Zolpidem Tartrate Extended-Release Tablets 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 Tartrate Extended-Release Tablets were headache, next-day somnolence, and dizziness.

In the 6-month trial evaluating Zolpidem Tartrate Extended-Release Tablets 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 Tartrate Extended-Release Tablets versus 2.6% for placebo).

Adverse Reactions Observed at an Incidence of ≥1% in Controlled Trials

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 Extended-Release Tablets 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 Tartrate Extended-Release Tablets. These trials involved patients with primary insomnia who were treated for 3 weeks with Zolpidem Tartrate Extended-Release Tablets 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 Tartrate Extended-Release Tablets patients and with an incidence greater than that seen in the placebo patients.

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

Body System Adverse Reaction Reactions reported by at least 1% of patients treated with Zolpidem Tartrate Extended-Release Tablets and at greater frequency than in the placebo group.	Zolpidem Tartrate Extended-Release Tablets 12.5 mg	Placebo
	(N=102)	(N=110)
Infections and infestations
Influenza	3	0
Gastroenteritis	1	0
Labyrinthitis	1	0
Metabolism and nutrition disorders
Appetite disorder	1	0
Psychiatric disorders
Hallucinations Hallucinations included hallucinations NOS as well as visual and hypnagogic hallucinations.	4	0
Disorientation	3	2
Anxiety	2	0
Depression	2	0
Psychomotor retardation	2	0
Binge eating	1	0
Depersonalization	1	0
Disinhibition	1	0
Euphoric mood	1	0
Mood swings	1	0
Stress symptoms	1	0
Nervous system disorders
Headache	19	16
Somnolence	15	2
Dizziness	12	5
Memory disorders Memory disorders include: memory impairment, amnesia, anterograde amnesia.	3	0
Balance disorder	2	0
Disturbance in attention	2	0
Hypoesthesia	2	1
Ataxia	1	0
Paresthesia	1	0
Eye disorders
Visual disturbance	3	0
Eye redness	2	0
Vision blurred	2	1
Altered visual depth perception	1	0
Asthenopia	1	0
Ear and labyrinth disorders
Vertigo	2	0
Tinnitus	1	0
Respiratory, thoracic and mediastinal disorders
Throat irritation	1	0
Gastrointestinal disorders
Nausea	7	4
Constipation	2	0
Abdominal discomfort	1	0
Abdominal tenderness	1	0
Frequent bowel movements	1	0
Gastroesophageal reflux disease	1	0
Vomiting	1	0
Skin and subcutaneous tissue disorders
Rash	1	0
Skin wrinkling	1	0
Urticaria	1	0
Musculoskeletal and connective tissue disorders
Back pain	4	3
Myalgia	4	0
Neck pain	1	0
Reproductive system and breast disorders
Menorrhagia	1	0
General disorders and administration site conditions
Fatigue	3	2
Asthenia	1	0
Chest discomfort	1	0
Investigations
Blood pressure increased	1	0
Body temperature increased	1	0
Injury, poisoning and procedural complications
Contusion	1	0
Social circumstances
Exposure to poisonous plant	1	0

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

Body System Adverse Reaction Reactions reported by at least 1% of patients treated with Zolpidem Tartrate Extended-Release Tablets and at greater frequency than in the placebo group.	Zolpidem Tartrate Extended-Release Tablets 6.25 mg	Placebo
	(N=99)	(N=106)
Infections and infestations
Nasopharyngitis	6	4
Lower respiratory tract infection	1	0
Otitis externa	1	0
Upper respiratory tract infection	1	0
Psychiatric disorders
Anxiety	3	2
Psychomotor retardation	2	0
Apathy	1	0
Depressed mood	1	0
Nervous system disorders
Headache	14	11
Dizziness	8	3
Somnolence	6	5
Burning sensation	1	0
Dizziness postural	1	0
Memory disorders Memory disorders include: memory impairment, amnesia, anterograde amnesia.	1	0
Muscle contractions involuntary	1	0
Paresthesia	1	0
Tremor	1	0
Cardiac disorders
Palpitations	2	0
Respiratory, thoracic and mediastinal disorders
Dry throat	1	0
Gastrointestinal disorders
Flatulence	1	0
Vomiting	1	0
Skin and subcutaneous tissue disorders
Rash	1	0
Urticaria	1	0
Musculoskeletal and connective tissue disorders
Arthralgia	2	0
Muscle cramp	2	1
Neck pain	2	0
Renal and urinary disorders
Dysuria	1	0
Reproductive system and breast disorders
Vulvovaginal dryness	1	0
General disorders and administration site conditions
Influenzalike illness	1	0
Pyrexia	1	0
Injury, poisoning and procedural complications
Neck injury	1	0

Dose Relationship for Adverse Reactions

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 Adverse Reactions Observed during the Premarketing Evaluation ofZolpidem Tartrate Extended-Release Tablets

Other treatment-emergent adverse reactions associated with participation in Zolpidem Tartrate Extended-Release Tablets 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 uled below.

Adverse Events Observed during the Premarketing Evaluation of Immediate-Release Zolpidem Tartrate

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 uled 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, 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Zolpidem Tartrate Extended-Release Tablets. 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 >2 × ULN, alkaline phosphatase ≥2 × ULN, transaminase ≥5 × ULN).

Psychiatric disorders:delirium

• Pregnancy: May cause respiratory depression and sedation in neonates with exposure late in the third trimester. ( 8.1)
• Lactation: A lactating woman may pump and discard breast milk during treatment and for 23 hours after Zolpidem Tartrate Extended-Release Tablets 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 a study of pediatric patients with Attention-Deficit/Hyperactivity Disorder. ( 5.5, 8.4)

8.1 Pregnancy

Risk Summary

Neonates 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 Considerationsand Data] . Published data on the use of zolpidem during pregnancy have not reported a clear association with zolpidem and major birth defects [see Data] . Oral administration of zolpidem to pregnant rats and rabbits did not indicate a 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 a 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 reactions

Zolpidem crosses the placenta and may produce respiratory depression and sedation in neonates. Monitor neonates exposed to Zolpidem Tartrate Extended-Release Tablets during pregnancy and labor for signs of excess sedation, hypotonia, and respiratory depression and manage accordingly.

Data

Human data

Published data from observational studies, birth registries, and case reports on the use of zolpidem during pregnancy do not report a 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 a few weeks after birth once treated.

Zolpidem has been shown to cross the placenta.

Animal data

Oral 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/m ²body surface area, caused delayed fetal development (incomplete fetal skeletal ossification) at maternally toxic (ataxia) doses 20 and 100 times the MRHD based on mg/m ²body 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/m ²body surface area, caused embryo-fetal death and delayed fetal development (incomplete fetal skeletal ossification) at a maternally toxic (decreased body weight gain) dose 30 times the MRHD based on mg/m ²body 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 a mg/m ²body surface area, delayed offspring growth and decreased survival at doses 20 and 100 times, respectively, the MRHD based on mg/m ²body surface area.

8.2 Lactation

Risk Summary

Limited 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 mother's clinical need for Zolpidem Tartrate Extended-Release Tablets and any potential adverse effects on the breastfed infant from Zolpidem Tartrate Extended-Release Tablets or from the underlying maternal condition.

Clinical Considerations

Infants exposed to Zolpidem Tartrate Extended-Release Tablets through breastmilk should be monitored for excess sedation, hypotonia, and respiratory depression. A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment and for 23 hours (approximately 5 elimination half-lives) after Zolpidem Tartrate Extended-Release Tablets administration in order to minimize drug exposure to a breastfed infant.

8.4 Pediatric Use

Zolpidem Tartrate Extended-Release Tablets are 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 Zolpidem Tartrate Extended-Release Tablets in the pediatric population based on these efficacy and safety findings.

8.5 Geriatric Use

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

The dose of Zolpidem Tartrate Extended-Release Tablets 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 a lower rate than men. C _maxand AUC parameters of zolpidem from Zolpidem Tartrate Extended-Release Tablets 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 Zolpidem Tartrate Extended-Release Tablets 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 Tartrate Extended-Release Tablets in geriatric patients is 6.25 mg regardless of gender.

8.7 Hepatic Impairment

The recommended dose of Zolpidem Tartrate Extended-Release Tablets in patients with mild to moderate hepatic impairment is 6.25 mg once daily immediately before bedtime. Avoid Zolpidem Tartrate Extended-Release Tablets 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)] .