label

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

AMBIEN safely and effectively. See full prescribing information for

AMBIEN.

AMBIEN

(zolpidem tartrate) tablets, for oral use, C-IV

Initial U.S. Approval: 1992

WARNING: COMPLEX SLEEP BEHAVIORS

See full prescribing information for complete boxed warning.

Complex sleep behaviors including sleep-walking, sleep-driving, and

engaging in other activities while not fully awake may occur following

use of AMBIEN. Some of these events may result in serious injuries,

including death. Discontinue AMBIEN immediately if a patient

experiences a complex sleep behavior. (4, 5.1)

------------------------------RECENT MAJOR CHANGES----------------------------

Dosage and Administration (2.1) 2/2022

Warnings and Precautions (5.5) 2/2022

Warnings and Precautions (5.7) 2/2022

----------------------------INDICATIONS AND USAGE---------------------------

AMBIEN, a gamma-aminobutyric acid (GABA) A receptor positive

modulator, is indicated for the short-term treatment of insomnia characterized

by difficulties with sleep initiation. (1)

----------------------DOSAGE AND ADMINISTRATION-----------------------

 Use the lowest dose effective for the patient and must not exceed a total of

10 mg daily (2.1)

 Treatment should be as short as possible (2.1)

 Recommended initial dose is a single dose of 5 mg for women and a single

dose of 5 or 10 mg for men, immediately before bedtime with at least 7-8

hours remaining before the planned time of awakening (2.1)

 Geriatric patients and patients with mild to moderate hepatic impairment:

Recommended dose is 5 mg for men and women (2.2)

 Lower doses of CNS depressants may be necessary when taken

concomitantly with AMBIEN (2.3)

 The effect of AMBIEN may be slowed if taken with or immediately after a

meal (2.4)

---------------------DOSAGE FORMS AND STRENGTHS----------------------

5 mg and 10 mg tablets. Tablets not scored. (3)

-------------------------------CONTRAINDICATIONS------------------------------

 Patients who have experienced complex sleep behaviors after taking

AMBIEN (4)

 Known hypersensitivity to zolpidem (4)

----------------------WARNINGS AND PRECAUTIONS-------------------------

 CNS-Depressant Effects: Impaired alertness and motor coordination

including risk of morning impairment. Risk increases with dose and use

with other CNS depressants and alcohol. Caution patients against driving and

other activities requiring 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 AMBIEN use in patients with severe hepatic

impairment. (5.8)

 Withdrawal Effects: Symptoms may occur with rapid dose reduction or

discontinuation. (5.9, 9.3)

-----------------------------ADVERSE REACTIONS--------------------------------

Most commonly observed adverse reactions were:

Short-term (<10 nights): Drowsiness, dizziness, and diarrhea

Long-term (28-35 nights): Dizziness and drugged feelings (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.

------------------------------DRUG INTERACTIONS-------------------------------

 CNS depressants, including alcohol: Possible adverse additive CNS-

depressant effects (5.2, 7.1)

 Opioids: Concomitant use may increase risk of respiratory depression (5.7,

7.1)

 Imipramine: Decreased alertness observed (7.1)



Chlorpromazine: Impaired alertness and psychomotor performance

observed (7.1)

 CYP3A4 inducers (rifampin or St. John’s wort): Combination use may

decrease effect (7.2)

 Ketoconazole: Combination use may increase effect (7.2)

------------------------USE IN SPECIFIC POPULATIONS-----------------------

 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 AMBIEN 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)

See 17 for PATIENT COUNSELING INFORMATION and Medication

Guide.

Revised: 2/2022

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: COMPLEX SLEEP BEHAVIORS 7.1 CNS-Active Drugs

1 INDICATIONS AND USAGE

7.2 Drugs that Affect Drug Metabolism via Cytochrome P450

2 DOSAGE AND ADMINISTRATION

8 USE IN SPECIFIC POPULATIONS

2.1 Dosage in Adults

8.1 Pregnancy

2.2 Special Populations

8.2 Lactation

2.3 Use with CNS Depressants

8.4 Pediatric Use

2.4 Administration

8.5 Geriatric Use

3 DOSAGE FORMS AND STRENGTHS

8.6 Gender Difference in Pharmacokinetics

4 CONTRAINDICATIONS

8.7 Hepatic Impairment

5 WARNINGS AND PRECAUTIONS

9 DRUG ABUSE AND DEPENDENCE

5.1 Complex Sleep Behaviors

9.1 Controlled Substance

5.2 CNS-Depressant Effects and Next-Day Impairment

9.2 Abuse

5.3 Need to Evaluate for Comorbid Diagnoses

9.3 Dependence

5.4 Severe Anaphylactic and Anaphylactoid Reactions

10 OVERDOSAGE

5.5 Abnormal Thinking and Behavioral Changes

10.1 Signs and Symptoms

5.6 Use in Patients with Depression

10.2 Recommended Treatment

5.7 Respiratory Depression

11 DESCRIPTION

5.8 Precipitation of Hepatic Encephalopathy

12 CLINICAL PHARMACOLOGY

5.9 Withdrawal Effects

12.1

Mechanism of Action

6 ADVERSE REACTIONS

12.2 Pharmacodynamics

6.1 Clinical Trials Experience

12.3 Pharmacokinetics

6.2 Postmarketing Experience

13 NONCLINICAL TOXICOLOGY

7 DRUG INTERACTIONS

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Reference ID: 4942373

14 CLINICAL STUDIES 17 PATIENT COUNSELING INFORMATION

14.1 Transient Insomnia

*Sections or subsections omitted from the full prescribing information are not

14.2 Chronic Insomnia

listed.

14.3 Studies Pertinent to Safety Concerns for Sedative/Hypnotic Drugs

16 HOW SUPPLIED/STORAGE AND HANDLING

Reference ID: 4942373

FULL PRESCRIBING INFORMATION

WARNING: COMPLEX SLEEP BEHAVIORS

Complex sleep behaviors including sleep-walking, sleep-driving, and engaging in other

activities while not fully awake may occur following use of AMBIEN. Some of these

events may result in serious injuries, including death. Discontinue AMBIEN

immediately if a patient experiences a complex sleep behavior [see Contraindications (4)

and Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

AMBIEN (zolpidem tartrate) is indicated for the short-term treatment of insomnia characterized

by difficulties with sleep initiation. AMBIEN has been shown to decrease sleep latency for up to

35 days in controlled clinical studies [see Clinical Studies (14)].

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.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage in Adults

Use the lowest effective dose for the patient. The recommended initial dose is 5 mg for women

and either 5 or 10 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 5 mg dose is not

effective, the dose can be increased to 10 mg. In some patients, the higher morning blood levels

following use of the 10 mg dose increase the risk of next-day impairment of driving and other

activities that require full alertness [see Warnings and Precautions (5.2)]. The total dose of

AMBIEN should not exceed 10 mg once daily immediately before bedtime. AMBIEN 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.

Long-term use of AMBIEN is not recommended. Treatment should be as short as possible.

Extended treatment should not take place without re-evaluation of the patient's status because

the risk of abuse and dependence increases with the duration of treatment [see Drug Abuse

and Dependence (9.3)].

2.2 Special Populations

Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate. The

recommended dose of AMBIEN in these patients is 5 mg once daily immediately before bedtime

[see Warnings and Precautions (5.2), Use in Specific Populations (8.5)].

Patients with mild to moderate hepatic impairment do not clear the drug as rapidly as normal

subjects. The recommended dose of AMBIEN in these patients is 5 mg once daily immediately

before bedtime. Avoid AMBIEN use in patients with severe hepatic impairment as it may

contribute to encephalopathy [see Warnings and Precautions (5.8), Use in Specific Populations

(8.7), Clinical Pharmacology (12.3)].

2.3 Use with CNS Depressants

Reference ID: 4942373

Dosage adjustment may be necessary when AMBIEN is combined with other CNS-depressant

drugs because of the potentially additive effects [see Warnings and Precautions (5.2, 5.7)].

2.4 Administration

The effect of AMBIEN may be slowed by ingestion with or immediately after a meal.

3 DOSAGE FORMS AND STRENGTHS

AMBIEN is available in 5 mg and 10 mg strength tablets for oral administration. Tablets are not

scored.

AMBIEN 5 mg tablets are capsule-shaped, pink, film coated, with AMB 5 debossed on one side

and 5401 on the other.

AMBIEN 10 mg tablets are capsule-shaped, white, film coated, with AMB 10 debossed on one

side and 5421 on the other.

4 CONTRAINDICATIONS

AMBIEN is contraindicated in patients

 who have experienced complex sleep behaviors after taking AMBIEN [see Warnings and

Precautions (5.1)].

 with known hypersensitivity to zolpidem. Observed reactions include anaphylaxis and

angioedema [see Warnings and Precautions (5.4)].

5 WARNINGS AND PRECAUTIONS

5.1 Complex Sleep Behaviors

Complex sleep behaviors, including sleep-walking, sleep-driving, and engaging in other

activities while not fully awake, may occur following the first or any subsequent use of

AMBIEN. 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 AMBIEN alone at recommended doses, with or without the concomitant use of

alcohol or other central nervous system (CNS) depressants [see Drug Interactions (7.1)].

Discontinue AMBIEN immediately if a patient experiences a complex sleep behavior [see

Contraindications (4)].

5.2 CNS-Depressant Effects and Next-Day Impairment

AMBIEN, like other sedative-hypnotic drugs, has CNS-depressant effects. Coadministration

with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol)

increases the risk of CNS depression [see Drug Interactions (7.1)]. Dosage adjustments of

AMBIEN and of other concomitant CNS depressants may be necessary when AMBIEN is

administered with such agents because of the potentially additive effects. The use of AMBIEN

with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of

the night is not recommended [see Dosage and Administration (2.3)].

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The risk of next-day psychomotor impairment, including impaired driving, is increased if

AMBIEN is taken with less than a full night of sleep remaining (7 to 8 hours); if a higher than

the recommended dose is taken; if coadministered with other CNS depressants or alcohol; or if

coadministered with other drugs that increase the blood levels of zolpidem. Patients should be

warned against driving and other activities requiring complete mental alertness if AMBIEN is

taken in these circumstances [see Dosage and Administration (2), Clinical Studies (14.3)].

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 AMBIEN 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 AMBIEN. 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 of AMBIEN 10 mg taken at bedtime <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 [see Use in Specific

Populations (8.4)]. There have been postmarketing reports of delirium with zolpidem use

[Adverse Reactions (6.2)].

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.

Reference ID: 4942373

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 AMBIEN is 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 AMBIEN 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 AMBIEN 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)]

Reference ID: 4942373

6.1 Clinical Trials Experience

Associated with Discontinuation of Treatment

Approximately 4% of 1,701 patients who received zolpidem 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.

Most Commonly Observed Adverse Reactions in Controlled Trials

During short-term treatment (up to 10 nights) with AMBIEN 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 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%).

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 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.

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Table 1: Incidences of Treatment-Emergent Adverse Reactions in Placebo-Controlled

Clinical Trials Lasting up to 10 Nights (percentage of patients reporting)

Body System

Adverse Reaction*

Zolpidem

(≤10 mg)

(N=685)

Placebo

(N=473)

Central and Peripheral Nervous System

Headache 7 6

Drowsiness 2 -

Dizziness 1 -

Gastrointestinal System

Diarrhea 1 -

* Reactions reported by at least 1% of patients treated with AMBIEN and at a greater frequency than placebo.

The following table was derived from results of three placebo-controlled long-term efficacy trials

involving AMBIEN (zolpidem tartrate). These trials involved patients with chronic insomnia

who were treated for 28 to 35 nights with zolpidem 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 events occurring at an incidence of at least 1% for zolpidem

patients.

Table 2: Incidences of Treatment-Emergent Adverse Experiences in Placebo-Controlled

Clinical Trials Lasting up to 35 Nights (percentage of patients reporting)

Body System

Adverse Event*

Zolpidem

(≤10 mg)

(N=152)

Placebo

(N=161)

Autonomic Nervous System

Dry mouth 3 1

Body as a Whole

Allergy 4 1

Back Pain 3 2

Influenza-like symptoms 2 -

Chest pain 1 -

Cardiovascular System

Palpitation 2 -

Central and Peripheral Nervous System

Drowsiness 8 5

Dizziness 5 1

Lethargy 3 1

Drugged feeling 3 -

Lightheadedness 2 1

Depression 2 1

Abnormal dreams 1 -

Amnesia 1 -

Sleep disorder 1 -

Gastrointestinal System

Diarrhea 3 2

Reference ID: 4942373

Body System

Adverse Event*

Zolpidem

(≤10 mg)

(N=152)

Placebo

(N=161)

Abdominal pain 2 2

Constipation 2 1

Respiratory System

Sinusitis 4 2

Pharyngitis 3 1

Skin and Appendages

Rash 2 1

* Reactions reported by at least 1% of patients treated with AMBIEN and at a greater frequency than placebo.

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.

Adverse Event Incidence Across the Entire Preapproval Database

AMBIEN 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: 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,

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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, tendinitis.

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

breast neoplasm, breast pain.

Respiratory system: Frequent: upper respiratory infection, lower respiratory infection.

Infrequent: bronchitis, coughing, dyspnea, rhinitis. Rare: bronchospasm, respiratory depression,

epistaxis, hypoxia, laryngitis, pneumonia.

Skin and appendages: Infrequent: pruritus. Rare: acne, bullous eruption, dermatitis,

furunculosis, injection-site inflammation, photosensitivity reaction, urticaria.

Special senses: Frequent: diplopia, vision abnormal. Infrequent: eye irritation, eye pain, scleritis,

taste perversion, tinnitus. Rare: conjunctivitis, corneal ulceration, lacrimation abnormal,

parosmia, photopsia.

Urogenital system: Frequent: urinary tract infection. Infrequent: cystitis, urinary incontinence.

Rare: acute renal failure, dysuria, micturition frequency, nocturia, polyuria, pyelonephritis, renal

pain, urinary retention.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of AMBIEN.

Because these reactions are reported voluntarily from a population of uncertain size, it is not

Reference ID: 4942373

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

7 DRUG INTERACTIONS

7.1 CNS-Active Drugs

CNS Depressants

Coadministration of zolpidem with other CNS depressants increases the risk of CNS depression.

Concomitant use of zolpidem with these drugs may increase drowsiness and psychomotor

impairment, including impaired driving ability [see Warnings and Precautions (5.1, 5.2)].

Zolpidem tartrate was evaluated in healthy volunteers in single-dose interaction studies for

several CNS drugs.

Alcohol

An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was

demonstrated [see Warnings and Precautions (5.1, 5.2)].

Opioids

The concomitant use of AMBIEN with opioids may increase the risk of respiratory depression.

Limit dosage and duration of concomitant use of AMBIEN and opioids [see Dosage and

Administration (2.3), Warnings and Precautions (5.7)].

Imipramine, Chlorpromazine

Imipramine in combination with zolpidem produced no pharmacokinetic interaction other than a

20% decrease in peak levels of imipramine, but there was an additive effect of decreased

alertness. Similarly, chlorpromazine in combination with zolpidem produced no pharmacokinetic

interaction, but there was an additive effect of decreased alertness and psychomotor performance

[see Clinical Pharmacology (12.3)].

Sertraline

Concomitant administration of zolpidem and sertraline increases exposure to zolpidem [see

Clinical Pharmacology (12.3)].

Fluoxetine

After multiple doses of zolpidem tartrate and fluoxetine an increase in the zolpidem half-life

(17%) was observed. There was no evidence of an additive effect in psychomotor performance

[see Clinical Pharmacology (12.3)].

Haloperidol

A study involving haloperidol and zolpidem revealed no effect of haloperidol on the

pharmacokinetics or pharmacodynamics of zolpidem. The lack of a drug interaction

following single-dose administration does not predict the absence of an effect following

chronic administration [see Clinical Pharmacology (12.3)].

Reference ID: 4942373

7.2 Drugs that Affect Drug Metabolism via Cytochrome P450

Some compounds known to induce or inhibit CYP3A may affect exposure to zolpidem. The

effect of drugs that induce or inhibit other P450 enzymes on the exposure to zolpidem is not

known.

CYP3A4 Inducers

Rifampin

Rifampin, a CYP3A4 inducer, significantly reduced the exposure to and the pharmacodynamic

effects of zolpidem. Use of Rifampin in combination with zolpidem may decrease the efficacy of

zolpidem and is not recommended [see Clinical Pharmacology (12.3)].

St. John’s wort

Use of St. John’s wort, a CYP3A4 inducer, in combination with zolpidem may decrease blood

levels of zolpidem and is not recommended.

CYP3A4 Inhibitors

Ketoconazole

Ketoconazole, a potent CYP3A4 inhibitor, increased the exposure to and pharmacodynamic

effects of zolpidem. Consideration should be given to using a lower dose of zolpidem when a

potent CYP3A4 inhibitor and zolpidem are given together [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

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

Considerations and 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 AMBIEN during pregnancy and labor for signs of excess sedation,

hypotonia, and respiratory depression and manage accordingly.

Data

Human data

Reference ID: 4942373

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 5, 25, and 120 times the maximum recommended

human dose (MRHD) of 10 mg/day (8 mg zolpidem base) based on mg/m

body surface area,

caused delayed fetal development (incomplete fetal skeletal ossification) at maternally toxic

(ataxia) doses 25 and 120 times the MRHD based on mg/m

body surface area.

Oral administration of zolpidem to pregnant rabbits during the period of organogenesis at 1, 4,

and 16 mg base/kg/day, which are approximately 2.5, 10, and 40 times the MRHD of 10 mg/day

(8 mg zolpidem base) based on mg/m

body surface area caused embryo-fetal death and delayed

fetal development (incomplete fetal skeletal ossification) at a maternally toxic (decreased body

weight gain) dose 40 times the MRHD based on mg/m

body surface area.

Oral administration of zolpidem to pregnant rats from day 15 of gestation through lactation at 4,

20, and 100 mg base/kg/day, which are approximately 5, 25, and 120 times the MRHD of 10

mg/day (8 mg zolpidem base) based on mg/m

body surface area, delayed offspring growth and

decreased survival at doses 25 and 120 times, respectively, the MRHD based on mg/m

body

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 AMBIEN and any potential adverse effects on the breastfed infant from

AMBIEN or from the underlying maternal condition.

Clinical Considerations

Infants exposed to AMBIEN 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 AMBIEN administration in order to minimize drug

exposure to a breast fed infant.

8.4 Pediatric Use

AMBIEN 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.

Reference ID: 4942373

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.

8.5 Geriatric Use

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. For 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 and for which the zolpidem incidence was at least twice the placebo

incidence (i.e., they could be considered drug related).

Adverse Event Zolpidem Placebo

Dizziness 3% 0%

Drowsiness 5% 2%

Diarrhea 3% 1%

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 AMBIEN in elderly patients is 5 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

max

and AUC

parameters of zolpidem were approximately 45% higher at the same dose in female subjects

compared with 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 for adult women is

5 mg, and the recommended dose for adult men is 5 or 10 mg.

In geriatric patients, clearance of zolpidem is similar in men and women. The recommended dose

of AMBIEN in geriatric patients is 5 mg regardless of gender.

8.7 Hepatic Impairment

The recommended dose of AMBIEN in patients with mild to moderate hepatic impairment is

5 mg once daily immediately before bedtime. Avoid AMBIEN 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)].

Reference ID: 4942373

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Zolpidem tartrate is classified as a Schedule IV controlled substance by federal regulation.

9.2 Abuse

Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is

characterized by misuse of the drug for non-medical purposes, often in combination with other

psychoactive substances. Tolerance is a state of adaptation in which exposure to a drug induces

changes that result in a diminution of one or more of the drug effects over time. Tolerance may

occur to both desired and undesired effects of drugs and may develop at different rates for

different effects.

Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and

environmental factors influencing its development and manifestations. It is characterized by

behaviors that include one or more of the following: impaired control over drug use, compulsive

use, continued use despite harm, and craving. Drug addiction is a treatable disease, using a

multidisciplinary approach, but relapse is common.

Studies of abuse potential in former drug abusers found that the effects of single doses of

zolpidem tartrate 40 mg were similar, but not identical, to diazepam 20 mg, while zolpidem

tartrate 10 mg was difficult to distinguish from placebo.

Because persons with a history of addiction to, or abuse of, drugs or alcohol are at increased risk

for misuse, abuse and addiction of zolpidem, they should be monitored carefully when receiving

zolpidem or any other hypnotic.

9.3 Dependence

Use of AMBIEN may lead to the development of physical and/or psychological dependence.

The risk of dependence increases with dose and duration of treatment. The risk of abuse and

dependence is also greater in patients with a history of alcohol or drug abuse. AMBIEN should

be used with extreme caution in patients with current or past alcohol or drug abuse

Physical dependence is a state of adaptation that is manifested by a specific withdrawal

syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level

of the drug, and/or administration of an antagonist.

Sedative/hypnotics have produced withdrawal signs and symptoms following abrupt

discontinuation. These reported symptoms range from mild dysphoria and insomnia to a

withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating,

tremors, convulsions, and delirium.

The following adverse events, which are considered to meet the DSM-III-R criteria for

uncomplicated sedative/hypnotic withdrawal, were reported during clinical trials with

AMBIEN following placebo substitution occurring within 48 hours following last zolpidem

treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach

cramps, panic attack, nervousness, and abdominal discomfort. These reported adverse events

occurred at an incidence of 1% or less. However, available data cannot provide a reliable

estimate of the incidence, if any, of dependence during treatment at recommended doses. There

have been postmarketing reports of abuse, dependence and withdrawal with zolpidem.

Reference ID: 4942373

10 OVERDOSAGE

10.1 Signs and Symptoms

In postmarketing experience of overdose with zolpidem tartrate alone, or in combination with

CNS-depressant agents, impairment of consciousness ranging from somnolence to coma,

cardiovascular and/or respiratory compromise, and fatal outcomes have been reported.

10.2 Recommended Treatment

General symptomatic and supportive measures should be used along with immediate gastric

lavage where appropriate. Intravenous fluids should be administered as needed. 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-to-date

information on the management of hypnotic drug product overdosage.

11 DESCRIPTION

AMBIEN contains zolpidem tartrate, a gamma-aminobutyric acid (GABA) A receptor positive

modulator of the imidazopyridine class. AMBIEN is available in 5 mg and 10 mg strength tablets

for oral administration.

Chemically, zolpidem is N,N,6-trimethyl-2-p-tolylimidazo[1,2-a] pyridine-3-acetamide

L-(+)-tartrate (2:1). It has the following structure:

COOH

Zolpidem tartrate is a white to off-white crystalline powder that is sparingly soluble in water,

alcohol, and propylene glycol. It has a molecular weight of 764.88.

Each AMBIEN tablet includes the following inactive ingredients: hydroxypropyl

methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol,

sodium starch glycolate, and titanium dioxide. The 5 mg tablet also contains FD&C Red No. 40,

iron oxide colorant, and polysorbate 80.

12 CLINICAL PHARMACOLOGY

Reference ID: 4942373

12.1 Mechanism of Action

Zolpidem is a GABA A receptor positive modulator presumed to exert its therapeutic effects in

the short-term treatment of insomnia through binding to the benzodiazepine site of α1 subunit

containing GABA A receptors, increasing the frequency of chloride channel opening resulting in

the inhibition of neuronal excitation.

12.2 Pharmacodynamics

Zolpidem binds to GABA A receptors with greater affinity for α1 subunit relative to α2 and α3

subunit containing receptors. Zolpidem has no appreciable binding affinity for α5 subunit

containing GABA A receptors. This binding profile may explain the relative absence of

myorelaxant effects in animal studies. Zolpidem has no appreciable binding affinity for

dopaminergic D2, serotonergic 5HT

, adrenergic, histaminergic or muscarinic receptors.

12.3 Pharmacokinetics

The pharmacokinetic profile of AMBIEN is characterized by rapid absorption from the

gastrointestinal tract and a short elimination half-life (T

1/2

) in healthy subjects.

In a single-dose crossover study in 45 healthy subjects administered 5 and 10 mg zolpidem

tartrate tablets, the mean peak concentrations (C

max

) were 59 (range: 29 to 113) and 121 (range:

58 to 272) ng/mL, respectively, occurring at a mean time (T

max

) of 1.6 hours for both. The mean

AMBIEN elimination half-life was 2.6 (range: 1.4 to 4.5) and 2.5 (range: 1.4 to 3.8) hours, for

the 5 and 10 mg tablets, respectively. AMBIEN is converted to inactive metabolites that are

eliminated primarily by renal excretion. AMBIEN demonstrated linear kinetics in the dose range

of 5 to 20 mg. Total protein binding 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 tablets for 2 weeks.

A food-effect study in 30 healthy male subjects compared the pharmacokinetics of AMBIEN

10 mg when administered while fasting or 20 minutes after a meal. Results demonstrated that

with food, mean AUC and C

max

were decreased by 15% and 25%, respectively, while mean T

max

was prolonged by 60% (from 1.4 to 2.2 hr). The half-life remained unchanged. These results

suggest that, for faster sleep onset, AMBIEN should not be administered with or immediately

after a meal.

Special Populations

Elderly

In the elderly, the dose for AMBIEN should be 5 mg [see Warnings and Precautions (5), Dosage

and Administration (2)]. This recommendation is based on several studies in which the mean

max

, T

1/2

, and AUC were significantly increased when compared to results in young adults. In

one study of eight elderly subjects (>70 years), the means for C

max

, T

1/2

, and AUC significantly

increased by 50% (255 vs 384 ng/mL), 32% (2.2 vs 2.9 hr), and 64% (955 vs 1,562 ngꞏhr/mL),

respectively, as compared to younger adults (20 to 40 years) following a single 20 mg oral dose.

AMBIEN did not accumulate in elderly subjects following nightly oral dosing of 10 mg for 1

week.

Hepatic impairment

Reference ID: 4942373

The pharmacokinetics of AMBIEN in eight patients with chronic hepatic insufficiency was

compared to results in healthy subjects. Following a single 20 mg oral zolpidem tartrate dose,

mean C

max

and AUC were found to be two times (250 vs 499 ng/mL) and five times (788 vs

4,203 ngꞏhr/mL) higher, respectively, in hepatically compromised patients. T

max

did not change.

The mean half-life in cirrhotic patients of 9.9 hr (range: 4.1 to 25.8 hr) was greater than that

observed in normal subjects of 2.2 hr (range: 1.6 to 2.4 hr) [see Dosage and Administration

(2.2), Warnings and Precautions (5.8), Use in Specific Populations (8.7)].

Renal impairment

The pharmacokinetics of zolpidem tartrate was studied in 11 patients with end-stage renal failure

(mean Cl

= 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 C

max

, T

max

, half-life, and AUC between the first and last day of

drug administration when baseline concentration adjustments were made. Zolpidem was not

hemodialyzable. No accumulation of unchanged drug appeared after 14 or 21 days. Zolpidem

pharmacokinetics was not significantly different in renally impaired patients. No dosage

adjustment is necessary in patients with compromised renal function.

Drug Interactions

CNS depressants

Coadministration of zolpidem with other CNS depressants increases the risk of CNS depression

[see Warnings and Precautions (5.2)]. Zolpidem tartrate was evaluated in healthy volunteers in

single-dose interaction studies for several CNS drugs. Imipramine in combination with zolpidem

produced no pharmacokinetic interaction other than a 20% decrease in peak levels of

imipramine, but there was an additive effect of decreased alertness. Similarly, chlorpromazine in

combination with zolpidem produced no pharmacokinetic interaction, but there was an additive

effect of decreased alertness and psychomotor performance.

A study involving haloperidol and zolpidem revealed no effect of haloperidol on the

pharmacokinetics or pharmacodynamics of zolpidem. The lack of a drug interaction following

single-dose administration does not predict the absence of an effect following chronic

administration.

An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was

demonstrated [see Warnings and Precautions (5.2)].

Following five consecutive nightly doses at bedtime of oral zolpidem tartrate 10 mg in the

presence of sertraline 50 mg (17 consecutive daily doses, at 7:00 am, in healthy female

volunteers), zolpidem C

max

was significantly higher (43%) and T

max

was significantly decreased

(-53%). Pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem.

A single-dose interaction study with zolpidem tartrate 10 mg and fluoxetine 20 mg at steady-state

levels in male volunteers did not demonstrate any clinically significant pharmacokinetic or

pharmacodynamic interactions. When multiple doses of zolpidem and fluoxetine were given at

steady state and the concentrations evaluated in healthy females, an increase in the zolpidem

half-life (17%) was observed. There was no evidence of an additive effect in psychomotor

performance.

Drugs that affect drug metabolism via cytochrome P450

Reference ID: 4942373

Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of

inhibitors of other P450 enzymes on the pharmacokinetics of zolpidem is unknown.

A single-dose interaction study with zolpidem tartrate 10 mg and itraconazole 200 mg at steady-

state levels in male volunteers resulted in a 34% increase in AUC



of zolpidem tartrate. There

were no pharmacodynamic effects of zolpidem detected on subjective drowsiness, postural sway,

or psychomotor performance.

A single-dose interaction study with zolpidem tartrate 10 mg and rifampin 600 mg at steady-state

levels in female subjects showed significant reductions of the AUC (-73%), C

max

(-58%), and

1/2

(-36%) of zolpidem together with significant reductions in the pharmacodynamic effects of

zolpidem tartrate. Rifampin, a CYP3A4 inducer, significantly reduced the exposure to and the

pharmacodynamic effects of zolpidem [see Drug Interactions (7.2)].

Similarly, St. John’s wort, a CYP3A4 inducer, may also decrease the blood levels of zolpidem.

A single-dose interaction study with zolpidem tartrate 5 mg and ketoconazole, a potent CYP3A4

inhibitor, given as 200 mg twice daily for 2 days increased C

max

of zolpidem (30%) and the total

AUC of zolpidem (70%) compared to zolpidem alone and prolonged the elimination half-life

(30%) along with an increase in the pharmacodynamic effects of zolpidem [see Drug

Interactions (7.2)].

Additionally, fluvoxamine (a strong inhibitor of CYP1A2 and a weak inhibitor of CYP3A4 and

CYP2C9) and ciprofloxacin (a strong inhibitor of CYP1A2 and a moderate inhibitor of

CYP3A4) are also likely to inhibit zolpidem’s metabolic pathways, potentially leading to an

increase in zolpidem exposure.

Other drugs with no interactions with zolpidem

A study involving cimetidine/zolpidem tartrate and ranitidine/zolpidem tartrate combinations

revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of zolpidem.

Zolpidem tartrate had no effect on digoxin pharmacokinetics and did not affect prothrombin time

when given with warfarin in healthy subjects.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Zolpidem was administered to mice and rats for 2 years at oral doses of 4, 18, and 80 mg

base/kg/day. In mice, these doses are approximately 2.5, 10, and 50 times the MRHD of 10

mg/day (8 mg zolpidem base) based on mg/m

body surface area and in rats, these doses are

approximately 5, 20, and 100 times the MRHD based on mg/m

body surface area. No evidence

of carcinogenic potential was observed in mice. In rats, renal tumors (lipoma, liposarcoma) were

seen at the mid and high doses.

Mutagenesis

Zolpidem was negative in in vitro (bacterial reverse mutation, mouse lymphoma, and

chromosomal aberration) and in vivo (mouse micronucleus) genetic toxicology assays.

Impairment of Fertility

Reference ID: 4942373

Zolpidem was administered to rats at 4, 20, and 100 mg base/kg/day, which are approximately 5,

25, and 120 times the MRHD of 10 mg/day (8 mg zolpidem base) based on mg/m

body surface

area, prior to and during mating, and continuing in females through postpartum day 25.

Zolpidem caused irregular estrus cycles and prolonged precoital intervals at the highest dose

tested, which is approximately 120 times the MRHD based on mg/m

body surface area. The

NOAEL for these effects is 25 times the MRHD based on a mg/m

body surface area. There was

no impairment of fertility at any dose tested.

14 CLINICAL STUDIES

14.1 Transient Insomnia

Normal adults experiencing transient insomnia (n=462) during the first night in a sleep

laboratory were evaluated in a double-blind, parallel group, single-night trial comparing two

doses of zolpidem (7.5 and 10 mg) and placebo. Both zolpidem doses were superior to placebo

on objective (polysomnographic) measures of sleep latency, sleep duration, and number of

awakenings.

Normal elderly adults (mean age 68) experiencing transient insomnia (n=35) during the first two

nights in a sleep laboratory were evaluated in a double-blind, crossover, 2-night trial comparing

four doses of zolpidem (5, 10, 15 and 20 mg) and placebo. All zolpidem doses were superior to

placebo on the two primary PSG parameters (sleep latency and efficiency) and all four subjective

outcome measures (sleep duration, sleep latency, number of awakenings, and sleep quality).

14.2 Chronic Insomnia

Zolpidem was evaluated in two controlled studies for the treatment of patients with chronic

insomnia (most closely resembling primary insomnia, as defined in the APA Diagnostic and

Statistical Manual of Mental Disorders, DSM-IV™). Adult outpatients with chronic insomnia

(n=75) were evaluated in a double-blind, parallel group, 5-week trial comparing two doses of

zolpidem tartrate and placebo. On objective (polysomnographic) measures of sleep latency and

sleep efficiency, zolpidem 10 mg was superior to placebo on sleep latency for the first 4 weeks

and on sleep efficiency for weeks 2 and 4. Zolpidem was comparable to placebo on number of

awakenings at both doses studied.

Adult outpatients (n=141) with chronic insomnia were also evaluated, in a double-blind, parallel

group, 4-week trial comparing two doses of zolpidem and placebo. Zolpidem 10 mg was superior

to placebo on a subjective measure of sleep latency for all 4 weeks, and on subjective measures

of total sleep time, number of awakenings, and sleep quality for the first treatment week.

Increased wakefulness during the last third of the night as measured by polysomnography has not

been observed in clinical trials with AMBIEN.

14.3 Studies Pertinent to Safety Concerns for Sedative/Hypnotic Drugs

Next-Day Residual Effects

Next-day residual effects of AMBIEN were evaluated in seven studies involving normal

subjects. In three studies in adults (including one study in a phase advance model of transient

insomnia) and in one study in elderly subjects, a small but statistically significant decrease in

performance was observed in the Digit Symbol Substitution Test (DSST) when compared to

placebo. Studies of AMBIEN in non-elderly patients with insomnia did not detect evidence of

Reference ID: 4942373

next-day residual effects using the DSST, the Multiple Sleep Latency Test (MSLT), and patient

ratings of alertness.

Rebound Effects

There was no objective (polysomnographic) evidence of rebound insomnia at recommended

doses seen in studies evaluating sleep on the nights following discontinuation of AMBIEN

(zolpidem tartrate). There was subjective evidence of impaired sleep in the elderly on the first

post-treatment night at doses above the recommended elderly dose of 5 mg.

Memory Impairment

Controlled studies in adults utilizing objective measures of memory yielded no consistent

evidence of next-day memory impairment following the administration of AMBIEN. However,

in one study involving zolpidem doses of 10 and 20 mg, there was a significant decrease in

next-morning recall of information presented to subjects during peak drug effect (90 minutes

post dose), i.e., these subjects experienced anterograde amnesia. There was also subjective

evidence from adverse event data for anterograde amnesia occurring in association with the

administration of AMBIEN, predominantly at doses above 10 mg.

Effects on Sleep Stages

In studies that measured the percentage of sleep time spent in each sleep stage, AMBIEN has

generally been shown to preserve sleep stages. Sleep time spent in stages 3 and 4 (deep sleep)

was found comparable to placebo with only inconsistent, minor changes in REM (paradoxical)

sleep at the recommended dose.

16 HOW SUPPLIED/STORAGE AND HANDLING

AMBIEN 5 mg tablets are capsule-shaped, pink, film coated, with AMB 5 debossed on one side

and 5401 on the other and supplied as:

NDC Number Size

0024-5401-31 bottle of 100

AMBIEN 10 mg tablets are capsule-shaped, white, film coated, with AMB 10 debossed on one

side and 5421 on the other and supplied as:

NDC Number Size

0024-5421-31 bottle of 100

Store at controlled room temperature 20°C-25°C (68°F-77°F).

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Inform patients and their families about the benefits and risks of treatment with AMBIEN.

Inform patients of the availability of a Medication Guide and instruct them to read the

Medication Guide prior to initiating treatment with AMBIEN and with each prescription refill.

Review the AMBIEN Medication Guide with every patient prior to initiation of treatment.

Instruct patients or caregivers that AMBIEN should be taken only as prescribed.

Complex Sleep Behaviors

Reference ID: 4942373

Instruct patients and their families that AMBIEN may cause complex sleep behaviors, including

sleep-walking, sleep-driving, preparing and eating food, making phone calls, or having sex while

not being fully awake. Serious injuries and death have occurred during complex sleep behavior

episodes. Tell patients to discontinue AMBIEN and notify their healthcare provider immediately

if they develop any of these symptoms [see Boxed Warning, Warnings and Precautions (5.1)].

CNS-Depressant Effects and Next-Day Impairment

Tell patients that AMBIEN has the potential to cause next-day impairment, and that this risk is

increased if dosing instructions are not carefully followed. Tell patients to wait for at least 8

hours after dosing before driving or engaging in other activities requiring full mental alertness.

Inform patients that impairment can be present despite feeling fully awake. Advise patients that

increased drowsiness and decreased consciousness may increase the risk of falls in some patients

[see Warnings and Precautions (5.2)].

Severe Anaphylactic and Anaphylactoid Reactions

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 [see Warnings and Precautions (5.4)].

Suicide

Tell patients to immediately report any suicidal thoughts.

Alcohol and other Drugs

Ask patients about alcohol consumption, medicines they are taking, and drugs they may be

taking without a prescription. Advise patients not to use AMBIEN if they drank alcohol that

evening or before bed.

Concomitant Use with Opioids

Inform patients and caregivers that potentially serious additive effects may occur if AMBIEN is

used with opioids and not to use such drugs concomitantly unless supervised by a healthcare

provider [see Warnings and Precautions (5.2, 5.7), Drug Interactions (7.1)].

Tolerance, Abuse, and Dependence

Tell patients not to increase the dose of AMBIEN on their own, and to inform you if they believe

the drug “does not work.”

Administration Instructions

Patients should be counseled to take AMBIEN 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. AMBIEN tablets should

not be taken with or immediately after a meal. Advise patients NOT to take AMBIEN if they

drank alcohol that evening.

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become

pregnant during treatment with AMBIEN. Advise patients that use of AMBIEN late in the third

trimester may cause respiratory depression and sedation in neonates. Advise mothers who used

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AMBIEN during the late third trimester of pregnancy to monitor neonates for signs of sleepiness

(more than usual), breathing difficulties, or limpness [see Use in Specific Populations (8.1)].

Lactation

Advise breastfeeding mothers using AMBIEN to monitor infants for increased sleepiness,

breathing difficulties, or limpness. Instruct breastfeeding mothers to seek immediate medical care

if they notice these signs. A lactating woman may consider pumping and discarding breastmilk

during treatment and for 23 hours after AMBIEN administration to minimize drug exposure to a

breastfed infant [see Use in Specific Populations (8.2)].

Manufactured by:

sanofi-aventis U.S. LLC

Bridgewater, NJ 08807

A SANOFI COMPANY

Reference ID: 4942373

MEDICATION GUIDE

AMBIEN (ām'bē-әn)

(zolpidem tartrate)

tablets, for oral use, C-IV

What is the most important information I should know about AMBIEN?

AMBIEN may cause serious side effects, including:

 Complex sleep behaviors. After taking AMBIEN, you may get up out of bed while not being fully awake and do

an activity that you do not know you are doing. The next morning, you may not remember that you did anything

during the night. These activities may happen with AMBIEN whether or not you drink alcohol or take other

medicines that make you sleepy. Some of these complex sleep behaviors have caused serious injury and

death. People taking AMBIEN have reported:

o sleep-walking

o sleep-driving

o making and eating food

o talking on the phone

o having sex

Stop taking ABMIEN and tell your healthcare provider right away if you find out that you have done any

of the above activities after taking AMBIEN.

What is AMBIEN?

AMBIEN is a prescription sleep medicine used for the short-term treatment of adults who have trouble falling asleep

(insomnia).

 It is not known if AMBIEN is safe and effective in children under the age of 18 years. AMBIEN is not

recommended for use in children under the age of 18 years.

 AMBIEN is a federally controlled substance (C-IV) because it can be abused or lead to dependence.

Keep AMBIEN in a safe place to protect it from theft. Never give your AMBIEN to anyone else because it may

cause death or harm them. Selling or giving away this medicine is against the law.

Do not take AMBIEN if you:

 have had complex sleep behaviors that happened after taking AMBIEN in the past. See “What is the most

important information I should know about AMBIEN?”

 are allergic to zolpidem or any of the ingredients in AMBIEN. See the end of this Medication Guide for a

complete list of ingredients in AMBIEN.

Before taking AMBIEN, tell your healthcare provider about all of your medical conditions, including if you:

 have a history of depression, mental illness, or suicidal thoughts or actions

 have a history of drug or alcohol abuse or addiction

 have kidney or liver disease

 have a lung disease or breathing problems

 have sleep apnea

 have myasthenia gravis

 are pregnant or plan to become pregnant. Taking AMBIEN in the third trimester of pregnancy may harm your

unborn baby.

o Tell your healthcare provider if you become pregnant or plan to become pregnant during treatment with

AMBIEN.

o Babies born to mothers who take AMBIEN during the third trimester of pregnancy may have symptoms of

breathing problems and sedation (such as sleepiness or low muscle tone).

 are breastfeeding or plan to breastfeed. AMBIEN passes into your breast milk and may harm your baby. Talk to

your healthcare provider about the best way to feed your baby during treatment with AMBIEN.

Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter

medicines, vitamins, and herbal supplements.

AMBIEN and other medicines can interact with each other causing serious side effects. AMBIEN may affect the way

other medicines work, and other medicines may affect how AMBIEN works.

Especially tell your healthcare provider if you:

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 take benzodiazepines

 take opioids as it may increase the risk of breathing problems (respiratory depression)

 take tricyclic antidepressants

 take other medicines that can make you sleepy or affect your breathing (including other zolpidem medicines)

 drink alcohol

You can ask your pharmacist for a list of medicines that interact with AMBIEN.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a

new medicine.

How should I take AMBIEN?

 Take AMBIEN exactly as prescribed. Do not change your dose on your own. Tell your healthcare provider if

you think AMBIEN is not working for you.

 AMBIEN is for short-term use only. Treatment with AMBIEN should be as short as possible because the risk

of dependence increases the longer you are being treated.

 Take 1 AMBIEN tablet at night right before bedtime.

 Do not take AMBIEN if you are not able to stay in bed a full night (7 to 8 hours) before you must be

active again.

 You should not take AMBIEN with or right after a meal. AMBIEN may help you fall asleep faster if you take it on

an empty stomach.

 Do not take AMBIEN if you drank alcohol that evening or before bed.

 Call your healthcare provider if your sleep problems get worse or do not get better within 7 to 10 days. This may

mean that there is another condition causing your sleep problems.

 If you take too much AMBIEN, call your healthcare provider or go to the nearest hospital emergency room right

away.

What are the possible side effects of AMBIEN?

AMBIEN may cause serious side effects, including:

 See “What is the most important information I should know about AMBIEN?”

 AMBIEN can make you sleepy or dizzy and can slow your thinking and motor skills. Because AMBIEN

can make you sleepy or dizzy you are at a higher risk for falls.

o Do not drive, operate heavy machinery, or do other dangerous activities until you know how AMBIEN

affects you.

o Do not drink alcohol or take opioids or other medicines that may make you sleepy or dizzy while taking

AMBIEN without first talking to your healthcare provider. When taken with alcohol or other medicines

that cause sleepiness or dizziness, AMBIEN may make your sleepiness or dizziness much worse.

 Severe allergic reactions. Symptoms include swelling of the tongue or throat, trouble breathing, and

nausea and vomiting. Get emergency medical help right away if you develop any of these symptoms during

treatment with AMBIEN.

 Abnormal thoughts and behavior. Symptoms include more outgoing or aggressive behavior than normal,

confusion (delirium), acting strangely, agitation, hallucinations, worsening of depression, and suicidal thoughts or

actions.

 Risk of suicide and worsening of depression. Worsening of depression, including suicidal thoughts and

actions can happen during treatment with medicines like AMBIEN. Call your healthcare provider right away if

you develop any thoughts of suicide, dying, or worsening depression during treatment with AMBIEN.

 Breathing problems. See “Before taking AMBIEN, tell your healthcare provider about all of your

medical conditions, including if you:” Call your healthcare provider or get emergency medical help right

away if you develop breathing problems during treatment with AMBIEN.

 Problems with your nervous system caused by severe liver disease (hepatic encephalopathy).

 Withdrawal symptoms. You may have withdrawal symptoms if you stop taking AMBIEN suddenly. Withdrawal

symptoms can be serious and include stomach and muscle cramps, vomiting, sweating, shakiness, seizures,

and confusion (delirium). Talk to your healthcare provider about slowly stopping AMBIEN to avoid withdrawal

symptoms.

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The most common side effects of AMBIEN include sleepiness, dizziness, diarrhea, and grogginess or feeling

like you have been drugged.

These are not all the side effects of AMBIEN.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store AMBIEN?

 Store AMBIEN at room temperature between 68°F to 77°F (20°C to 25°C).

Keep AMBIEN and all medicines out of reach of children.

General Information about the safe and effective use of AMBIEN.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use

AMBIEN for a condition for which it was not prescribed. Do not give AMBIEN to other people, even if they have the

same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for

information about AMBIEN that is written for healthcare professionals.

What are the ingredients in AMBIEN?

Active Ingredient: zolpidem tartrate

Inactive Ingredients: hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose,

polyethylene glycol, sodium starch glycolate, and titanium dioxide. In addition, the 5 mg tablet contains FD&C Red

No. 40, iron oxide colorant, and polysorbate 80

Manufactured by:

sanofi-aventis U.S. LLC

Bridgewater, NJ 08807

A SANOFI COMPANY

For more information, go to WWW.TRADENAME.com or call 1-800-633-1610.

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 2/2022

Reference ID: 4942373