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

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

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

Initial US Approval: 1992

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

Dosage and Administration, Dosage in Adults (2.1) 08/2016

Dosage and Administration, Special Populations (2.2) 12/2016

Warnings and Precautions, CNS Depressant Effects and Next-

Day Impairment (5.1) 08/2016

Warnings and Precautions, Precipitation of Hepatic

Encephalopathy (5.7) 12/2016

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

AMBIEN, a gamma-aminobutyric acid (GABA) A agonist, 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)

• 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------------------------------

Known hypersensitivity to zolpidem (4)

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

• CNS depressant effects: Impairs alertness and motor coordination. Instruct

patients on correct use. (5.1)

• Need to evaluate for co-morbid diagnosis: Reevaluate if insomnia persists

after 7 to 10 days of use. (5.2)

• Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis

have been reported. Do not rechallenge if such reactions occur. (5.3)

• “Sleep-driving” and other complex behaviors while not fully awake. Risk

increases with dose and use with other CNS depressants and alcohol.

Immediately evaluate any new onset behavioral changes. (5.4)

• Depression: Worsening of depression or suicidal thinking may occur.

Prescribe the least amount of tablets feasible to avoid intentional overdose.

(5.5)

• Respiratory Depression: Consider this risk before prescribing in patients

with compromised respiratory function (5.6)

• Hepatic Impairment: Avoid AMBIEN use in patients with severe hepatic

impairment. (5.7)

• Withdrawal effects: Symptoms may occur with rapid dose reduction or

discontinuation (5.8, 9.3)

• Severe Injuries: Drowsiness may lead to fall including severe injuries (5.9)

-----------------------------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

http://www.fda.gov/medwatch

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

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

depressant effects (5.1, 7.1)

• Imipramine: Decreased alertness observed (7.1)

• Chlorpromazine: Impaired alertness and psychomotor performance

observed (7.1)

• CYP3A4 inducers (e.g. rifampin): Combination use may decrease effect

(7.2)

• CYP3A4 inhibitors (e.g. ketoconazole): Combination use may increase

effect (7.2)

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

• Pregnancy: Based on animal data, may cause fetal harm (8.1)

• 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 (5.4, 8.4)

See 17 for PATIENT COUNSELING INFORMATION and Medication

Guide.

Revised: 12/2016

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Dosage in Adults

2.2 Special Populations

2.3 Use with CNS Depressants

2.4 Administration

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 CNS Depressant Effects and Next-Day Impairment

5.2 Need to Evaluate for Co-morbid Diagnoses

5.3 Severe Anaphylactic and Anaphylactoid Reactions

5.4 Abnormal Thinking and Behavioral Changes

5.5 Use in Patients with Depression

5.6 Respiratory Depression

5.7 Precipitation of Hepatic Encephalopathy

5.8 Withdrawal Effects

5.9 Severe Injuries

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 CNS-active Drugs

7.2 Drugs that Affect Drug Metabolism via Cytochrome P450

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Labor and Delivery

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Gender Differences in Pharmacokinetics

8.7 Hepatic Impairment

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

9.2 Abuse

9.3 Dependence

10 OVERDOSAGE

10.1

Signs and Symptoms

10.2 Recommended Treatment

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Transient Insomnia

14.2 Chronic Insomnia

14.3 Studies Pertinent to Safety Concerns for Sedatives/Hypnotic

Drugs

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16 HOW SUPPLIED/STORAGE AND HANDLING

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

17 PATIENT COUNSELING INFORMATION

listed

FULL PRESCRIBING INFORMATION

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 (5.1)]. 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.

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 (5.1), 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 (5.7), Use in Specific Populations

(8.7), Clinical Pharmacology (12.3)].

2.3 Use with CNS Depressants

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

drugs because of the potentially additive effects [see Warnings and Precautions (5.1)].

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.

Reference ID: 4022123

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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 with known hypersensitivity to zolpidem. Observed

reactions include anaphylaxis and angioedema [see Warnings and Precautions (5.3)].

5 WARNINGS AND PRECAUTIONS

5.1 CNS Depressant Effects and Next-Day Impairment

AMBIEN, like other sedative-hypnotic drugs, has central nervous system (CNS) depressant

effects. Co-administration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic

antidepressants, alcohol) increases the risk of CNS depression. 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)].

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 co-administered with other CNS depressants or alcohol; or if

co-administered with other drugs that increase the blood levels of zolpidem. Patients should be

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

taken in these circumstances [see Dosage and Administration (2) and 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.

5.2 Need to Evaluate for Co-morbid Diagnoses

Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric

disorder, symptomatic treatment of insomnia should be initiated only after a careful 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.

5.3 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.

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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.

5.4 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)].

Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of

a sedative-hypnotic, with amnesia for the event) have been reported in sedative-hypnotic-naive

as well as in sedative-hypnotic-experienced persons. Although behaviors such as “sleep-driving”

have occurred with AMBIEN alone at therapeutic doses, the co-administration of AMBIEN with

alcohol and other CNS depressants increases the risk of such behaviors, as does the use of

AMBIEN at doses exceeding the maximum recommended dose. Due to the risk to the patient

and the community, discontinuation of AMBIEN should be strongly considered for patients who

report a “sleep-driving” episode.

Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex)

have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with

“sleep-driving”, patients usually do not remember these events. Amnesia, anxiety and other

neuro-psychiatric symptoms may also occur.

It can rarely be determined with certainty whether a particular instance of the abnormal

behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying

psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or

symptom of concern requires careful and immediate evaluation.

5.5 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.

5.6 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%,

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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. Post-marketing reports of respiratory insufficiency in patients receiving 10 mg of

zolpidem tartrate, most of whom had pre-existing respiratory impairment, have been reported.

The risk of respiratory depression should be considered prior to prescribing AMBIEN in patients

with respiratory impairment including sleep apnea and myasthenia gravis.

5.7 Precipitation of Hepatic Encephalopathy

GABA agonists such as zolpidem tartrate have been associated with precipitation of hepatic

encephalopathy in patients with hepatic insufficiency. In addition, patients with hepatic

insufficiency do not clear zolpidem tartrate as rapidly as patients with normal hepatic function.

Avoid 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)].

5.8 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) and (9.3)].

5.9 Severe Injuries

Zolpidem can cause drowsiness and a decreased level of consciousness, which may lead to falls

and consequently to severe injuries. Severe injuries such as hip fractures and intracranial

hemorrhage have been reported.

6 ADVERSE REACTIONS

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

labeling:

• CNS-depressant effects and next-day impairment [see Warnings and Precautions (5.1)]

• Serious anaphylactic and anaphylactoid reactions [see Warnings and Precautions (5.3)]

• Abnormal thinking and behavior changes, and complex behaviors [see Warnings and

Precautions (5.4)]

• Withdrawal effects [see Warnings and Precautions (5.8)]

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%).

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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.

Incidence of Treatment-Emergent Adverse Experiences in

Placebo-Controlled Clinical Trials Lasting up to 10 Nights

(Percentage of patients reporting)

Zolpidem

Body System/ (≤10 mg) Placebo

Adverse Event*

(N=685)

(N=473)

Central and Peripheral Nervous System

Headache 7 6

Drowsiness 2 -

Dizziness 1 -

Gastrointestinal System

Diarrhea

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*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.

Incidence of Treatment-Emergent Adverse Experiences in

Placebo-Controlled Clinical Trials Lasting up to 35 Nights

(Percentage of patients reporting)

Zolpidem

Body System/ (≤10 mg) Placebo

Adverse Event*

(N=152)

(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

Abdominal pain 2 2

Constipation 2 1

Respiratory System

Sinusitis 4 2

Pharyngitis 3 1

Skin and Appendages

Rash

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*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, 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,

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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 post-approval use of AMBIEN.

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

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always possible to reliably estimate their frequency or establish a causal relationship to drug

exposure.

Liver and biliary system: acute hepatocellular, cholestatic or mixed liver injury with or without

jaundice (i.e., bilirubin >2x ULN, alkaline phosphatase ≥2x ULN, transaminase ≥5x ULN).

7 DRUG INTERACTIONS

7.1 CNS-active Drugs

Co-administration 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)]. Zolpidem

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

drugs.

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)].

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)].

Alcohol

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

demonstrated [see Warnings and Precautions (5.1)].

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)].

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.

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CYP3A4 Inducers

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

effects of zolpidem. Use of CYP3A4 inducers in combination with zolpidem may decrease the

efficacy of zolpidem [see Clinical Pharmacology (12.3)].

CYP3A4 Inhibitors

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

Pregnancy Category C

There are no adequate and well-controlled studies of AMBIEN in pregnant women.

Studies in children to assess the effects of prenatal exposure to zolpidem have not been

conducted; however, cases of severe neonatal respiratory depression have been reported when

zolpidem was used at the end of pregnancy, especially when taken with other CNS-depressants.

Children born to mothers taking sedative-hypnotic drugs may be at risk for withdrawal

symptoms during the postnatal period. Neonatal flaccidity has also been reported in infants born

to mothers who received sedative-hypnotic drugs during pregnancy. AMBIEN should be used

during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring

development at doses greater than the AMBIEN maximum recommended human dose (MRHD)

of 10 mg/day (approximately 8 mg/day zolpidem base); however, teratogenicity was not

observed.

When zolpidem was administered at oral doses of 4, 20, and 100 mg base/kg/day to pregnant rats

during the period of organogenesis, dose-related decreases in fetal skull ossification occurred at

all but the lowest dose, which is approximately 5 times the MRHD on a mg/m

basis. In rabbits

treated during organogenesis with zolpidem at oral doses of 1, 4, and 16 mg base/kg/day

increased embryo-fetal death and incomplete fetal skeletal ossification occurred at the highest

dose tested. The no-effect dose for embryo-fetal toxicity in rabbits is approximately 10 times the

MRHD on a mg/m

basis. Administration of zolpidem to rats at oral doses of 4, 20, and 100 mg

base/kg/day during the latter part of pregnancy and throughout lactation produced decreased

offspring growth and survival at all but the lowest dose, which is approximately 5 times the

MRHD on a mg/m

basis.

8.2 Labor and Delivery

AMBIEN has no established use in labor and delivery [see Pregnancy (8.1)].

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8.3 Nursing Mothers

Zolpidem is excreted in human milk. Caution should be exercised when AMBIEN is

administered to a nursing woman.

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.

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(5.4)]. 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

Drowsiness 5% 2%

Diarrhea

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 (5.1)].

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

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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 (5.7), Clinical Pharmacology (12.3)].

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

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

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

tremors, and convulsions. The following adverse events which are considered to meet the

DSM-III-R criteria for uncomplicated sedative/hypnotic withdrawal were reported during U.S.

clinical trials following placebo substitution occurring within 48 hours following last zolpidem

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

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

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

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

Post-marketing reports of abuse, dependence and withdrawal have been received.

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 (zolpidem tartrate) is a gamma-aminobutyric acid (GABA) A agonist of the

imidazopyridine class and 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:

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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, micro-crystalline 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

12.1 Mechanism of Action

Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic agent with a chemical structure

unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties. It

interacts with a GABA-BZ receptor complex and shares some of the pharmacological properties

of the benzodiazepines. In contrast to the benzodiazepines, which non-selectively bind to and

activate all BZ receptor subtypes, zolpidem in vitro binds the BZ

receptor preferentially with a

high affinity ratio of the α

/α

subunits. This selective binding of zolpidem on the BZ

receptor

is not absolute, but it may explain the relative absence of myorelaxant and anticonvulsant effects

in animal studies as well as the preservation of deep sleep (stages 3 and 4) in human studies of

zolpidem tartrate at hypnotic doses.

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

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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) and

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

mean C

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 ng·hr/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:

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

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 ng·hr/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 (5.7), Use in Specific Populations (8.7)].

Renal Impairment:

The pharmacokinetics of zolpidem tartrate were 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 were not significantly different in renally impaired patients. No dosage

adjustment is necessary in patients with compromised renal function.

Drug Interactions

CNS-depressants

Co-administration of zolpidem with other CNS depressants increases the risk of CNS depression

[see Warnings and Precautions (5.1)]. 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.

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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 (5.1)].

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

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

0-∞

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 T

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)].

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.

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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. In mice, these doses are approximately 2.5, 10, and 50 times the maximum

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

basis. In

rats, these doses are approximately 5, 20, and 100 times the MRHD on a mg/m

basis. 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: Oral administration of zolpidem (doses of 4, 20, and 100 mg

base/kg/day) to rats prior to and during mating, and continuing in females through postpartum

day 25, resulted in irregular estrus cycles and prolonged precoital intervals at the highest dose

tested. The no-effect dose for these findings is approximately 24 times the MRHD on a mg/m

basis. 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

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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 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

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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

0024-5421-50 bottle of 500

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

17 PATIENT COUNSELING INFORMATION

See 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.

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.

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.

Sleep-driving and Other Complex Behaviors

Instruct patients and their families that sedative hypnotics can cause abnormal thinking and

behavior change, including “sleep driving” and other complex behaviors while not being fully

awake (preparing and eating food, making phone calls, or having sex). Tell patients to call you

immediately if they develop any of these symptoms.

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.

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”.

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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.

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MEDICATION GUIDE

AMBIEN

(ām'bē-ən)

(zolpidem tartrate)

Tablets C-IV

Read the Medication Guide that comes with AMBIEN before you start taking it and each time

you get a refill. There may be new information. This Medication Guide does not take the

place of talking to your healthcare provider about your medical condition or treatment.

What is the most important information I should

know about AMBIEN?

• Do not take more AMBIEN than prescribed.

• Do not take AMBIEN unless you are able to

stay in bed a full night (7 to 8 hours) before

you must be active again.

• Take AMBIEN right before you get in bed, not

sooner.

AMBIEN may cause serious side effects,

including:

• 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. You

have a higher chance for doing these activities if

you drink alcohol or take other medicines that

make you sleepy with AMBIEN. Reported

activities include:

o driving a car ("sleep-driving")

o making and eating food

o talking on the phone

o having sex

o sleep-walking

Call your healthcare provider right away if you

find out that you have done any of the above

activities after taking AMBIEN.

Do not take AMBIEN if you:

• drank alcohol that evening or before bed

• took another medicine to help you sleep.

What is AMBIEN?

AMBIEN is a sedative-hypnotic (sleep) medicine.

AMBIEN is used in adults for the short-term

treatment of a sleep problem called insomnia

(trouble falling asleep).

It is not known if AMBIEN is safe and effective 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

prevent misuse and abuse. Selling or giving

away AMBIEN may harm others, and is

against the law. Tell your healthcare provider

if you have ever abused or have been

dependent on alcohol, prescription medicines

or street drugs.

Who should not take AMBIEN?

• Do not take AMBIEN if you are allergic to

zolpidem or any other ingredients in

AMBIEN. See the end of this Medication

Guide for a complete list of ingredients in

AMBIEN.

• Do not take AMBIEN if you have had an

allergic reaction to drugs containing

zolpidem, such as Ambien CR, Edluar,

Zolpimist, or Intermezzo.

Symptoms of a serious allergic reaction to

zolpidem can include:

• swelling of your face, lips, and throat that

may cause difficulty breathing or

swallowing

What should I tell my healthcare provider

before taking AMBIEN?

AMBIEN may not be right for you. Before

starting AMBIEN, tell your healthcare

provider about all of your health

conditions, including if you:

• have a history of depression, mental

illness, or suicidal thoughts

• have a history of drug or alcohol abuse or

addiction

• have kidney or liver disease

• have a lung disease or breathing

problems

Reference ID: 4022123

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

• are pregnant, planning to become pregnant. It is

not known if AMBIEN will harm your unborn

baby.

• are breastfeeding or plan to breastfeed.

AMBIEN can pass into your breast milk. It is not

known if AMBIEN will harm your baby. Talk to

your healthcare provider about the best way to

feed your baby while you take AMBIEN.

Tell your healthcare provider about all of the

medicines you take, including prescription and

nonprescription medicines, vitamins and herbal

supplements.

Medicines can interact with each other, sometimes

causing serious side effects. Do not take AMBIEN

with other medicines that can make you sleepy

unless your healthcare provider tells you to.

Know the medicines you take. Keep a list of your

medicines with you to show your healthcare provider

and pharmacist each time you get a new medicine.

How should I take AMBIEN?

• See “What is the most important information

I should know about AMBIEN?”

• Take AMBIEN exactly as prescribed. Only take

1 AMBIEN tablet a night if needed.

• Do not take AMBIEN if you drank alcohol that

evening or before bed.

• 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.

• Call your healthcare provider if your insomnia

worsens or is not better within 7 to 10 days. This

may mean that there is another condition

causing your sleep problem.

• If you take too much AMBIEN or overdose, get

emergency treatment.

What are the possible side effects of AMBIEN?

AMBIEN may cause serious side effects,

including:

• getting out of bed while not being fully

awake and do an activity that you do not

know you are doing. See “What is the most

important information I should know about

AMBIEN?”

• abnormal thoughts and behavior. Symptoms

include more outgoing or aggressive behavior

than normal, confusion, agitation, hallucinations,

worsening of depression, and suicidal thoughts

or actions.

• memory loss

• anxiety

severe allergic reactions. Symptoms

include swelling of the tongue or throat,

and trouble breathing. Get emergency

medical help if you get these symptoms

after taking AMBIEN.

• falls, which may lead to severe injuries

Call your healthcare provider right away if

you have any of the above side effects or

any other side effects that worry you while

using AMBIEN.

The most common side effects of AMBIEN

are:

• drowsiness

• dizziness

• diarrhea

• grogginess or feeling as if you have been

drugged

After you stop taking a sleep medicine, you

may have symptoms for 1 to 2 days such as:

• trouble sleeping

• nausea

• flushing

• lightheadedness

• uncontrolled crying

• vomiting

• stomach cramps

• panic attack

• nervousness

• stomach area pain

These are not all the side effects of AMBIEN.

Ask your healthcare provider or pharmacist for

more information.

Call your healthcare provider 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, 68°F

to 77°F (20°C to 25°C).

Keep AMBIEN and all medicines out of

reach of children.

Reference ID: 4022123

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

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 share AMBIEN with other people,

even if they have the same symptoms that you have.

It may harm them and it is against the law.

This Medication Guide summarizes the most

important information about AMBIEN. If you would

like more information, talk with your healthcare

provider. You can ask your healthcare provider or

pharmacist for information about AMBIEN that is

written for healthcare professionals.

For more information, call 1-800-633-1610.

What are the ingredients in AMBIEN?

Active Ingredient: Zolpidem tartrate

Inactive Ingredients: hydroxypropyl

methylcellulose, lactose, magnesium stearate,

micro-crystalline 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.

This Medication Guide has been approved by the

U.S. Food and Drug Administration.

sanofi-aventis U.S. LLC

Bridgewater, NJ 08807

A SANOFI COMPANY

October 2014

Reference ID: 4022123

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda